Roger Evans

Contrast angiography of the rat renal microcirculation in vivo using synchrotron radiation

Publisher: American Physiological Society

Date: 05-2009

DOI: 10.1152/AJPRENAL.90499.2008

Abstract: We have developed a new method for contrast microangiography of the rat renal circulation using synchrotron radiation. The method was applied to determine responses of the renal arterial vasculature to angiotensin II and electrical stimulation of the renal nerves (RNS). Iodinated contrast agent was administered directly into the renal artery of pentobarbital-anesthetized rats before and during 1) intravenous infusion of angiotensin II (1.6 μg·kg −1 ·min −1 ) or 2) its vehicle, or 3) RNS at 2 Hz. Images were obtained at 30 Hz, before and during these treatments, and vascular caliber was determined by use of a newly developed algorithm described herein. Up to four levels of branching could be observed simultaneously along the arterial tree, comprising vessels with resting diameter of 28–400 μm. Vessel diameter was not significantly altered by vehicle infusion (+3.1 ± 3.5% change) but was significantly reduced by angiotensin II (−24.3 ± 3.4%) and RNS (−17.1 ± 3.8%). Angiotensin II-induced vasoconstriction was independent of vessel size, but RNS-induced vasoconstriction was greatest in vessels with a resting caliber of 100–200 μm and least in vessels with a resting caliber 40–100 μm. In conclusion, the method we describe herein provides a new approach for assessing responses of the renal arterial circulation to vasoactive factors along several orders of branching.

A Novel Stable Inhibitor of Endopeptidases EC 3.4.24.15 and 3.4.24.16 Potentiates Bradykinin-Induced Hypotension

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 02-2000

DOI: 10.1161/01.HYP.35.2.626

Abstract: Abstract —We have developed a novel inhibitor of the metalloendopeptidases EC 3.4.24.15 (EP24.15) and EC 3.4.24.16 (EP24.16), N -[1-(R, S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr- p -aminobenzoate (JA2), in which α-aminoisobutyric acid (Aib) is substituted for an alanine in a well-described but unstable inhibitor, cFP-AAY-pAB. This substitution increases the resistance of the inhibitor to degradation without altering potency. In the present study, we investigated the effects of JA2 (5 mg/kg) on the responses of mean arterial pressure to bradykinin, angiotensin I, and angiotensin II in conscious rabbits. The depressor responses to both low (10 ng/kg) and high (100 ng/kg) doses of bradykinin were increased 7.0±2.7-fold and 1.5±0.3-fold, respectively, during the 30 minutes after JA2 administration (mean±SEM, n=8). Bradykinin potentiation was undiminished 4 hours after JA2 injection. In contrast, the hypertensive effects of angiotensins I and II were unaltered, indicating that the bradykinin-potentiating effects were not due to angiotensin-converting enzyme inhibition. These data suggest that JA2 is not only a potent and specific inhibitor of EP24.15 and EP24.16 but is also stable in vivo. Furthermore, the potentiation of bradykinin-induced hypotension by JA2 suggests for the first time a role for one or both of these peptidases in the metabolism of bradykinin in the circulation.

Chronic intrarenal infusion of low-dose angiotensin II in dogs increases arterial pressure without impairment of renal function

Publisher: Wiley

Date: 06-1997

DOI: 10.1111/J.1440-1681.1997.TB01219.X

Abstract: 1. To determine whether chronic angiotensin II (AngII) infusion into the renal artery, at a dose which increases systemic arterial pressure, reduces glomerular filtration rate (GFR) and renal blood flow, AngII was infused at 0.5 ng/kg per min into the renal artery or intravenously in chronically instrumented dogs for 1 month. 2. Mean arterial pressure (MAP) rose significantly (P < 0.05) during the infusion of AngII into the renal artery (+7 +/- 2 mmHg on days 26-30). There were no significant changes in GFR or renal blood flow. When the same dose of AngII was infused intravenously, MAP did not change significantly (-2 +/- 2 mmHg) and there were no significant changes in GFR or in renal blood flow. 3. We conclude that AngII infused into the renal artery for 1 month, at a dose which was initially subpressor, causes a rise in arterial pressure that is not associated with impairment of renal function.

EFFECTS OF N^G‐NITRO‐l‐ARGININE ON PRESSURE NATRIURESIS IN ANAESTHETIZED RABBITS

Publisher: Wiley

Date: 02-1995

DOI: 10.1111/J.1440-1681.1995.TB01962.X

Abstract: 1. We tested the effects of blockade of nitric oxide synthesis on renal function under conditions of controlled renal artery pressure. Our hypothesis was that endogenous nitric oxides plays a role in the natriuresis that accompanies increased renal perfusion pressure. We used a novel technique which employed an extracorporeal circuit to produce step changes over a wide range of renal artery pressures in pentobarbitone-anaesthetized rabbits. 2. Rabbits were treated with either NG-nitro-L-arginine (NOLA, 20 mg/kg, i.v. n = 8) or its vehicle (n = 8). Renal artery pressure was set (by adjusting the extracorporeal circuit) at 65, 80, 95, 110 and then 130 mmHg respectively, at the beginning of each of five 30 min experimental periods. 3. NOLA treatment caused profound renal vasoconstriction that was largely independent of the level of renal artery pressure, renal blood flow being 35-43% lower in NOLA-treated than in vehicle-treated rabbits across the range of renal artery pressures tested (P = 0.002). NOLA treatment increased filtration fraction (P = 0.02), and tended to reduce glomerular filtration rate (P = 0.09). 4. NOLA-treatment affected sodium excretion in a manner dependent on the legel of renal artery pressure, with the slope of the relationship between sodium excretion and renal artery pressure being lower in NOLA-treated than in vehicle-treated rabbits (P = 0.006). 5. These data provide direct evidence that in anaesthetized rabbits endogenous nitric oxide (i) tonically dilates the renal vasculature across a wide range of renal perfusion pressures, and (ii) enhances sodium excretion to a progressively greater degree as renal artery pressure is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

AT₂ receptors contribute to acute blood pressure-lowering and vasodilator effects of AT₁ receptor antagonism in conscious normotensive but not hypertensive rats

Publisher: American Physiological Society

Date: 05-2005

DOI: 10.1152/AJPHEART.01096.2004

Abstract: The aims of this study were to determine the contribution of the AT 2 receptor to the antihypertensive and regional vasodilatory effects of AT 1 receptor blockade in adult spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive (2K1C) rats, and sham-operated normotensive rats. Several studies have provided evidence to support the notion that the AT 2 receptor may have opposing effects to those mediated by the AT 1 receptor. We therefore tested the hypothesis that the depressor and vasodilator effects of acute AT 1 receptor blockade are dependent on AT 2 receptor activation. Heart rate, mean arterial pressure, and regional hemodynamics were measured over a 4-day protocol in rats that received the following treatments in randomized order: saline vehicle, the AT 1 receptor antagonist candesartan (0.1 mg/kg iv bolus), the AT 2 receptor antagonist PD-123319 (50 μg·kg −1 ·min −1 ), or both antagonists. Intravenous candesartan reduced mean arterial pressure in all groups of rats, and this was accompanied by renal and mesenteric vasodilation. Neither saline nor PD-123319 significantly affected these variables. Concomitant PD-123319 administration partially reversed the depressor and mesenteric vasodilator effects of candesartan in sham-operated normotensive rats but not in SHR or 2K1C rats. These data indicate that the AT 2 receptor contributes to the blood pressure-lowering and mesenteric vasodilator effects of AT 1 receptor blockade in the acute setting in conscious normotensive but not hypertensive rats.

Letter to the editor: “The plausibility of arterial-to-venous oxygen shunting in the kidney: it all depends on radial geometry”

Publisher: American Physiological Society

Date: 15-07-2015

DOI: 10.1152/AJPRENAL.00094.2015

Renal hemodynamics, function, and oxygenation during cardiac surgery performed on cardiopulmonary bypass: a modeling study

Publisher: Wiley

Date: 2015

DOI: 10.14814/PHY2.12260

What Makes the Kidney Susceptible to Hypoxia?

Publisher: Wiley

Date: 30-09-2020

DOI: 10.1002/AR.24260

Abstract: Per gram of tissue, the kidneys are among our most highly perfused organs. Yet the renal cortex and, in particular, the renal medulla are susceptible to hypoxia. In turn, hypoxia is a major pathophysiological feature of both acute kidney injury and chronic kidney disease. We identify seven factors that render the kidney susceptible to hypoxia: (1) the large metabolic demand imposed by active reabsorption of sodium (2) limitations on oxygen delivery to cortical tissue imposed by the density of peritubular capillaries (3) the poor capacity for angiogenesis in the adult kidney (4) the limited ability of the renal vasculature to dilate in response to hypoxia (5) diffusive oxygen shunting between arteries and veins in the cortex and descending and ascending vasa recta in the medulla (6) the physiological requirement for low medullary blood flow to facilitate urinary concentration and (7) the topography of vascular-tubular arrangements in the outer medulla that limit oxygen delivery to the thick ascending limb of Henle's loop. Recent collaborative efforts between anatomists, physiologists, and mathematicians have improved our understanding of the roles of these factors in both physiological regulation of intrarenal oxygenation and development of renal hypoxia under pathophysiological conditions. We are also better able to understand these apparent maladaptations in the context of evolution. That is, they can be explained by the combined effects of historical contingency (our ancestral life in the sea) and selection pressures imposed by the multiple functions of the kidney to regulate extracellular fluid volume, retain water, and control erythrocyte production.

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

Publisher: American Physiological Society

Date: 08-2007

DOI: 10.1152/AJPREGU.00807.2006

Abstract: We determined whether nitric oxide (NO) counters the development of hypertension at the onset of diabetes in mice, whether this is dependent on endothelial NO synthase (eNOS), and whether non-NO endothelium-dependent vasodilator mechanisms are altered in diabetes in mice. Male mice were instrumented for chronic measurement of mean arterial pressure (MAP). In wild-type mice, MAP was greater after 5 wk of N ω -nitro-l-arginine methyl ester (l-NAME 100 mg·kg −1 ·day −1 in drinking water 97 ± 3 mmHg) than after vehicle treatment (88 ± 3 mmHg). MAP was also elevated in eNOS null mice (113 ± 4 mmHg). Seven days after streptozotocin treatment (200 mg/kg iv) MAP was further increased in l-NAME-treated mice (108 ± 5 mmHg) but not in vehicle-treated mice (88 ± 3 mmHg) nor eNOS null mice (104 ± 3 mmHg). In wild-type mice, maximal vasorelaxation of mesenteric arteries to acetylcholine was not altered by chronic l-NAME or induction of diabetes but was reduced by 42 ± 6% in l-NAME-treated diabetic mice. Furthermore, the relative roles of NO and endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced vasorelaxation were altered the EDHF component was enhanced by l-NAME and blunted by diabetes. These data suggest that NO protects against the development of hypertension during early-stage diabetes in mice, even in the absence of eNOS. Furthermore, in mesenteric arteries, diabetes is associated with reduced EDHF function, with an apparent compensatory increase in NO function. Thus, prior inhibition of NOS results in endothelial dysfunction in early diabetes, since the diabetes-induced reduction in EDHF function cannot be compensated by increases in NO production.

Augmented endothelial-specific L-arginine transport prevents obesity-induced hypertension

Publisher: Wiley

Date: 05-08-2014

DOI: 10.1111/APHA.12344

Abstract: Hypertension is a major clinical complication of obesity. Our previous studies show that abnormal uptake of the nitric oxide precursor L-arginine, via the cationic amino acid transporter-1 (CAT1), contributes to endothelial dysfunction in cardiovascular disease. In this study, we tested the hypothesis that abnormal L-arginine transport may be a key mediator of obesity-induced hypertension. Mean arterial pressure (MAP) was monitored by telemetry in conscious wild-type (WT n = 13) mice, and transgenic mice with endothelial-specific overexpression of CAT1 (CAT+ n = 14) fed a normal or a high fat diet for 20 weeks. Renal angiotensin II (Ang II), CAT1 mRNA and plasma nitrate/nitrite levels were then quantified. In conjunction, plasma nitrate/nitrite levels were assessed in obese normotensive (n = 15) and obese hypertensive subjects (n = 15). Both genotypes of mice developed obesity when fed a high fat diet (P ≤ 0.002). Fat fed WT mice had 13% greater MAP and 78% greater renal Ang II content, 42% lesser renal CAT1 mRNA levels and 42% lesser plasma nitrate/nitrite levels, than WT mice fed a normal fat diet (P ≤ 0.02). In contrast, none of these variables were significantly altered by high fat feeding in CAT+ mice (P ≥ 0.36). Plasma nitrate/nitrite levels were 17% less in obese hypertensives compared with obese normotensives (P = 0.02). Collectively, these data indicate that obesity-induced down-regulation of CAT1 expression and subsequent reduced bioavailability of nitric oxide may contribute to the development of obesity-induced hypertension.

Exploring Barriers to and Enablers of the Adoption of Information and Communication Technology for the Care of Older Adults With Chronic Diseases: Scoping Review (Preprint)

Publisher: JMIR Publications Inc.

Date: 17-12-2020

DOI: 10.2196/PREPRINTS.25251

Abstract: nformation and communication technology (ICT) offers considerable potential for supporting older adults in managing their health, including chronic diseases. However, there are mixed opinions about the benefits and effectiveness of ICT interventions for older adults with chronic diseases. e aim to map the use of ICT interventions in health care and identified barriers to and enablers of its use among older adults with chronic disease. scoping review was conducted using 5 databases (Ovid MEDLINE, Embase, Scopus, PsycINFO, and ProQuest) to identify eligible articles from January 2000 to July 2020. Publications incorporating the use of ICT interventions, otherwise known as eHealth, such as mobile health, telehealth and telemedicine, decision support systems, electronic health records, and remote monitoring in people aged ≥55 years with chronic diseases were included. We conducted a i strengths, weaknesses, opportunities, and threats /i framework analysis to explore the implied enablers of and barriers to the use of ICT interventions. f the 1149 identified articles, 31 (2.7% n=4185 participants) met the inclusion criteria. Of the 31 articles, 5 (16%) mentioned the use of various eHealth interventions. A range of technologies was reported, including mobile health (8/31, 26%), telehealth (7/31, 23%), electronic health record (2/31, 6%), and mixed ICT interventions (14/31, 45%). Various chronic diseases affecting older adults were identified, including congestive heart failure (9/31, 29%), diabetes (7/31, 23%), chronic respiratory disease (6/31, 19%), and mental health disorders (8/31, 26%). ICT interventions were all designed to help people self-manage chronic diseases and demonstrated positive effects. However, patient-related and health care provider–related challenges, in integrating ICT interventions in routine practice, were identified. Barriers to using ICT interventions in older adults included knowledge gaps, a lack of willingness to adopt new skills, and reluctance to use technologies. Implementation challenges related to ICT interventions such as slow internet connectivity and lack of an appropriate reimbursement policy were reported. Advantages of using ICT interventions include their nonpharmacological nature, provision of health education, encouragement for continued physical activity, and maintenance of a healthy diet. Participants reported that the use of ICT was a fun and effective way of increasing their motivation and supporting self-management tasks. It gave them reassurance and peace of mind by promoting a sense of security and reducing anxiety. CT interventions have the potential to support the care of older adults with chronic diseases. However, they have not been effectively integrated with routine health care. There is a need to improve awareness and education about ICT interventions among those who could benefit from them, including older adults, caregivers, and health care providers. More sustainable funding is required to promote the adoption of ICT interventions. We recommend involving clinicians and caregivers at the time of designing ICT interventions.

Data presentation and the use of statistical tests in biomedical journals: can we reach a consensus?

Publisher: Wiley

Date: 28-04-2011

DOI: 10.1111/J.1440-1681.2011.05508.X

Influence of higher brain centres and vasopressin on the haemodynamic response to acute central hypovolaemia in rabbits

Publisher: Elsevier BV

Date: 07-1991

DOI: 10.1016/0165-1838(91)90033-Y

Abstract: We tested whether suprapontine brain centres contribute to the sudden failure of vasoconstriction that occurs in unanaesthetized rabbits during acute reduction in central blood volume. Haemorrhage was simulated by gradually inflating a cuff around the thoracic inferior vena cava so that cardiac output fell by about 8% per min. In intact rabbits, and in rabbits that had undergone craniectomy but not decerebration, the haemodynamic response to simulated haemorrhage was always biphasic. During the first, compensatory phase, systemic vascular conductance fell almost in proportion to the fall in cardiac output so that arterial pressure fell by only about 10 mmHg. When cardiac output had fallen by about 50%, a decompensatory phase supervened in which systemic vascular conductance rose abruptly, arterial pressure fell steeply to less than 40 mmHg, and the plasma arginine vasopressin (AVP) level rose. High mesencephalic decerebration did not affect the compensatory phase, but it abolished the decompensatory phase and there was no rise in the plasma AVP level. The decompensatory phase was not restored by intravenous administration of AVP. We came to two conclusions as a result of this study. Suprapontine brain centres do not influence the arterial baroreflex-mediated vasoconstriction that occurs during the first phase of acute central hypovolaemia. However, the sudden failure of vasoconstriction that occurs during the second phase of acute central hypovolaemia, attributable to a signal from the heart and mediated by a delta-opioid receptor mechanism in the brainstem, does depend on the integrity of suprapontine brain centres, though not on neurohypophysial AVP release.

Deficiency of MicroRNA-181a Results in Transcriptome-Wide Cell-Specific Changes in the Kidney and Increases Blood Pressure.

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 11-2021

DOI: 10.1161/HYPERTENSIONAHA.121.17384

Abstract: MicroRNA miR-181a is downregulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here, we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a KO (knockout) mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radiotelemetry probes were implanted in 12-week-old C57BL/6J WT (wild type) and miR-181a/b-1 KO mice. Systolic and diastolic BP were 4- to 5-mm Hg higher in KO compared with WT mice over 24 hours ( P .01). Compared with WT mice, renal renin was higher in the juxtaglomerular cells of KO mice. BP was similar in WT mice on a high- (3.1%) versus low- (0.3%) sodium diet (+0.4±0.8 mm Hg), but KO mice showed salt sensitivity (+3.3±0.8 mm Hg P .001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA sequencing in 6699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4 , Col4a1 , Cd81 , Flt3l , Cxcl16 , and Smad4 . We observed upregulation of pathways related to the immune system, inflammatory response, reactive oxygen species, and nerve development, consistent with higher tyrosine hydroxylase in the kidney. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.

A new era for Clinical and Experimental Pharmacology and Physiology

Publisher: Wiley

Date: 29-11-2010

DOI: 10.1111/J.1440-1681.2010.05446.X

THE NEW EDITORIAL TEAM AT CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY

Publisher: Wiley

Date: 18-06-2007

DOI: 10.1111/J.1440-1681.2007.04662.X

Dysfunction of the Cholinergic Anti-Inflammatory Pathway Mediates Organ Damage in Hypertension

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 02-2011

DOI: 10.1161/HYPERTENSIONAHA.110.160077

Abstract: Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the α7 nicotinic acetylcholine receptor (α7nAChR) in inflammation has recently been identified. We tested the hypothesis that α7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation–induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the α7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and α7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the α7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor κB. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in α7nAChR −/− mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension.

Effects of indomethacin on responses of regional kidney perfusion to vasoactive agents in rabbits

Publisher: Wiley

Date: 05-09-2002

DOI: 10.1046/J.1440-1681.2002.03742.X

Abstract: 1. To determine whether differential release of products of arachidonic acid metabolism, via the cyclo-oxygenase pathway, underlies the ersity of responses of regional kidney perfusion to vasoactive agents, we tested the effects of intravenous indomethacin on responses to renal arterial bolus doses of vasoactive agents in pentobarbitone-anaesthetized rabbits. 2. Total renal blood flow (RBF) and regional kidney perfusion were determined by transit time ultrasound flowmetry and laser-Doppler flowmetry, respectively. 3. Responses of regional kidney blood flow to vasoactive agents were erse: noradrenaline reduced cortical but not medullary perfusion, [Phe 2,Ile 3,Orn 8]-vasopressin reduced medullary perfusion more than cortical perfusion, endothelin-1 and angiotensin II increased medullary perfusion in the face of reduced cortical perfusion, while acetylcholine, bradykinin and the nitric oxide donor methylamine hexamethylene methylamine (MAHMA) NONOate all increased both cortical and medullary perfusion. 4. Indomethacin administration was followed by reductions in total RBF (17 +/- 6%), cortical perfusion (13 +/- 5%) and medullary perfusion (40 +/- 8%). Angiotensin II- and endothelin-1-induced increases in medullary perfusion were abolished by indomethacin, but indomethacin had no significant effects on responses of regional kidney perfusion to acetylcholine, bradykinin, MAHMA NONOate, noradrenaline and [Phe 2,Ile 3,Orn 8]-vasopressin. 5. Our results suggest that vasodilator cyclo-oxygenase products contribute to the maintenance of resting renal vascular tone, particularly in vascular elements controlling medullary perfusion. Cyclo-oxygenase products also appear to mediate endothelin-1- and angiotensin II-induced increases in medullary perfusion. However, regionally specific engagement of cyclo-oxygenase-dependent arachidonic acid metabolism does not appear to contribute to the differential effects of noradrenaline and [Phe 2,Ile 3,Orn 8]-vasopressin on cortical and medullary perfusion.

Renal preglomerular arterial-venous O2 shunting is a structural anti-oxidant defence mechanism of the renal cortex

Publisher: Wiley

Date: 21-06-2006

DOI: 10.1111/J.1440-1681.2006.04391.X

Abstract: 1. High blood flow to the kidney facilitates a high glomerular filtration rate, but total renal O2 delivery greatly exceeds renal metabolic requirements. However, tissue Po2 in much of the renal cortex is lower than may be expected, being similar to that of other organs in which perfusion is closely matched to metabolic demand. 2. The lower than expected renal cortical Po2 is now attributed largely to diffusional shunting of as much as 50% of inflowing O2 from blood within preglomerular arterial vessels to post-glomerular venous vessels. However, the functional significance of this O2 shunting remains unclear. Indeed, this mechanism may appear maladaptive, given the kidney's susceptibility to hypoxic insults. 3. We hypothesize that renal preglomerular arterial-venous O2 shunting acts to protect the kidney from the potentially damaging consequences of tissue hyperoxia. The diffusion of O2 from arteries to veins within the kidney acts to reduce the O2 content of the blood before it is distributed to the renal microcirculation. Because high tissue Po2 may increase the production of reactive oxygen species, we suggest that renal arterial-venous O2 shunting may provide a physiological benefit to the organism by limiting O2 delivery to renal tissue, thereby reducing the risk of cellular oxidation.

John Ludbrook APPS Symposium Neural Mechanisms In The Cardiovascular Responses To Acute Central Hypovolaemia

Publisher: Wiley

Date: 11-05-2001

DOI: 10.1046/J.1440-1681.2001.03473.X

Abstract: 1. The haemodynamic response to acute central hypovolaemia consists of two phases. During phase I, arterial pressure is well maintained in the face of falling cardiac output (CO) by baroreceptor‐mediated reflex vasoconstriction and cardio‐acceleration. Phase II commences once CO has fallen to a critical level of 50–60% of its resting value, equivalent to loss of approximately 30% of blood volume. 2. During phase II, sympathetic vasoconstrictor and cardiac drive fall abruptly and cardiac vagal drive increases. In humans, this response is invariably associated with fainting and has been termed vasovagal syncope. 3. In both experimental animals and in humans, the responses to acute central hypovolaemia are greatly affected by anaesthetic agents, in that the compensatory responses during phase I (e.g. halothane) or their failure during phase II (e.g. alfentanil) are blunted or abolished. 4. Therefore, our present knowledge of the neurochemical basis of the response to hypovolaemia depends chiefly on the results of experiments in conscious animals. Use of techniques for simulating haemorrhage has greatly enhanced this research effort, by allowing the effects of multiple treatments on the response to acute central hypovolaemia to be tested in the same animal. 5. The results of such experiments indicate that phase II of the response to hypovolaemia is triggered, at least in part, by a signal from cardiac vagal afferents. There is also strong evidence that phase II depends on brainstem δ 1 ‐opioid receptor and nitrergic mechanisms and can potentially be modulated by circulating or neuronally released adrenocorticotropic hormone, brainstem serotonergic pathways operating through 5‐HT 1A receptors and opioids acting through μ‐ and κ ‐opioid receptors in the brainstem. 6. Phase II also appears to require input from supramedullary brain centres. Future studies should determine how these neurotransmitter systems interact and their precise neuroanatomical arrangements.

Progression of cardiovascular and endocrine dysfunction in a rabbit model of obesity

Publisher: Springer Science and Business Media LLC

Date: 14-02-2013

DOI: 10.1038/HR.2013.2

Abstract: In rabbits, mean arterial pressure (MAP) increases in response to fat feeding, but does not increase further with progressive weight gain. We documented the progression of adiposity and the alterations in endocrine/cardiovascular function in response to fat feeding in rabbits, to determine whether stabilization of MAP after 3 weeks could be explained by stabilization of neurohormonal factors. Rabbits were fed a control diet or high-fat diet for 9 weeks (n=23). Fat feeding progressively increased body mass and adiposity. Heart rate (HR) was elevated by week 3 (15±3%) but changed little thereafter. The effects of fat feeding on MAP were dependent on baseline MAP and peaked at 3 weeks. From baseline, MAP 80 mm Hg, MAP had increased by 8.1±1.3, 4.7±1.7 and 5.6±1.2 mm Hg, respectively, 3, 6 and 9 weeks after commencing the high-fat diet, but by only 2.6±1.5, 3.0±1.7 and 3.9±1.4 mm Hg, respectively, in control rabbits. Fat feeding did not increase MAP from a baseline >80 mm Hg. Plasma concentrations of leptin and insulin increased during the first 3-6 weeks of fat feeding and then stabilized (increasing by 111±17% and 731±302% by week 9, respectively), coinciding with the pattern of changes in MAP and HR. Plasma total cholesterol, triglycerides, renin activity, aldosterone and atrial natriuretic peptide were not significantly altered by fat feeding. Given that the changes in plasma leptin and insulin mirrored the changes in MAP and HR, leptin and insulin may be important factors in the development of hypertension and tachycardia in the rabbit model of obesity.

Benefits of synchrotron microangiography for dynamic studies of smooth muscle and endothelial roles in the pathophysiology of vascular disease

Publisher: AIP

Date: 2010

DOI: 10.1063/1.3478204

Hypertension in Rural India: The Contribution of Socioeconomic Position

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 09-04-2020

DOI: 10.1161/JAHA.119.014486

Abstract: Various indicators of socioeconomic position ( SEP ) may have opposing effects on the risk of hypertension in disadvantaged settings. For ex le, high income may reflect sedentary employment, whereas greater education may promote healthy lifestyle choices. We assessed whether education modifies the association between income and hypertension in 3 regions of South India at different stages of epidemiological transition. Using a cross‐sectional design, we randomly selected villages within each of rural Trivandrum, West Godavari, and Rishi Valley. S ling was stratified by age group and sex. We measured blood pressure and anthropometry and administered a questionnaire to identify lifestyle factors and SEP , including education, literacy, and income. Logistic regression was used to assess associations between various components of SEP and hypertension, and interaction analyses were used to determine whether educational attainment modified the association between income and hypertension. Trivandrum, the region of highest SEP , had the greatest prevalence of hypertension, whereas Rishi Valley, the lowest SEP region, had the least. Overall, greater income was associated with greater risk of hypertension. In interaction analyses, there was no evidence that educational attainment modified the association between income and hypertension. Education is widely considered to ameliorate the risk of hypertension in high‐income countries. Why this effect is absent in rural India merits investigation.

Simultaneous measurement of pO2 and perfusion in the rabbit kidney in vivo.

Publisher: Springer US

Date: 2007

DOI: 10.1007/978-0-387-71764-7_13

Abstract: Recently, a combined probe has been developed capable of simultaneous measurement of local tissue pO2 (fluorescence oximetry) and microvascular perfusion (laser Doppler flux) within the same local region. The aim of the current study was to test the utility of these combined probes to measure pO2 and perfusion in the kidney. Studies were performed in anesthetized, artificially ventilated rabbits (n=7). Baseline measurements of renal medullary perfusion and pO2 obtained using combined probes (537 +/- 110 units & 28.7 +/- 6.l mmHg, respectively) were indistinguishable from those obtained using independent probes (435 +/- 102 units & 26.9 +/- 6.4 mmHg). Baseline measurements of renal cortical pO2 were also similar between combined (9.7 +/- 1.6 mmHg) and independent probes (9.5 +/- 2.3 mmHg). Baseline levels of cortical perfusion however, were significantly greater when measured using independent probes (1130 +/- 114 units) compared to combined probes (622 +/- 59 units P < 0.02). Relative changes in perfusion and pO2 resulting from graded stimulation of the renal nerves were not significantly different when measured using combined probes to those obtained using independent probes. We conclude that combined probes are equally suitable to independent probes for tissue pO2 and microvascular perfusion measurement in the kidney. Our results raise some concerns regarding the accuracy of these OxyLite fluorescence probes for pO2 measurement in the kidney, particularly within the renal cortex.

Synthetic inhibitors of endopeptidase EC 3.4.24.15: potency and stability in vitro and in vivo

Publisher: Wiley

Date: 07-1996

DOI: 10.1111/J.1476-5381.1996.TB15533.X

Abstract: 1. The role of the metalloendopeptidase EC 3.4.24.15 (EP 24.15) in peptide metabolism in vivo is unknown, in part reflecting the lack of a stable enzyme inhibitor. The most commonly used inhibitor, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB, Ki = 16 nM), although selective in vitro, is rapidly degraded in the circulation to cFP-Ala-Ala, an angiotensin converting enzyme (ACE) inhibitor. This metabolite is thought to be generated by neutral endopeptidase (NEP EC 3.4.24.11), as the Ala-Tyr bond of cFP-AAY-pAB is cleaved by NEP in vitro. In the present study, we have examined the role of NEP in the metabolism of cFP-AAY-pAB in vivo, and have tested a series of inhibitor analogues, substituted at the second alanine, for both potency and stability relative to the parent compound. 2. Analogues were screened for inhibition of fluorescent substrate cleavage by recombinant rat testes EP 24.15. D-Ala or Asp substitution abolished inhibitory activity, while Val-, Ser- and Leu-substituted analogues retained activity, albeit at a reduced potency. A relative potency order of Ala (1) > Val (0.3) > Ser (0.16) > Leu (0.06) was observed. Resistance to cleavage by NEP was assessed by incubation of the analogues with rabbit kidney membranes. The parent compound was readily degraded, but the analogues were twice (Ser) and greater than 10 fold (Leu and Val) more resistant to cleavage. 3. Metabolism of cFP-AAY-pAB and the Val-substituted analogue was also examined in conscious rabbits. A bolus injection of cFP-AAY-pAB (5 mg kg-1, i.v.) significantly reduced the blood pressure response to angiotensin I, indicating ACE inhibition. Pretreatment with NEP inhibitors, SCH 39370 or phosphoramidon, slowed the loss of cFP-AAY-pAB from the plasma, but did not prevent inhibition of ACE. Injection of 1 mg kg-1 inhibitor resulted in plasma concentrations at 10 s of 23.5 microM (cFP-AAY-pAB) and 18.0 microM (cFP-AVY-pAB), which fell 100 fold over 5 min. Co-injection of 125I-labelled inhibitor revealed that 80-85% of the radioactivity had disappeared from the circulation within 5 min, and h.p.l.c. analysis demonstrated that only 25-30% of the radiolabel remained as intact inhibitor at this time. Both analogues were cleared from the circulation at the same rate, and both inhibitors blunted the pressor response to angiotensin I, indicative of ACE inhibition. 4. These results suggest that both NEP and other clearance/degradation mechanisms severely limit the usefulness of peptide-based inhibitors such as cFP-AAY-pAB. To examine further EP 24.15 function in vivo, more stable inhibitors, preferably non-peptide, must be developed, for which these peptide-based inhibitors may serve as useful molecular templates.

Urinary Oxygenation as a Surrogate Measure of Medullary Oxygenation During Angiotensin II Therapy in Septic Acute Kidney Injury

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 2018

DOI: 10.1097/CCM.0000000000002797

Abstract: Angiotensin II is an emerging therapy for septic acute kidney injury, but it is unknown if its vasoconstrictor action induces renal hypoxia. We therefore examined the effects of angiotensin II on intrarenal P o 2 in ovine sepsis. We also assessed the validity of urinary P o 2 as a surrogate measure of medullary P o 2 . Interventional study. Research Institute. Sixteen adult Merino ewes ( n = 8/group). Sheep were instrumented with fiber-optic probes in the renal cortex, medulla, and within a bladder catheter to measure P o 2 . Conscious sheep were infused with Escherichia coli for 32 hours. At 24–30 hours, angiotensin II (0.5–33.0 ng/kg/min) or saline vehicle was infused. Septic acute kidney injury was characterized by hypotension and a 60% ± 6% decrease in creatinine clearance. During sepsis, medullary P o 2 decreased from 36 ± 1 to 30 ± 3 mm Hg after 1 hour and to 20 ± 2 mm Hg after 24 hours at these times, urinary P o 2 was 42 ± 2, 34 ± 2, and 23 ± 2 mm Hg. Increases in urinary neutrophil gelatinase-associated lipocalin (12% ± 3%) and serum creatinine (60% ± 23%) were only detected at 8 and 24 hours, respectively. IV infusion of angiotensin II, at 24 hours of sepsis, restored arterial pressure and improved creatinine clearance, while not exacerbating medullary or urinary hypoxia. In septic acute kidney injury, renal medullary and urinary hypoxia developed several hours before increases in currently used biomarkers. Angiotensin II transiently improved renal function without worsening medullary hypoxia. In septic acute kidney injury, angiotensin II appears to be a safe, effective therapy, and urinary P o 2 may be used to detect medullary hypoxia.

Lack of contribution of P2X receptors to neurally mediated vasoconstriction in the rabbit kidney in vivo

Publisher: Wiley

Date: 31-01-2006

DOI: 10.1111/J.1748-1716.2006.01526.X

Abstract: The contribution of adenosine triphosphate (ATP) to the neural control of regional renal perfusion in vivo remains unknown. We therefore examined whether P2X receptors mediate renal vascular responses to electrical stimulation of the renal nerves (RNS) in pentobarbitone anaesthetized rabbits. Responses to RNS were tested before and during renal arterial infusion of alpha,beta-methylene ATP (alpha,beta-mATP, 7-56 microg kg(-1) min(-1)) to desensitize P2X1 receptors. RNS consisted of 3 min trains at graded frequencies and short trains of RNS (4-32 pulses). Three-minute trains of RNS reduced renal blood flow (RBF), cortical laser Doppler flux (CLDF), and medullary LDF (MLDF) by -90 +/- 3%, -89 +/- 3% and -31 +/- 11%, respectively, at 4 Hz. MLDF was reduced less than CLDF or RBF. During short train RNS, RBF, CLDF and MLDF were reduced by -22 +/- 2%, -15 +/- 2% and -12 +/- 2%, respectively, for 32 s at 1 Hz. CLDF and MLDF were reduced to a similar extent. Infusion of alpha,beta-mATP induced transient reductions in RBF, CLDF and MLDF, but within 5 min these variables had recovered to control levels. Vascular responses to RNS were not significantly altered by alpha,beta-mATP treatment. In the rabbit kidney in vivo, alpha,beta-mATP-sensitive receptors mediate vasoconstriction and reduce perfusion in both cortical and medullary vascular beds. However, these receptors do not mediate neurally induced reductions in renal perfusion.

Renal oxygenation during the early stages of adenine-induced chronic kidney disease

Publisher: American Physiological Society

Date: 11-2019

DOI: 10.1152/AJPRENAL.00253.2019

Abstract: To assess whether renal hypoxia is an early event in adenine-induced chronic kidney disease, adenine (100 mg) or its vehicle was administered to male Sprague-Dawley rats by daily oral gavage for 7 days. Kidney oxygenation was assessed by 1) blood oximetry and Clark electrode in thiobutabarbital-anesthetized rats, 2) radiotelemetry in unanesthetized rats, and 3) expression of hypoxia-inducible factor (HIF)-1α and HIF-2α protein. After 7 days of treatment, under anesthesia, renal O 2 delivery was 51% less, whereas renal O 2 consumption was 65% less, in adenine-treated rats than in vehicle-treated rats. Tissue Po 2 measured by Clark electrode was similar in the renal cortex but 44% less in the medulla of adenine-treated rats than in that of vehicle-treated rats. In contrast, in unanesthetized rats, both cortical and medullary tissue Po 2 measured by radiotelemetry remained stable across 7 days of adenine treatment. Notably, anesthesia and laparotomy led to greater reductions in medullary tissue Po 2 measured by radiotelemetry in rats treated with adenine (37%) than in vehicle-treated rats (16%), possibly explaining differences between our observations with Clark electrodes and radiotelemetry. Renal expression of HIF-1α was less after 7 days of adenine treatment than after vehicle treatment, whereas expression of HIF-2α did not differ significantly between the two groups. Renal dysfunction was evident after 7 days of adenine treatment, with glomerular filtration rate 65% less and serum creatinine concentration 183% greater in adenine-treated rats than in vehicle-treated rats. Renal cortical tissue hypoxia may not precede renal dysfunction in adenine-induced chronic kidney disease and so may not be an early pathological feature in this model.

Effects of chronic sympatho-inhibition on reflex control of renal blood flow and plasma renin activity in renovascular hypertension

Publisher: Wiley

Date: 2010

DOI: 10.1111/J.1476-5381.2009.00546.X

Gender Differences in Pressure-Natriuresis and Renal Autoregulation

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 02-2010

DOI: 10.1161/HYPERTENSIONAHA.110.166827

Abstract: Sexual dimorphism in arterial pressure regulation has been observed in humans and animal models. The mechanisms underlying this gender difference are not fully known. Previous studies in rats have shown that females excrete more salt than males at a similar arterial pressure. The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. This study examined the role of the angiotensin type 2 receptor (AT 2 R) in pressure-natriuresis in male and female rats because AT 2 R expression has been reported to be enhanced in females. Renal function was examined at renal perfusion pressures of 120, 100, and 80 mm Hg in vehicle-treated and AT 2 R antagonist-treated (PD123319 1 mg/kg/h) groups. The pressure-natriuresis relationship was gender-dependent such that it was shifted upward in female vs male rats ( P .001). AT 2 R blockade modulated the pressure-natriuresis relationship, shifting the curve downward in male ( P .01) and female ( P .01) rats to a similar extent. In females, AT 2 R blockade also reduced the lower end of the autoregulatory range of renal blood flow ( P .05) and glomerular filtration rate ( P .01). Subsequently, the renal blood flow response to graded angiotensin II infusion was also measured with and without AT 2 R blockade. We found that AT 2 R blockade enhanced the renal vasoconstrictor response to angiotensin II in females but not in males ( P .05). In conclusion, the AT 2 R modulates pressure-natriuresis, allowing the same level of sodium to be excreted at a lower pressure in both genders. However, a gender-specific role for the AT 2 R in renal autoregulation was evident in females, which may be a direct vascular AT 2 R effect.

EFFECTS OF HALOTHANE, KETAMINE, PROPOFOL AND ALFENTANIL ANAESTHESIA ON CIRCULATORY CONTROL IN RABBITS

Publisher: Wiley

Date: 11-1990

DOI: 10.1111/J.1440-1681.1990.TB01280.X

Abstract: 1. We have made a within-rabbit comparison of the effects of four general anaesthetic regimens on the haemodynamic response to acute reduction in central blood volume and on baroreflex control of heart rate. 2. Acute haemorrhage was simulated by gradually inflating a cuff on the inferior vena cava in order to cause cardiac output to fall at a constant rate of 8.5%/min while the responses of systemic vascular resistance, arterial pressure and heart rate were measured. The full range of the baroreceptor-heart rate reflex was elicited by inflating aortic and vena caval cuffs. These indices of circulatory control were repeatedly measured within five protocols, to which each rabbit was exposed in randomized order. 3. In each protocol the rabbit was first studied unanaesthetized. Then a small dose of thiopentone sodium was given (16 mg/kg). In the four main protocols the rabbit was then intubated and ventilated, first with 100% oxygen and then with 50% nitrous oxide, during administration of one of four anaesthetic agents. These were halothane (2.0 and 2.5%), ketamine (2.5 mg/kg per min), propofol (0.83 and 1.25 mg/kg per min) and alfentanil (2.5 and 3.33 micrograms/kg per min). In a sham protocol the effects of 100% oxygen, then those of 50 and 75% nitrous oxide, were studied while the rabbit remained conscious. 4. In unanaesthetized rabbits, in the presence or absence of nitrous oxide, the normal biphasic haemodynamic response to simulated haemorrhage occurred. The first, vasoconstrictor, phase was attenuated by halothane, ketamine and propofol, so that arterial pressure fell more steeply than normal. Not only was the vasoconstrictor phase unaffected by alfentanil but it was extended, so that arterial pressure remained at a normal level even when cardiac output had fallen by 59%. This effect of alfentanil appeared to be mediated centrally, since it could be reproduced by injecting small doses (1.5-7.5 micrograms) into the fourth ventricle. All four anaesthetic agents and nitrous oxide attenuated the baroreceptor control of heart rate. The effect was least with nitrous oxide and alfentanil, greatest with halothane.

ANG II type 2 receptors and neural control of intrarenal blood flow

Publisher: American Physiological Society

Date: 12-2006

DOI: 10.1152/AJPREGU.00183.2006

Abstract: We tested the hypothesis that activation of angiotensin type 2 (AT 2 ) receptors, by both exogenous and endogenous ANG II, modulates neurally mediated vasoconstriction in the renal cortical and medullary circulations. Under control conditions in pentobarbital-anesthetized rabbits, electrical stimulation of the renal nerves (RNS 0.5–8 Hz) reduced renal blood flow (RBF −88 ± 3% at 8 Hz) and cortical perfusion (CBF −92 ± 2% at 8 Hz) more than medullary perfusion (MBF −67 ± 6% at 8 Hz). Renal arterial infusion of ANG II, at a dose titrated to reduce RBF by ∼40–50% (5–50 ng·kg −1 ·min −1 ) blunted responses of MBF to RNS, without significantly affecting responses of RBF or CBF. Subsequent administration of PD123319 (1 mg/kg plus 1 mg·kg −1 ·h −1 ) during continued renal arterial infusion of ANG II did not significantly affect responses of RBF or CBF to RNS but enhanced responses of MBF, so that they were similar to those observed under control conditions. In contrast, administration of PD123319 alone blunted responses of CBF and MBF to RNS. Subsequent renal arterial infusion of ANG II in PD123319 -pretreated rabbits restored CBF responses to RNS back to control levels. In contrast, ANG II infusion in PD123319 -pretreated rabbits did not alter MBF responses to RNS. These data indicate that exogenous ANG II can blunt neurally mediated vasoconstriction in the medullary circulation through activation of AT 2 receptors. However, AT 2 -receptor activation by endogenous ANG II appears to enhance neurally mediated vasoconstriction in both the cortical and medullary circulations.

Dominance of pressure natriuresis in acute depressor responses to increased renal artery pressure in rabbits and rats.

Publisher: Wiley

Date: 02-2002

DOI: 10.1113/JPHYSIOL.2001.013280

Abstract: Increasing renal artery pressure (RAP) activates pressure diuresis/natriuresis and inhibits renal renin release. There is also evidence that increasing RAP stimulates release of a putative depressor hormone from the renal medulla, although this hypothesis remains controversial. We examined the relative roles of these antihypertensive mechanisms in the acute depressor responses to increased RAP in anaesthetized rabbits and rats. In rabbits, an extracorporeal circuit was established which allows RAP to be set and controlled without direct effects on systemic haemodynamics. When RAP was maintained at approximately 65 mmHg, cardiac output (CO) and mean arterial pressure (MAP) did not change significantly. In contrast, when RAP was increased to approximately 160 mmHg, CO and MAP fell 20 +/- 5 % and 36 +/- 5 %, respectively, over 30 min. Urine flow also increased more than 28-fold when RAP was increased. When compound sodium lactate was infused intravenously at a rate equal to urine flow, neither CO nor MAP fell significantly in response to increased RAP. In 1 kidney-1 clip hypertensive rats, MAP fell by 54 +/- 10 mmHg over a 2 h period after unclipping. In rats in which isotonic NaCl was administered intravenously at a rate equal to urine flow, MAP did not change significantly after unclipping (-14 +/- 9 mmHg). Our results suggest that the depressor responses to increasing RAP in these experimental models are chiefly attributable to hypovolaemia secondary to pressure diuresis/natruresis. These models therefore appear not to be bioassays for release of a putative renal medullary depressor hormone.

Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor

Publisher: Wiley

Date: 03-1995

DOI: 10.1111/J.1476-5381.1995.TB13332.X

Abstract: 1. We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2. In conscious rabbits, cFP (5 mg kg-1, i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-1), and inhibited the pressor response to right atrial angiotensin I (10-100 ng kg-1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg-1h-1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3. In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg-1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 micrograms kg-1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4. CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 microM respectively), and inhibited rat plasma ACE activity (KI = 2.4 microM). Addition of phosphoramidon (10 microM), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems. 5. Taken together these findings suggest that the actions of cFP in vivo are attributable to inhibition of ACE rather than EP 24.15. Given that cFP is a poor inhibitor of ACE in the presence of phosphoramidon in vitro, it is likely that cFP is cleaved by a phosphoramidon-sensitive metallopeptidase in vivo to liberate N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala, a potent ACE inhibitor.

Oxygen signaling: Call for papers

Publisher: American Physiological Society

Date: 11-2016

DOI: 10.1152/AJPREGU.00416.2016

Renal perfusion, oxygenation, and sympathetic nerve activity during volatile or intravenous general anaesthesia in sheep

Publisher: Elsevier BV

Date: 03-2019

DOI: 10.1016/J.BJA.2018.11.018

Abstract: Global and intra-renal perfusion and oxygenation may be affected by the choice of anaesthetic. We compared the effects of isoflurane with those of propofol and fentanyl on renal blood flow (RBF) and intra-renal perfusion and oxygenation, and assessed how these were associated with renal sympathetic nerve activity (RSNA). A renal artery flow probe and laser Doppler and oxygen-sensing probes were surgically implanted in the renal medulla and cortex in 20 Merino ewes. RSNA was measured in 12 additional ewes. We compared the effects of volatile or i.v. anaesthesia on global RBF, renal oxygen delivery (RDO Compared with a non-anaesthetised state, volatile anaesthesia reduced global RBF [-76 (82-68)%], RDO Volatile and i.v. general anaesthesia markedly reduced global RBF, RDO

Arterial spin labelling MRI to measure renal perfusion: a systematic review and statement paper

Publisher: Oxford University Press (OUP)

Date: 23-08-2018

DOI: 10.1093/NDT/GFY180

Renal oxygenation: From data to insight.

Publisher: Wiley

Date: 14-02-2020

DOI: 10.1111/APHA.13450

AT₂ receptors mediate tonic renal medullary vasoconstriction in renovascular hypertension

Publisher: Wiley

Date: 02-2005

DOI: 10.1038/SJ.BJP.0706036

Determinants of renal tissue hypoxia in a rat model of polycystic kidney disease

Publisher: American Physiological Society

Date: 15-11-2014

DOI: 10.1152/AJPREGU.00202.2014

Abstract: Renal tissue oxygen tension (Po 2 ) and its determinants have not been quantified in polycystic kidney disease (PKD). Therefore, we measured kidney tissue Po 2 in the Lewis rat model of PKD (LPK) and in Lewis control rats. We also determined the relative contributions of altered renal oxygen delivery and consumption to renal tissue hypoxia in LPK rats. Po 2 of the superficial cortex of 11- to 13-wk-old LPK rats, measured by Clark electrode with the rat under anesthesia, was higher within the cysts (32.8 ± 4.0 mmHg) than the superficial cortical parenchyma (18.3 ± 3.5 mmHg). Po 2 in the superficial cortical parenchyma of Lewis rats was 2.5-fold greater (46.0 ± 3.1 mmHg) than in LPK rats. At each depth below the cortical surface, tissue Po 2 in LPK rats was approximately half that in Lewis rats. Renal blood flow was 60% less in LPK than in Lewis rats, and arterial hemoglobin concentration was 57% less, so renal oxygen delivery was 78% less. Renal venous Po 2 was 38% less in LPK than Lewis rats. Sodium reabsorption was 98% less in LPK than Lewis rats, but renal oxygen consumption did not significantly differ between the two groups. Thus, in this model of PKD, kidney tissue is severely hypoxic, at least partly because of deficient renal oxygen delivery. Nevertheless, the observation of similar renal oxygen consumption, despite markedly less sodium reabsorption, in the kidneys of LPK compared with Lewis rats, indicates the presence of inappropriately high oxygen consumption in the polycystic kidney.

An Ovine Model for Studying the Pathophysiology of Septic Acute Kidney Injury

Publisher: Springer New York

Date: 2018

DOI: 10.1007/978-1-4939-7526-6_16

Abstract: The development of acute kidney injury (AKI) is both a significant and independent prognostic factor of mortality in patients with sepsis, but its pathophysiology remains unclear. Herein, we describe an ovine model of sepsis evoked by the administration of live Escherichia coli in which there is hypotension, peripheral vasodilatation with a large increase in cardiac output a similar hyperdynamic state to that commonly reported in humans. Interestingly, in this sheep model of sepsis, despite an increase in global kidney blood flow, there is a progressive reduction in renal function. Although renal hyperperfusion develops, renal tissue hypoxia due to redistribution of intrarenal blood flow may contribute to the pathogenesis of septic AKI. We have, therefore, developed a novel methodology to chronically implant combination probes to monitor intrarenal tissue perfusion and oxygen tension during the development of septic AKI in conscious sheep with hyperdynamic sepsis.

Effects of ovarian steroids on hypothalamic opioid receptor subtypes in ovariectomized ewes: regional changes in density and affinity

Publisher: Bioscientifica

Date: 06-1995

DOI: 10.1677/JOE.0.1450559

Abstract: The negative feedback regulation by ovarian steroids of luteinizing hormone secretion may be partially mediated by a hypothalamic endogenous opioid mechanism. This could be affected by ovarian steroid-regulated changes in hypothalamic opioid receptor binding mechanisms. In this report we show that in the presence of blocking concentrations of site-selective opioid analogues, [ 3 H]diprenorphin homogeneously labelled μ, δ or κ receptor subtypes respectively. Using this receptor binding model, we characterized each opioid receptor subtype in the hypothalamic preoptic area and medio-basal hypothalamus of ovariectomized (OVX) and OVX plus progesterone- or oestradiol-17β (OE 2 )-treated ewes. In the preoptic area, progesterone treatment did not influence the affinity or capacity of δ or κ receptor binding sites, but significantly reduced μ receptor subtype content (20% less than control) with no statistically significant change in affinity. There was no effect of OE 2 on either the affinity or capacity of each opioid receptor subtype in this area. In the mediobasal hypothalamus, progesterone treatment significantly decreased δ subtype receptor affinity (22 ± 11 n m vs control 7 ± 2 n m ) and increased binding capacity (78 ± 9 fmol/mg protein vs control 37 ± 16 fmol/mg protein). OE 2 treatment had a similar, though more profound effect on affinity (51 ± 17 n m ) and binding capacity (139 ± 26 fmol/mg protein) at the δ receptor binding site. There were no significant changes in the affinity or capacity of μ or κ binding sites in the medio-basal hypothalamus. These results indicate that steroid hormones modulate hypothalamic opioid receptors in the OVX ewe in a receptor subtype- and region-dependent manner. The precise role of these steroid-induced changes in opioid receptor characteristics remains to be determined. Journal of Endocrinology (1995) 145, 559–567

Renal medullary tissue oxygenation is dependent on both cortical and medullary blood flow

Publisher: American Physiological Society

Date: 03-2006

DOI: 10.1152/AJPRENAL.00275.2005

Abstract: The aim of the current study was to determine whether renal medullary oxygenation is independent of the level of cortical blood flow by testing responses to stimuli that selectively reduce blood flow in either the cortex or medulla. In anesthetized rabbits, renal arterial infusion of [Phe 2 ,Ile 3 ,Orn 8 ]-vasopressin selectively reduced medullary perfusion and Po 2 (−54 ± 24 and −50 ± 10%, respectively) but did not significantly affect cortical perfusion or tissue oxygenation. In contrast, stimulation of the renal nerves resulted in renal cortical ischemia with reductions in total renal blood flow (−76 ± 3% at 4 Hz), cortical perfusion (−57 ± 17%), and cortical Po 2 (−44 ± 12%). Medullary tissue Po 2 was reduced by −70 ± 5% at 4 Hz, despite medullary perfusion being unaffected and distal tubular sodium reabsorption being reduced (by −83.3 ± 1.2% from baseline). In anesthetized rats, in which renal perfusion pressure was maintained with an aortic constrictor, intravenous infusion of ANG II (0.5–5 μg·kg −1 ·min −1 ) dose dependently reduced cortical perfusion (up to −65 ± 3% P 0.001) and cortical Po 2 (up to −57 ± 4% P 0.05). However, medullary perfusion was only significantly reduced at the highest dose (5 μg·kg −1 ·min −1 by 29 ± 6%). Medullary perfusion was not reduced by 1 μg·kg −1 ·min −1 ANG II, but medullary Po 2 was significantly reduced (−12 ± 4%). Thus, although cortical and medullary blood flow may be independently regulated, medullary oxygenation may be compromised during moderate to severe cortical ischemia even when medullary blood flow is maintained.

Intraoperative renal hypoxia and risk of cardiac surgery‐associated acute kidney injury

Publisher: Hindawi Limited

Date: 29-07-2021

DOI: 10.1111/JOCS.15859

Abstract: Acute kidney injury (AKI) is common after cardiac surgery requiring cardiopulmonary bypass. Renal hypoxia may precede clinically detectable AKI. We compared the efficacy of two indices of renal hypoxia, (i) intraoperative urinary oxygen tension (UPO In 82 patients undergoing on-pump cardiac surgery, blood s les were taken upon induction of anesthesia and upon entry into the intensive care unit. UPO Thirty-two (39%) patients developed postoperative AKI. pEPO increased during surgery, but this increase did not predict AKI, regardless of risk of postoperative mortality assessed by EuroSCORE-II. For patients categorized at higher risk by EuroSCORE-II >1.98 (median score for the cohort), UPO Intraoperative change in pEPO does not predict AKI. However, UPO

Altered responsiveness of the kidney to activation of the renal nerves in fat-fed rabbits

Publisher: American Physiological Society

Date: 06-2009

DOI: 10.1152/AJPREGU.90931.2008

Abstract: We tested whether mild adiposity alters responsiveness of the kidney to activation of the renal sympathetic nerves. After rabbits were fed a high-fat or control diet for 9 wk, responses to reflex activation of renal sympathetic nerve activity (RSNA) with hypoxia and electrical stimulation of the renal nerves (RNS) were examined under pentobarbital anesthesia. Fat pad mass and body weight were, respectively, 74% and 6% greater in fat-fed rabbits than controls. RNS produced frequency-dependent reductions in renal blood flow, cortical and medullary perfusion, glomerular filtration rate, urine flow, and sodium excretion and increased renal plasma renin activity (PRA) overflow. Responses of sodium excretion and medullary perfusion were significantly enhanced by fat feeding. For ex le, 1 Hz RNS reduced sodium excretion by 79 ± 4% in fat-fed rabbits and 46 ± 13% in controls. RNS (2 Hz) reduced medullary perfusion by 38 ± 11% in fat-fed rabbits and 9 ± 4% in controls. Hypoxia doubled RSNA, increased renal PRA overflow and medullary perfusion, and reduced urine flow and sodium excretion, without significantly altering mean arterial pressure (MAP) or cortical perfusion. These effects were indistinguishable in fat-fed and control rabbits. Neither MAP nor PRA were significantly greater in conscious fat-fed than control rabbits. These observations suggest that mild excess adiposity can augment the antinatriuretic response to renal nerve activation by RNS, possibly through altered neural control of medullary perfusion. Thus, sodium retention in obesity might be driven not only by increased RSNA, but also by increased responsiveness of the kidney to RSNA.

Studies of the effects of subacute treatment with N‐(cyclopropylmethyl)−19‐isopentylnororvinol (M320) on timing of parturition in the rat

Publisher: Wiley

Date: 11-1988

DOI: 10.1111/J.1476-5381.1988.TB11704.X

Abstract: 1. Administration of 10 micrograms kg-1 of the long lasting potent kappa- and weaker mu-opioid agonist N-(cyclopropylmethyl)-19-isopentylnororvinol (M320) twice daily from day 20 of gestation prolonged the internal gestation period of the rat and retarded the development of the offspring in the perinatal period. 2. The capacities of myometrial, placental and cervical tissues to produce prostaglandin E2 (PGE2) were not affected by M320 treatment. 3. During the period in which parturition normally occurred in saline-treated rats, foetal pituitary levels of immunoreactive oxytocin (ir-OXY) but not immunoreactive arginine-vasopressin (ir-AVP) were greater in M320-compared to saline-treated animals. Following the completion of parturition, foetal pituitary ir-OXY and ir-AVP levels continued to rise in saline-treated rats, but fell dramatically in rats treated subacutely with M320. 4. These data indicate that subacute treatment with M320 may inhibit foetal oxytocin release at term. This foetal OXY release may be a stimulus for the initiation of labour.

Basal renal O₂ consumption and the efficiency of O₂ utilization for Na⁺ reabsorption

Publisher: American Physiological Society

Date: 03-2014

DOI: 10.1152/AJPRENAL.00473.2013

Abstract: We examined how the presence of a fixed level of basal renal O 2 consumption (V̇o 2 basal O 2 used for processes independent of Na + transport) confounds the utility of the ratio of Na + reabsorption (T Na + ) to total renal V̇o 2 (V̇o 2 total ) as an index of the efficiency of O 2 utilization for T Na + . We performed a systematic review and additional experiments in anesthetized rabbits to obtain the best possible estimate of the fractional contribution of V̇o 2 basal to V̇o 2 total under physiological conditions (basal percent renal V̇o 2 ). Estimates of basal percent renal V̇o 2 from 24 studies varied from 0% to 81.5%. Basal percent renal V̇o 2 varied with the fractional excretion of Na + (FE Na + ) in the 14 studies in which FE Na + was measured under control conditions. Linear regression analysis predicted a basal percent renal V̇o 2 of 12.7–16.5% when FE Na + = 1% ( r 2 = 0.48, P = 0.001). Experimentally induced changes in T Na + altered T Na + /V̇o 2 total in a manner consistent with theoretical predictions. We conclude that, because V̇o 2 basal represents a significant proportion of V̇o 2 total , T Na + /V̇o 2 total can change markedly when T Na + itself changes. Therefore, caution should be taken when T Na + /V̇o 2 total is interpreted as a measure of the efficiency of O 2 utilization for T Na + , particularly under experimental conditions where T Na + or V̇o 2 total changes.

Renal functional recovery among inpatients: A plausible marker of reduced renal functional reserve

Publisher: Wiley

Date: 20-09-2021

DOI: 10.1111/1440-1681.13545

Abstract: Renal functional reserve (RFR) reflects the ability of the kidney to enhance glomerular filtration rate (GFR) in response to a protein load. Chronic kidney disease (CKD) leads to diminished RFR, since the capacity for whole‐body GFR to increase through hyperfiltration of remaining nephrons is limited. Evaluating 41,456 inpatients following computerised tomography we reported many exhibiting acute kidney injury (AKI) but more patients with recovering kidney function (AKR), presumably reflecting resolution of their critical conditions. The incidences of AKI and AKR were closely co‐associated and were both inversely correlated with baseline kidney function. We discuss this phenomenon, arguing that AKR among inpatients with an acute illness, like AKI, may often reflect underlying subtle CKD with diminished RFR.

Impact of choice of kinetic model for the determination of transcutaneous FITC-sinistrin clearance in rats with streptozotocin-induced type 1 diabetes

Publisher: Wiley

Date: 24-03-2020

DOI: 10.1111/1440-1681.13301

Influence of blood haemoglobin concentration on renal haemodynamics and oxygenation during experimental cardiopulmonary bypass in sheep

Publisher: Wiley

Date: 03-12-2021

DOI: 10.1111/APHA.13583

Effects of Fluid Bolus Therapy on Renal Perfusion, Oxygenation, and Function in Early Experimental Septic Kidney Injury

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 2019

DOI: 10.1097/CCM.0000000000003507

Abstract: To examine the effects of fluid bolus therapy on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, P o 2 , renal function, and fluid balance in experimental early septic acute kidney injury. Interventional study. Research institute. Adult Merino ewes. Implantation of flow probes on the pulmonary and renal arteries and laser Doppler oxygen-sensing probes in the renal cortex, medulla, and within a bladder catheter in sheep. Infusion of Escherichia coli to induce septic acute kidney injury ( n = 8). After 24, 25, and 26 hours of sepsis, fluid bolus therapy (500 mL of Hartmann’s solution over 15 min) was administered. In conscious sheep, infusion of Escherichia coli decreased creatinine clearance and increased plasma creatinine, renal blood flow (+46% ± 6%) and cortical perfusion (+25% ± 4%), but medullary perfusion (–48% ± 5%), medullary P o 2 (–56% ± 4%), and urinary P o 2 (–54% ± 3%) decreased ( p 0.01). The first fluid bolus therapy increased blood pressure (+6% ± 1%), central venous pressure (+245% ± 65%), cardiac output (+11% ± 2%), medullary P o 2 (+280% ± 90%), urinary P o 2 (+164% ± 80%), and creatinine clearance (+120% ± 65%) at 30 minutes. The following two boluses had no beneficial effects on creatinine clearance. The improvement in medullary oxygenation dissipated following the third fluid bolus therapy. Study animals retained 69% of the total volume and 80% of sodium infused. Throughout the study, urinary P o 2 correlated significantly with medullary P o 2 . In early experimental septic acute kidney injury, fluid bolus therapy transiently improved renal function and medullary P o 2 , as also reflected by increased urinary P o 2. These initial effects of fluid bolus therapy dissipated within 4 hours, despite two additional fluid boluses, and resulted in significant volume retention.

Increasing hypoxia progressively slows early embryonic development in an oviparous reptile, the green turtle, Chelonia mydas

Publisher: The Royal Society

Date: 08-2022

DOI: 10.1098/RSOS.220709

Abstract: Green turtle ( Chelonia mydas ) embryos are in an arrested state of development when the eggs are laid, but in the presence of oxygen, arrest is broken and development resumes within 12–16 h. However, the precise oxygen level at which embryos break arrest and continue development is not known. To better understand the impact of oxygen concentration on breaking of arrest and early embryonic development, we incubated freshly laid eggs of the green sea turtle for three days at each of six different oxygen concentrations (less than or equal to 1%, 3%, 5%, 7%, 9% and 21%) and monitored the appearance and growth of white spots on the shell, indicative of embryonic development. As reported previously, white spots did not develop on eggs incubated in anoxia (less than or equal to 1% oxygen). For all other treatments, mean time to white spot detection and white spot growth rate varied inversely with oxygen concentration. In nearly all cases the difference between eggs at different oxygen levels was statistically significant ( p ≤ 0.05). This suggests that sea turtle embryonic development may respond to oxygen in a dose-dependent manner. Our results indicate that the development of green turtle embryos may be slowed if they are exposed to the most hypoxic conditions reported in mature natural nests.

Hypertension and the risk of intracerebral haemorrhage: special considerations in patients with renal disease

Publisher: Oxford University Press (OUP)

Date: 10-1999

DOI: 10.1093/NDT/14.10.2291

Evidence for decreased structurally determined preglomerular resistance in the young spontaneously hypertensive rat after 4 weeks of renal denervation

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-1997

DOI: 10.1097/00004872-199715100-00018

Abstract: To study the effects of denervation of the kidney on renal vascular resistance at maximal dilatation and renal function during the development of hypertension in the spontaneously hypertensive rat (SHR). SHR aged 6 weeks were subjected to left renal denervation or a sham-operation (n = 18 denervated, n = 13 sham). When they were aged 10 weeks, pairs of denervated and sham-operated left kidneys were perfused with 2% dextran in Tyrode's solution and pressure-flow and pressure-glomerular filtration rate (GFR) relationships at maximal vasodilation were established. The awake mean arterial blood pressure, in-vivo renal function and renal noradrenaline content were also measured. There were no significant differences between the pressure-flow relationships for denervated and sham-operated kidneys. However, there was a marked, parallel, shift leftwards in the pressure-GFR relationship (P < 0.001). Thus, the denervated kidneys commenced filtering at a lower threshold perfusion pressure than did the sham-operated ones. In-vivo renal plasma flow and GFR were significantly greater in the denervated left kidneys of SHR than they were in the contralateral kidneys. The noradrenaline content in denervated kidneys was 5 +/- 3% of that in innervated kidneys. The awake mean arterial pressure was 135 +/- 1 and 138 +/- 2 mmHg in the denervated and sham-operated groups respectively. Denervation of the kidney of SHR aged 6 weeks of age altered the pressure-GFR but not the pressure-flow relationship for these rats 4 weeks later. The results are compatible with there having been an increase in average preglomerular and a decrease in post-glomerular vessel lumen diameters. These changes suggest that the renal nerves affect the structural development of the renal vasculature in SHR.

Effects of intrarenal infusion of 17-octadecynoic acid on renal antihypertensive mechanisms in anesthetized rabbits.

Publisher: Oxford University Press (OUP)

Date: 07-1998

DOI: 10.1016/S0895-7061(98)00045-4

Abstract: To characterize the role of cytochrome P450 metabolism of fatty acids in the renal response to increased renal perfusion pressure, we tested the effects of renal arterial infusion of 17-octadecynoic acid (17-ODYA, 450 nmol/min) on renal and systemic hemodynamic, and renal excretory responses to step-wise increases in renal perfusion pressure (RPP) in anesthetized rabbits, using an extracorporeal circuit for renal autoperfusion. Inhibition of cytochrome P450-dependent fatty acid metabolism was estimated by comparing the metabolism of arachidonic acid in microsomes prepared from the kidneys of control and 17-ODYA-treated animals. Step-wise increases in RPP decreased mean arterial pressure, which previous studies have indicated is attributable to the release of a depressor hormone from the renal medulla. Elevations in RPP also increased renal blood flow and glomerular filtration rate, and the absolute and fractional excretions of urine and sodium. Intrarenal infusion of 17-ODYA reduced the metabolism of arachidonic acid to 20-hydroxyeicosatetraenoic acid by 41%, but it did not significantly influence the responses to increased renal perfusion pressure. We conclude that either the responses elicited by increased renal perfusion pressure in anesthetized rabbits do not depend on cytochrome P450-dependent fatty acid metabolism, or that cytochrome P450 activity must be inhibited by more than was achieved in the present study (41%), before functional effects on the response to increased renal perfusion pressure are observed.

Total peripheral resistance responsiveness during the development of secondary renal hypertension in dogs

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2007

DOI: 10.1097/HJH.0B013E3280112CF6

CARDIAC CHEMORECEPTORS: PHARMACOLOGICAL CURIOSITIES OR PHYSIOLOGICAL TOOLS?

Publisher: Wiley

Date: 02-1991

DOI: 10.1111/J.1440-1681.1991.TB01416.X

Abstract: 1. We have tested in unanaesthetized rabbits two hypotheses regarding a physiological role for cardiogenic chemoreflexes in acute central hypovolaemia. 2. In rabbits, the sympathoinhibitory phase of acute central hypovolaemia depends on the activation of a brain-stem delta-opioid receptor mechanism by a signal from the heart. Blockade of this by fourth ventricular injection of the delta-receptor antagonist ICI 174864 had no effect on the reflex haemodynamic responses to left atrial phenylbiguanide or intrapericardial nicotine. 3. Intravenous administration of the 5-HT3 receptor antagonist MDL 72222, or intrapericardial administration of the nicotinic ganglionic cholinoceptor antagonist mecamylamine HCl, had no effect on the haemodynamic response to acute central hypovolaemia. 4. We conclude that phenylbiguanide-sensitive myocardial afferents and nicotine-sensitive epicardial afferents play no part in the response to acute hypovolaemia in rabbits, and that the reflex effects evoked by chemically exciting these afferents do not depend on a brain-stem delta-opioid mechanism.

Editorial update 2012

Publisher: Wiley

Date: 27-12-2011

DOI: 10.1111/J.1440-1681.2011.05646.X

Type 1 neuropeptide Y receptors and α₁-adrenoceptors in the neural control of regional renal perfusion

Publisher: American Physiological Society

Date: 02-2006

DOI: 10.1152/AJPREGU.00317.2005

Abstract: The aim of this study was to determine the contribution of neuropeptide Y (NPY) Y 1 receptors in neurally mediated reductions in renal medullary perfusion. In pentobarbital sodium-anesthetized rabbits, electrical stimulation of the renal nerves (RNS, 0.5–16 Hz) decreased renal perfusion in a frequency-dependent manner. Under control conditions, 4 Hz reduced cortical and medullary perfusion by −85 ± 3% and −43 ± 7%, whereas 8 Hz reduced them by −93 ± 2% and −73 ± 4%, respectively. After Y 1 receptor antagonism with BIBO3304TF (0.1 mg/kg plus 0.2 mg·kg· −1 ·h −1 ), RNS reduced perfusion less (by −65 ± 9% and −12 ± 8% at 4 Hz). α 1 -Adrenoceptor antagonism with prazosin (0.2 mg/kg plus 0.2 mg kg −1 h −1 ) also inhibited RNS-induced reductions in renal perfusion (−80 ± 4% and −37 ± 10% reductions in the cortex and medulla, respectively, at 8 Hz). When given after BIBO3304TF treatment, prazosin inhibited RNS-induced reductions in cortical and medullary perfusion more profoundly (−57 ± 12% and −25 ± 9% reductions, respectively, at 8 Hz). Y 1 receptor- and α 1 -adrenoceptor-blockade were confirmed by testing vascular responses to renal arterial NPY and phenylephrine boluses. NPY-positive immunolabeling was observed around interlobular arteries, afferent and efferent arterioles, and in the outer medulla. In conclusion, Y 1 receptors and α 1 -adrenoceptors contribute to RNS-induced vasoconstriction in the vessels that control both cortical and medullary perfusion. Consistent with this, NPY immunostaining was associated with blood vessels that control perfusion in both regions. There also seems to be an interaction between Y 1 receptors and α 1 -adrenoceptor-mediated neurotransmission in the control of renal perfusion.

Urinary hypoxia: An intraoperative marker of risk of cardiac surgery-associated acute kidney injury

Publisher: Oxford University Press (OUP)

Date: 14-03-2018

DOI: 10.1093/NDT/GFY047

Abstract: Acute kidney injury (AKI) is common after cardiac surgery and profoundly affects postoperative mortality and morbidity. There are no validated methods to assess risk of AKI intraoperatively. We determined the association between postoperative AKI and intraoperative urinary oxygen tension (PO2), measured via a fiber optic probe in the tip of the urinary catheter, in 65 patients undergoing high-risk cardiac surgery requiring cardiopulmonary bypass (CPB). AKI was diagnosed by modified Kidney Disease: Improving Global Outcomes criteria. Urinary PO2 fell during the operation, often reaching its nadir during rewarming or after weaning from CPB. Nadir urinary PO2 was lower in the 26 patients who developed AKI (mean ± SD, 8.9 ± 5.6 mmHg) than in the 39 patients who did not (14.9 ± 10.2 mmHg, P = 0.008). Patients who developed AKI had longer periods of urinary PO2 ≤15 and 10 mmHg than patients who did not. Odds of AKI increased when urinary PO2 fell to ≤10 mmHg {3.60 [95% confidence interval (CI) 1.27-10.21]} or ≤5 mmHg [3.60 (95% CI 1.04-12.42), P = 0.04] during the operation. When urinary PO2 fell to ≤15 mmHg, for more than or equal to the median duration for all patients (4.8 min/h surgery), the odds of AKI were 4.85 (95% CI 1.64-14.40), P = 0.004. The area under the receiver-operator curve for this parameter alone was 0.69, and was 0.89 when other variables with P ≤ 0.10 in univariable analysis were included in the model. Low urinary PO2 during adult cardiac surgery requiring CPB predicts AKI, so may identify patients in which intervention to improve renal oxygenation might reduce the risk of AKI.

Renal Cortical Perfusion, Measured by Superb Microvascular Imaging, during Infusion of Norepinephrine in Experimental Cardiopulmonary Bypass.

Publisher: American Thoracic Society

Date: 15-06-2019

DOI: 10.1164/RCCM.201807-1275IM

Evaluation of a training program of hypertension for accredited social health activists (ASHA) in rural India

Publisher: Springer Science and Business Media LLC

Date: 02-05-2018

DOI: 10.1186/S12913-018-3140-8

Renal and dietary factors associated with hypertension in a setting of disadvantage in rural India

Publisher: Springer Science and Business Media LLC

Date: 18-01-2021

DOI: 10.1038/S41371-020-00473-5

Abstract: Using a case-control design, we determined risk factors associated with hypertension in a disadvantaged rural population in southern India. Three hundred adults with hypertension and 300 age- and sex-matched controls were extensively phenotyped. Underweight (29%, body mass index < 18.0 kg m

EFFECTS OF SUBACUTE OPIOID ADMINISTRATION DURING LATE PREGNANCY IN THE RAT ON THE INITIATION, DURATION AND OUTCOME OF PARTURITION AND MATERNAL LEVELS OF OXYTOCIN AND ARGININE VASOPRESSIN

Publisher: Wiley

Date: 03-1989

DOI: 10.1111/J.1440-1681.1989.TB01541.X

Abstract: 1. The effects, on parturition in the rat, of subacute and acute opioid administration were studied. Further experiments investigated the role of modulation of maternal plasma and pituitary oxytocin (OXY) and arginine vasopressin (AVP) levels in these effects. 2. Subacute opioid (M320, buprenorphine or bremazocine) administration prolonged the gestation of rats. This was accompanied by toxic effects on the offspring. Acute subcutaneous (s.c.) M320 (10 micrograms/kg) administration was accompanied by prolonged gestation without toxic effects. 3. Subacute M320 (10 micrograms/kg, s.c., twice daily) treatment was accompanied by increased interbirth intervals in parturient rats. 4. Maternal OXY but not AVP release, as assessed by measurement of plasma and pituitary immunoreactivity, was elevated during and up to 1 h after the completion of parturition. Subacute M320 treatment did not inhibit this elevated OXY release.

Postprandial heat production in skeletal muscle is associated with altered mitochondrial function and altered futile calcium cycling

Publisher: American Physiological Society

Date: 15-11-2012

DOI: 10.1152/AJPREGU.00036.2012

Abstract: This study aimed to determine whether postprandial temperature excursions in skeletal muscle are consistent with thermogenesis or altered blood flow. Temperature probes were implanted into the vastus lateralis muscle of ovariectomized ewes, and blood flow was assessed using laser-Doppler flowmetry (tissue flow) and transit-time ultrasound flowmetry (femoral artery flow). The animals were program-fed between 1100 and 1600, and temperature and blood flow were measured during intravenous administration of either isoprenaline or phenylephrine and during feeding and meal anticipation. In addition, muscle biopsies were collected prefeeding and postfeeding to measure uncoupling protein (UCP) expression and mitochondrial function, as well as indices of calcium cycling (ryanodine 1 receptor: RyR1 and sarcoendoplasmic calcium-dependent ATPases SERCA1/ SERCA2a). Isoprenaline increased femoral artery blood flow, whereas phenylephrine reduced blood flow. At high doses only, isoprenaline treatment increased heat production in muscle. Phenylephrine treatment did not alter muscle temperature. Meal anticipation was evoked in fasted animals (previously program-fed) that were housed beside animals that were fed. Increases in muscle temperature were elicited by feeding and meal anticipation, without changes in blood flow during either paradigm. Analyses of respiration in isolated mitochondria indicated that the postprandial increase in heat production was associated with an increase in state 4 respiration, without increased UCP1, UCP2, or UCP3 expression. Feeding increased the expression of RyR1 and SERCA2a. We conclude that excursions in muscle temperature may occur independent of blood flow, suggesting that postprandial heat production is driven by altered mitochondrial function and changes in calcium cycling.

Effects of ETA- and ETB-receptor antagonists on regional kidney blood flow, and responses to intravenous endothelin-1, in anaesthetized rabbits

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2001

DOI: 10.1097/00004872-200110000-00013

Abstract: To determine the roles of endothelin (ET)-receptor subtypes in the effects of exogenous and endogenous ETs on regional kidney blood flow in anaesthetized rabbits. The effects on regional kidney blood flow of the ET(A) antagonist BQ610, and the ET(B) antagonist BQ788, were tested. We also examined the effects of intravenous and renal arterial bolus doses of ET-1, and how these responses are modified by pretreatment with BQ610 and BQ788. BQ610 reduced mean arterial pressure (MAP, 3%), and increased total renal blood flow (RBF, 10%), cortical perfusion (CBF, 11%) and medullary perfusion (MBF, 16%). BQ788 increased MAP (6%) and reduced RBF (16%) and CBF (13%) but not MBF. The effects of BQ788 were abolished by pretreatment with BQ610. Intravenous ET-1 (300 ng/kg) reduced RBF and CBF, but increased MBF. BQ788 potentiated ET-1 mediated reductions in CBF, and abolished increases in MBF. BQ610 blunted reductions in RBF and CBF produced by ET-1, but did not significantly affect MBF responses. The renal vascular effects of intravenous ET-1 were mimicked by lower doses (1-30 ng/kg) administered into the renal artery. Endogenous ETs act at ET(A)-receptors to reduce MBF and CBF, but ET(B)-receptors have little direct role in physiological control of renal haemodynamics. Bolus doses of ET-1 act at ET(B)-receptors in the kidney to increase MBF. The effects of bolus ET-1 on the cortical vasculature appear to result from the competing influences of ET(A)-mediated vasoconstriction and ET(B)-mediated vasodilatation.

Neural control of renal medullary perfusion

Publisher: Wiley

Date: 05-2004

DOI: 10.1111/J.1440-1681.2004.04003.X

Abstract: 1. There is strong evidence that the renal medullary circulation plays a key role in long‐term blood pressure control. This, and evidence implicating sympathetic overactivity in development of hypertension, provides the need for understanding how sympathetic nerves affect medullary blood flow (MBF). 2. The precise vascular elements that regulate MBF under physiological conditions are unknown, but likely include the outer medullary portions of descending vasa recta and afferent and efferent arterioles of juxtamedullary glomeruli, all of which receive dense sympathetic innervation. 3. Many early studies of the impact of sympathetic drive on MBF were flawed, both because of the methods used for measuring MBF and because single and often intense neural stimuli were tested. 4. Recent studies have established that MBF is less sensitive than cortical blood flow (CBF) to electrical renal nerve stimulation, particularly at low stimulus intensities. Indeed, MBF appears to be refractory to increases in endogenous renal sympathetic nerve activity within the physiological range in all but the most extreme cases. 5. Multiple mechanisms appear to operate in concert to blunt the impact of sympathetic drive on MBF, including counter‐regulatory roles of nitric oxide and perhaps even paradoxical angiotensin II‐induced vasodilatation. Regional differences in the geometry of glomerular arterioles are also likely to predispose MBF to be less sensitive than CBF to any given vasoconstrictor stimulus. 6. Failure of these mechanisms would promote reductions in MBF in response to physiological activation of the renal nerves, which could, in turn, lead to salt and water retention and hypertension.

Sex differences in pressure diuresis/natriuresis in rabbits

Publisher: Wiley

Date: 08-2000

DOI: 10.1046/J.1365-201X.2000.00749.X

Abstract: We tested for sex-related differences in the pressure diuresis/natriuresis relationships in anaesthetized, renally denervated rabbits, using an extracorporeal circuit to perfuse the left kidney with the rabbit's own blood, through a series of step-wise increases in renal artery pressure (RAP) (from 65 to 130 mmHg). Urine flow, sodium excretion, and the fractional excretions of sodium and urine increased with increasing RAP, and were greater in male than in female rabbits at all levels of RAP-tested. However, these apparent sex-related differences in the acute pressure diuresis/natriuresis relationships were not reflected in alterations in chronic regulation of mean arterial pressure (MAP). Thus, in rabbits on a normal salt diet (0.85 g day(-1)), resting conscious MAP was significantly greater in males (87 +/- 3 mmHg) compared with females (77+/-1 mmHg). Chronically increasing daily salt intake to 4.98 g day(-1) for 28 days had no significant effect on resting conscious MAP in either sex. Thus, although our observations indicate sex differences, at least under the present experimental conditions, in the factors regulating extracellular fluid volume, these do not appear to have a major impact in setting the level of MAP in the long term.

Renal sympathetic neuroeffector function in renovascular and angiotensin II-dependent hypertension in rabbits

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 04-2007

DOI: 10.1161/01.HYP.0000260251.11364.1F

Abstract: We tested the hypotheses that the gains of specific renal sympathetic neuroeffector mechanisms are altered in secondary hypertension and that the nature of these alterations depends on the precise experimental setting of the kidney. Rabbits were sham operated, or made comparably hypertensive (mean arterial pressure increased 17% to 24%) by clipping the left or right renal artery or by chronic infusion of angiotensin II (20 to 50 ng kg −1 min −1 SC). Four to 6 weeks later, under pentobarbital anesthesia, the left renal nerves were sectioned and electrically stimulated at low (0 to 2 Hz) and high (4 to 8 Hz) frequencies. Neurally evoked reductions in total renal blood flow, cortical perfusion, urine flow, and sodium excretion and increases in renal norepinephrine spillover were not significantly greater in kidneys of hypertensive rabbits than normotensive controls. Neurally evoked increases in renal renin release and the slope of the relationship between renin release and norepinephrine spillover were less in kidneys of hypertensive rabbits than normotensive controls. Low-frequency renal nerve stimulation reduced medullary perfusion, which was negatively correlated with renal norepinephrine spillover in kidneys from all 3 groups of hypertensive rabbits but not normotensive controls. Two-hertz stimulation reduced medullary perfusion by 19% in hypertensive rabbits but not in normotensive rabbits. Thus, of all of the renal sympathetic neuroeffector mechanisms studied, only neural control of medullary perfusion was enhanced in these models of secondary hypertension. This effect appears to be mediated postjunctionally, not through enhanced neural norepinephrine release, and may contribute to the development and/or maintenance of hypertension in these models.

Methods for studying the physiology of kidney oxygenation

Publisher: Wiley

Date: 29-10-2008

DOI: 10.1111/J.1440-1681.2008.05063.X

Abstract: 1. An improved understanding of the regulation of kidney oxygenation has the potential to advance preventative, diagnostic and therapeutic strategies for kidney disease. Here, we review the strengths and limitations of available and emerging methods for studying kidney oxygen status. 2. To fully characterize kidney oxygen handling, we must quantify multiple parameters, including renal oxygen delivery (DO2) and consumption (VO2), as well as oxygen tension (Po2). Ideally, these parameters should be quantified both at the whole-organ level and within specific vascular, tubular and interstitial compartments. 3. Much of our current knowledge of kidney oxygen physiology comes from established techniques that allow measurement of global kidney DO2 and VO2, or local tissue Po2. When used in tandem, these techniques can help us understand oxygen mass balance in the kidney. Po2 can be resolved to specific tissue compartments in the superficial cortex, but not deep below the kidney surface. We have limited ability to measure local kidney tissue DO2 and VO2. 4. Mathematical modelling has the potential to provide new insights into the physiology of kidney oxygenation, but is limited by the quality of the information such models are based on. 5. Various imaging techniques and other emerging technologies have the potential to allow Po2 mapping throughout the kidney and/or spatial resolution of Po2 in specific renal tissues, even in humans. All currently available methods have serious limitations, but with further refinement should provide a pathway through which data obtained from experimental animal models can be related to humans in the clinical setting.

Renal functional reserve: from physiological phenomenon to clinical biomarker and beyond

Publisher: American Physiological Society

Date: 12-2020

DOI: 10.1152/AJPREGU.00237.2020

Abstract: Glomerular filtration rate (GFR) is acutely increased following a high-protein meal or systemic infusion of amino acids. The mechanisms underlying this renal functional response remain to be fully elucidated. Nevertheless, they appear to culminate in preglomerular vasodilation. Inhibition of the tubuloglomerular feedback signal appears critical. However, nitric oxide, vasodilator prostaglandins, and glucagon also appear important. The increase in GFR during amino acid infusion reveals a “renal reserve,” which can be utilized when the physiological demand for single nephron GFR increases. This has led to the concept that in subclinical renal disease, before basal GFR begins to reduce, renal functional reserve can be recruited in a manner that preserves renal function. The extension of this concept is that once a decline in basal GFR can be detected, renal disease is already well progressed. This concept likely applies both in the contexts of chronic kidney disease and acute kidney injury. Critically, its corollary is that deficits in renal functional reserve have the potential to provide early detection of renal dysfunction before basal GFR is reduced. There is growing evidence that the renal response to infusion of amino acids can be used to identify patients at risk of developing either chronic kidney disease or acute kidney injury and as a treatment target for acute kidney injury. However, large multicenter clinical trials are required to test these propositions. A renewed effort to understand the renal physiology underlying the response to amino acid infusion is also warranted.

Renal medullary interstitial infusion is a flawed technique for examining vasodilator mechanisms in anesthetized rabbits.

Publisher: Elsevier BV

Date: 05-2002

DOI: 10.1016/S1056-8719(02)00230-7

Targeting oxidative stress in septic acute kidney injury: From theory to practice

Publisher: MDPI AG

Date: 25-08-2021

DOI: 10.3390/JCM10173798

Abstract: Sepsis is the leading cause of acute kidney injury (AKI) and leads to increased morbidity and mortality in intensive care units. Current treatments for septic AKI are largely supportive and are not targeted towards its pathophysiology. Sepsis is commonly characterized by systemic inflammation and increased production of reactive oxygen species (ROS), particularly superoxide. Concomitantly released nitric oxide (NO) then reacts with superoxide, leading to the formation of reactive nitrogen species (RNS), predominantly peroxynitrite. Sepsis-induced ROS and RNS can reduce the bioavailability of NO, mediating renal microcirculatory abnormalities, localized tissue hypoxia and mitochondrial dysfunction, thereby initiating a propagating cycle of cellular injury culminating in AKI. In this review, we discuss the various sources of ROS during sepsis and their pathophysiological interactions with the immune system, microcirculation and mitochondria that can lead to the development of AKI. We also discuss the therapeutic utility of N-acetylcysteine and potential reasons for its efficacy in animal models of sepsis, and its inefficacy in ameliorating oxidative stress-induced organ dysfunction in human sepsis. Finally, we review the pre-clinical studies examining the antioxidant and pleiotropic actions of vitamin C that may be of benefit for mitigating septic AKI, including future implications for clinical sepsis.

Morbidity and utilisation of healthcare services among people with cardiometabolic disease in three diverse regions of rural India

Publisher: SAGE Publications

Date: 06-02-2023

DOI: 10.1177/17423953231153550

Abstract: To assess the prevalence and determinants of cardiometabolic disease (CMD), and the factors associated with healthcare utilisation, among people with CMD. Using a cross-sectional design, 11,657 participants were recruited from randomly selected villages in 3 regions located in Kerala and Andhra Pradesh from 2014 to 2016. Multivariable logistic regression was used to identify factors independently associated with CMD and healthcare utilisation (public or private). Thirty-four per cent (n = 3629) of participants reported having ≥1 CMD, including hypertension (21.6%), diabetes (11.6%), heart disease (5.0%) or chronic kidney disease (CKD) (1.6%). The prevalence of CMD was progressively greater in regions of greater socio-economic position (SEP), ranging from 19.1% to 40.9%. Among those with CMD 41% had sought any medical advice in the last month, with only 19% utilising public health facilities. Among people with CMD, those with health insurance utilised more healthcare (age-gender adjusted odds ratio (AOR) (95% confidence interval (CI)): 1.31 (1.13, 1.51)) as did those who reported accessing private rather than public health services (1.43 (1.23, 1.66)). The prevalence of CMD is high in these regions of rural India and is positively associated with indices of SEP. The utilisation of outpatient health services, particularly public services, among those with CMD is low.

Prenatal glucocorticoid exposure in the sheep alters renal development in utero: implications for adult renal function and blood pressure control

Publisher: American Physiological Society

Date: 08-2011

DOI: 10.1152/AJPREGU.00818.2010

Abstract: Treatment of the pregnant ewe with glucocorticoids early in pregnancy results in offspring with hypertension. This study examined whether glucocorticoids can reduce nephron formation or alter gene expression for sodium channels in the late gestation fetus. Sodium channel expression was also examined in 2-mo-old lambs, while arterial pressure and renal function was examined in adult female offspring before and during 6 wk of increased dietary salt intake. Pregnant ewes were treated with saline (SAL), dexamethasone (DEX 0.48 mg/h) or cortisol (CORT 5 mg/h) over days 26–28 of gestation (term = 150 days). At 140 days of gestation, glomerular number in CORT and DEX animals was 40 and 25% less, respectively, compared with SAL controls. Real-time PCR showed greater gene expression for the epithelial sodium channel (α-, β-, γ-subunits) and Na + -K + -ATPase (α-, β-, γ-subunits) in both the DEX and CORT group fetal kidneys compared with the SAL group with some of these changes persisting in 2-mo-old female offspring. In adulthood, sheep treated with dexamethasone or cortisol in utero had elevated arterial pressure and an apparent increase in single nephron glomerular filtration rate, but global renal hemodynamics and excretory function were normal and arterial pressure was not salt sensitive. Our findings show that the nephron-deficit in sheep exposed to glucocorticoids in utero is acquired before birth, so it is a potential cause, rather than a consequence, of their elevated arterial pressure in adulthood. Upregulation of sodium channels in these animals could provide a mechanistic link to sustained increases in arterial pressure in cortisol- and dexamethasone-exposed sheep, since it would be expected to promote salt and water retention during the postnatal period.

Comparison of the oxytocin response to water-deprivation, hyperosmolarity and administration of morphine or naltrexone in lactating and virgin female rats

Publisher: Elsevier BV

Date: 11-1988

DOI: 10.1016/0304-3940(88)90291-1

Abstract: In rats, lactation is accompanied by changes in the pattern of oxytocin (OXY) release associated with the onset of reflex milk ejection during suckling. The present study attempted to identify further differences between OXY release in virgin and lactating rats. Basal levels of plasma immunoreactive (ir)-OXY and the OXY responses to both water-deprivation and intraperitoneal administration of hypertonic saline were lower in lactating than in virgin female rats. Subcutaneous administration of morphine (0.01-10.0 mg/kg) was followed by a dose-related reduction in plasma ir-OXY levels in virgin but not lactating rats. The OXY response to naltrexone (3 mg/kg) was similar in both types of animal. Lactation-associated changes in the control of metabolism and/or release of OXY may involve changes in neurohypophysial morphology but do not involve alteration of tonic endogenous opioid influences on OXY release.

Angiotensin II and nitric oxide in neural control of intrarenal blood flow

Publisher: American Physiological Society

Date: 09-2005

DOI: 10.1152/AJPREGU.00477.2004

Abstract: We investigated the roles of the renin-angiotensin system and the significance of interactions between angiotensin II and nitric oxide, in responses of regional kidney perfusion to electrical renal nerve stimulation (RNS) in pentobarbital sodium-anesthetized rabbits. Under control conditions, RNS (0.5–8 Hz) reduced total renal blood flow (RBF −89 ± 3% at 8 Hz) and cortical perfusion (CBF −90 ± 2% at 8 Hz) more than medullary perfusion (MBF −55 ± 5% at 8 Hz). Angiotensin II type 1 (AT 1 )-receptor antagonism (candesartan) blunted RNS-induced reductions in RBF ( P = 0.03), CBF ( P = 0.007), and MBF ( P = 0.04), particularly at 4 and 8 Hz. Nitric oxide synthase inhibition with N G -nitro-l-arginine (l-NNA) enhanced RBF ( P = 0.003), CBF ( P = 0.001), and MBF ( P = 0.03) responses to RNS, particularly at frequencies of 2 Hz and less. After candesartan pretreatment, l-NNA significantly enhanced RNS-induced reductions in RBF ( P = 0.04) and CBF ( P = 0.007) but not MBF ( P = 0.66). Renal arterial infusion of angiotensin II (5 ng·kg −1 ·min −1 ) selectively enhanced responses of MBF to RNS in l-NNA-pretreated but not in vehicle-pretreated rabbits. In contrast, greater doses of angiotensin II (5–15 ng·kg −1 ·min −1 ) blunted responses of MBF to RNS in rabbits with intact nitric oxide synthase. These results suggest that endogenous angiotensin II enhances, whereas nitric oxide blunts, neurally mediated vasoconstriction in the renal cortical and medullary circulations. In the renal medulla, but not the cortex, angiotensin II also appears to be able to blunt neurally mediated vasoconstriction.

Diversity of responses of renal cortical and medullary blood flow to vasoconstrictors in conscious rabbits

Publisher: Wiley

Date: 08-2000

DOI: 10.1046/J.1365-201X.2000.00741.X

Abstract: The medullary microcirculation receives only about 10% of total renal blood flow, but plays a critical role in long-term arterial pressure regulation, so we need to better understand its regulation. Although there is evidence that circulating and locally acting hormones can differentially affect cortical and medullary blood flow in anaesthetized animals, there is little information from studies in conscious animals. This study is aimed (i) to develop a method for chronic measurement of cortical and medullary blood flow in conscious rabbits, and (ii) to test whether renal cortical and medullary blood flow can be differentially affected by intravenous (i.v.) infusions of various vasoconstrictor hormones in conscious rabbits. At preliminary operations, rabbits were equipped with single-fibre laser-Doppler flowprobes in the (left) renal cortex and medulla, and Transonic flowprobes for measuring cardiac output and renal blood flow. Intravenous angiotensin II (300 ng kg(-1) min(-1)), [Phe2,Ile3,Orn8]-vasopressin (30 ng kg(-1) min(-1)), noradrenaline (300 ng kg(-1) min(-1)), endothelin-1 (20 ng kg(-1) min(-1)) and N G-nitro-L-arginine (10 mg kg(-1)) increased mean arterial pressure (by 10-45% of baseline) and reduced heart rate (by 16-35%) and cardiac output (by 16-45%). Consistent with previous observations in anaesthetized rabbits, all treatments except [Phe2,Ile3, Orn8]-vasopressin reduced renal blood flow (13-63%) and cortical blood flow (16-47%), but medullary blood flow was significantly reduced only by [Phe2,Ile3,Orn8]-vasopressin (41%) and N G-nitro-L-arginine (42%). The ersity of these responses of cortical and medullary blood flow to i.v. infusions of vasoconstrictors provides further evidence for physiological roles of circulating and local hormones in the differential regulation of regional kidney blood flow.

Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep

Publisher: Wiley

Date: 03-2006

DOI: 10.1113/JPHYSIOL.2005.102186

Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow

Publisher: Wiley

Date: 18-08-2016

DOI: 10.1113/JP270731

Do different levels and patterns of sympathetic activation all provoke renal vasoconstriction?

Publisher: Elsevier BV

Date: 03-1998

DOI: 10.1016/S0165-1838(98)00010-1

Abstract: Renal sympathetic nerve activity (RSNA) is postulated to influence renal function in selective ways with changes in renal hemodynamics only occurring during high stimulus intensities. The aim of this study was to determine the renal blood flow (RBF) response to a number of stimuli designed to increase RSNA by a modest amount and assess the possibility that different afferent stimuli produce differential levels of vasoconstriction by differentially altering the pattern of RSNA. Experiments were performed in eight conscious rabbits subjected to 20 min periods of three stimuli noise stress, air jet stress or hypoxia (10% O2). RSNA was significantly increased 12 +/- 4, 31 +/- 8 and 14 +/- 5% (means of 20 min periods +/- SEM) and these effects were mirrored in the significant changes in RBF over the period of each stimuli with mean reductions of 8 +/- 1, 10 +/- 3 and 8 +/- 4% during noise, air jet stress and hypoxia respectively. Changes in plasma renin activity did not occur without changes in RBF. With regard to the pattern of RSNA discharges, hypoxia selectively increased the litude (number of recruited nerves) while noise and air jet stress increased both the litude and frequency of discharges. The role of the renal nerves in these responses and in providing a tonic level of vasoconstriction within the kidney, was demonstrated in experiments on a group of eight renal denervated animals. The renal denervated rabbits had greater resting RBF than the intact rabbits (54 +/- 1 denervated vs. 38 +/- 1 ml min(-1) intact), and RBF was not altered by any of the afferent stimuli. We conclude that small changes in RSNA, irrespective of the stimulus, modulate renal blood flow.

Don't be so BOLD: Potential limitations in the use of BOLD MRI for studies of renal oxygenation [7]

Publisher: Elsevier BV

Date: 06-2007

DOI: 10.1038/SJ.KI.5002321

Haemodynamic characteristics of hypertension induced by prenatal cortisol exposure in sheep

Publisher: Wiley

Date: 10-2009

DOI: 10.1111/J.1440-1681.2009.05180.X

Abstract: 1. Administration of glucocorticoids to ewes early in pregnancy results in offspring with hypertension in adulthood. The hypertension in female offspring exposed to dexamethasone is associated with increased cardiac output, but whether this is also true in cortisol-exposed offspring is unknown. 2. Systemic haemodynamic variables were measured under basal conditions in castrated male and female adult sheep exposed to cortisol (5 mg/h) or saline (0.19 mL/h) from 26 to 28 days of gestation. To examine the contribution of the autonomic nervous system to maintenance of basal arterial pressure in established hypertension in cortisol-exposed sheep, responses to adrenoceptor blockade (intravenous infusion of 0.15 mg/kg per h phentolamine plus 0.4 mg/kg per h propranolol) and ganglionic blockade (intravenous infusion of 125 mg/h hexamethonium) were examined in castrated male offspring. 3. Mean arterial pressure and calculated systemic vascular resistance were 9% and 17% greater, whereas cardiac output tended to be 8% less, in cortisol-compared with saline-exposed sheep. These effects were not sex dependent. The depressor response to ganglionic blockade and the initial phase of the depressor response to adrenoceptor blockade were greater in cortisol-compared with saline-exposed sheep. 4. These results indicate that hypertension in offspring exposed prenatally to cortisol is associated with increased total peripheral resistance, mimicking observations in human patients with chronic hypertension. Furthermore, the increased vascular resistance appears to be dependent, at least in part, on an increased effect of sympathetic vasomotor drive. Taken together with previous findings, the present observations suggest that prenatal cortisol and dexamethasone programme altered adult cardiovascular function via distinct mechanistic pathways.

Effects of chronic sympatho-inhibition on renal excretory function in renovascular hypertension

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-2011

DOI: 10.1097/HJH.0B013E3283449529

Local maximum oxygen disappearance rate has limited utility as a measure of local renal tissue oxygen consumption

Publisher: Elsevier BV

Date: 05-2010

DOI: 10.1016/J.VASCN.2010.01.007

Abstract: Methods for measurement of local oxygen consumption (VO2) are required to allow development of treatments for kidney disease that target kidney oxygen dysregulation. In anaesthetized rabbits, we determined whether local oxygen disappearance rate (ODR) during complete renal ischaemia reflects tissue VO2 in the kidney and in hindlimb skeletal muscle (biceps femoris). Whole kidney VO2 was determined under conditions employed to alter oxygen consumption. The ureter was ligated to reduce VO2 (n=6) or the mitochondrial uncoupler 2,4-dinitrophenol was administered to increase VO2 (n=6). An additional 10 rabbits were studied which received neither treatment. Immediately following VO2 measurements, oxygen partial pressure (PO2) was measured, over the first 60s after abrupt cardiac arrest, using fluorescence optodes and in a subset of experiments (n=6), Clark electrodes. Parallel experiments were performed in hindlimb skeletal muscle (biceps femoris). ODR in the renal cortex and medulla, and in biceps femoris, was linear during the first approximately 15s after cardiac arrest (r(2) approximately 0.98). Using fluorescence optodes, maximum ODR averaged across all 22 rabbits in which the kidney was studied was -0.75+/-0.09 and -0.60+/-0.06 mm Hg/s respectively in the renal cortex and medulla. Maximum ODR averaged across all 10 rabbits in which the biceps femoris was studied was -0.30+/-0.06 mm Hg/s. ODR increased at greater initial PO2 only in the renal cortex. ODR in neither the renal medulla nor biceps femoris varied with whole organ VO2, although renal cortical ODR normalized for initial PO2 was significantly correlated with whole organ VO2 (r(2)=0.19). Maximum ODR obtained by Clark electrode was approximately four-fold greater than that obtained by fluorescence optode. Because ODR correlates poorly with whole organ VO2, it likely has limited utility as a measure of local VO2.

Another step forward for methods for studying renal oxygenation

Publisher: Elsevier BV

Date: 09-2019

DOI: 10.1016/J.KINT.2019.05.010

Abstract: All available methods for assessing renal oxygenation are limited either in terms of their temporal or spatial resolution, their ability to quantify tissue oxygen tension (PO

Prostaglandins and nitric oxide in regional kidney blood flow responses to renal nerve stimulation

Publisher: Springer Science and Business Media LLC

Date: 03-08-2004

DOI: 10.1007/S00424-004-1320-3

Abstract: We examined the roles of cyclooxygenase products and of interactions between the cyclooxygenase and nitric oxide systems in the mechanisms underlying the relative insensitivity of medullary perfusion to renal nerve stimulation (RNS) in anaesthetized rabbits. To this end we examined the effects of ibuprofen and N(G)-nitro-L: -arginine (L-NNA), both alone and in combination, on the responses of regional kidney perfusion to RNS. Under control conditions, RNS produced frequency-dependent reductions in total renal blood flow (RBF -82+/-3% at 6 Hz), cortical laser-Doppler flux (CLDF -84+/-4% at 6 Hz) and, to a lesser extent, medullary laser-Doppler flux (MLDF -46+/-7% at 6 Hz). Ibuprofen did not affect these responses significantly, suggesting that cyclooxygenase products have little net role in modulating renal vascular responses to RNS. L-NNA enhanced RBF (P=0.002), CLDF (P=0.03) and MLDF (P=0.03) responses to RNS. As we have shown previously, this effect of L-NNA was particularly prominent for MLDF at RNS frequencies < or = 1.5 Hz. Subsequent administration of ibuprofen, in L-NNA-pretreated rabbits, did not affect responses to RNS significantly. We conclude that counter-regulatory actions of NO, but not of prostaglandins, partly underlie the relative insensitivity of medullary perfusion to renal nerve activation.

Strategies that improve renal medullary oxygenation during experimental cardiopulmonary bypass may mitigate postoperative acute kidney injury

Publisher: Elsevier BV

Date: 06-2019

DOI: 10.1016/J.KINT.2019.01.032

Abstract: Renal medullary hypoxia may contribute to cardiac surgery-associated acute kidney injury (AKI). However, the effects of cardiopulmonary bypass (CPB) on medullary oxygenation are poorly understood. Here we tested whether CPB causes medullary hypoxia and whether medullary oxygenation during CPB can be improved by increasing pump flow or mean arterial pressure (MAP). Twelve sheep were instrumented to measure whole kidney, medullary, and cortical blood flow and oxygenation. Five days later, under isoflurane anesthesia, CPB was initiated at a pump flow of 80 mL kg

Renal effects of infusion of rilmenidine and guanabenz in conscious dogs: contribution of peripheral and central nervous system alpha 2-adrenoceptors.

Publisher: Wiley

Date: 09-1995

DOI: 10.1111/J.1476-5381.1995.TB16373.X

Abstract: 1. We tested the renal effects of the alpha 2-adrenoceptor agonists, rilmenidine and guanabenz and the antagonists, 2-methoxyidazoxan and idazoxan, in conscious dogs. Our aim was to test the hypothesis that putative imidazoline (I) receptors influence renal function. We reasoned that since rilmenidine and guanabenz are selective for I1- and I2-binding sites respectively, an influence of one of these receptive sites on renal function would be reflected in qualitative differences between the effects of these agents. Moreover, effects mediated by putative I-receptors should be relatively resistant to antagonism by the selective alpha 2-adrenoceptor antagonist, 2-methoxyidazoxan. Since the effects of these drugs on renal function could be mediated in the central nervous system or periphery, the dogs were studied under both normal and ganglion-blocked conditions. 2. In dogs with intact autonomic reflexes, 2-methoxyidazoxan (15 micrograms kg-1 plus 0.6 micrograms kg-1 min-1) produced effects consistent with a generalized increase in sympathetic drive, including increases in mean arterial pressure and plasma renin activity, and a reduction in sodium excretion. In ganglion-blocked dogs, 2-methoxyidazoxan reduced sodium excretion but had no discernible effect on systemic or renal haemodynamics. We conclude that an alpha 2-adrenoceptor-mediated mechanism in the central nervous system tonically inhibits sympathetic drive in the conscious dog. 3. In ganglion-blocked dogs idazoxan (3-300 micrograms kg-1) dose-dependently increased arterial pressure. This was not abolished by concomitant administration of 2-methoxyidazoxan (0.3-30 micrograms kg-1). The pressor effect of idazoxan is therefore probably mediated by an agonist action at alpha 1-adrenoceptors. 4. The effects of infusions of rilmenidine (0.1-1.0 mg kg-1) and guanabenz (10-100 micrograms kg-1) were indistinguishable. They comprised dose-dependent increases in mean arterial pressure, urine excretion, and glomerular filtration rate (the latter in ganglion blocked dogs only), and dose-dependent reductions in heart rate, renal blood flow and sodium excretion (only in dogs with intact autonomic reflexes). All of these effects were antagonized by 2-methoxyidazoxan. 5. We conclude that the renal effects of rilmenidine and guanabenz infusions in conscious dogs are predominantly, if not completely, attributable to activation of alpha 2-adrenoceptors. Our results do not support the hypothesis that putative I-receptors contribute towards the renal effects of these agents.

Evidence that renal arginine transport is impaired in spontaneously hypertensive rats

Publisher: American Physiological Society

Date: 15-06-2012

DOI: 10.1152/AJPRENAL.00084.2011

Abstract: Low renal nitric oxide (NO) bioavailability contributes to the development and maintenance of chronic hypertension. We investigated whether impaired l-arginine transport contributes to low renal NO bioavailability in hypertension. Responses of renal medullary perfusion and NO concentration to renal arterial infusions of the l-arginine transport inhibitor l-lysine (10 μmol·kg −1 ·min −1 30 min) and subsequent superimposition of l-arginine (100 μmol·kg −1 ·min −1 30 min), the NO synthase inhibitor N G -nitro-l-arginine (2.4 mg/kg iv bolus), and the NO donor sodium nitroprusside (0.24 μg·kg −1 ·min −1 ) were examined in Sprague-Dawley rats (SD) and spontaneously hypertensive rats (SHR). Renal medullary perfusion and NO concentration were measured by laser-Doppler flowmetry and polarographically, respectively, 5.5 mm below the kidney surface. Renal medullary NO concentration was less in SHR (53 ± 3 nM) compared with SD rats (108 ± 12 nM P = 0.004). l-Lysine tended to reduce medullary perfusion (−15 ± 7% P = 0.07) and reduced medullary NO concentration (−9 ± 3% P = 0.03) while subsequent superimposition of l-arginine reversed these effects of l-lysine in SD rats. In SHR, l-lysine and subsequent superimposition of l-arginine did not significantly alter medullary perfusion or NO concentration. Collectively, these data suggest that renal l-arginine transport is impaired in SHR. Renal l-[ 3 H]arginine transport was less in SHR compared with SD rats ( P = 0.01). Accordingly, we conclude that impaired arginine transport contributes to low renal NO bioavailability observed in the SHR kidney.

Intrarenal oxygenation: Unique challenges and the biophysical basis of homeostasis

Publisher: American Physiological Society

Date: 11-2008

DOI: 10.1152/AJPRENAL.90230.2008

Abstract: The kidney is faced with unique challenges for oxygen regulation, both because its function requires that perfusion greatly exceeds that required to meet metabolic demand and because vascular control in the kidney is dominated by mechanisms that regulate glomerular filtration and tubular reabsorption. Because tubular sodium reabsorption accounts for most oxygen consumption (V̇o 2 ) in the kidney, renal V̇o 2 varies with glomerular filtration rate. This provides an intrinsic mechanism to match changes in oxygen delivery due to changes in renal blood flow (RBF) with changes in oxygen demand. Renal V̇o 2 is low relative to supply of oxygen, but diffusional arterial-to-venous (AV) oxygen shunting provides a mechanism by which oxygen superfluous to metabolic demand can bypass the renal microcirculation. This mechanism prevents development of tissue hyperoxia and subsequent tissue oxidation that would otherwise result from the mismatch between renal V̇o 2 and RBF. Recent evidence suggests that RBF-dependent changes in AV oxygen shunting may also help maintain stable tissue oxygen tension when RBF changes within the physiological range. However, AV oxygen shunting also renders the kidney susceptible to hypoxia. Given that tissue hypoxia is a hallmark of both acute renal injury and chronic renal disease, understanding the causes of tissue hypoxia is of great clinical importance. The simplistic paradigm of oxygenation depending only on the balance between local perfusion and V̇o 2 is inadequate to achieve this goal. To fully understand the control of renal oxygenation, we must consider a triad of factors that regulate intrarenal oxygenation: local perfusion, local V̇o 2 , and AV oxygen shunting.

Limited Oxygen Availability In Utero May Constrain the Evolution of Live Birth in Reptiles

Publisher: University of Chicago Press

Date: 02-2013

DOI: 10.1086/668827

Abstract: Although viviparity (live birth) has evolved from oviparity (egg laying) at least 140 times in vertebrates, nearly 120 of these independent events occurred within a single reptile taxon. Surprisingly, only squamate reptiles (lizards and snakes) are capable of facilitating embryonic development to increasingly advanced stages inside the mother during extended periods of oviducal egg retention. Viviparity has never evolved in turtle lineages, presumably because embryos enter and remain in an arrested state until after eggs are laid, regardless of the duration of egg retention. Until now, the limiting factor that initiates and maintains developmental arrest has remained elusive. Here, we show that oviducal hypoxia arrests embryonic development. We demonstrate that hypoxia can maintain developmental arrest after oviposition and that subsequent exposure of arrested embryos to normoxia triggers resumption of their development. We discovered remarkably low oxygen partial pressure in the oviducts of gravid turtles and found that secretions produced by the oviduct retard oxygen diffusion. Our results suggest that an extremely hypoxic environment in the oviduct arrests embryonic development and may constrain the evolution of viviparity in turtles, with the reduced diffusive capacity of oviducal secretions possibly creating or contributing to this hypoxia. We anticipate that these findings will allow us to better understand the mechanisms underlying the evolutionary transition between reproductive modes.

Dynamic responses of renal oxygenation at the onset of cardiopulmonary bypass in sheep and man

Publisher: SAGE Publications

Date: 12-05-2021

DOI: 10.1177/02676591211013640

Abstract: The renal medulla is susceptible to hypoxia during cardiopulmonary bypass (CPB), which may contribute to the development of acute kidney injury. But the speed of onset of renal medullary hypoxia remains unknown. We continuously measured renal medullary oxygen tension (MPO 2 ) in 24 sheep, and urinary PO 2 (UPO 2 ) as an index of MPO 2 in 92 patients, before and after induction of CPB. In laterally recumbent sheep with a right thoracotomy ( n = 20), even before CPB commenced MPO 2 fell from (mean ± SEM) 52 ± 4 to 41 ±5 mmHg simultaneously with reduced arterial pressure (from 108 ± 5 to 88 ± 5 mmHg). In dorsally recumbent sheep with a medial sternotomy ( n = 4), MPO 2 was even more severely reduced (to 12 ± 12 mmHg) before CPB. In laterally recumbent sheep in which a crystalloid prime was used ( n = 7), after commencing CPB, MPO 2 fell abruptly to 24 ±6 mmHg within 20–30 minutes. MPO 2 during CPB was not improved by adding donor blood to the prime ( n = 13). In patients undergoing cardiac surgery, UPO 2 fell by 4 ± 1 mmHg and mean arterial pressure fell by 7 ± 1 mmHg during the 30 minutes before CPB. UPO 2 then fell by a further 12 ± 2 mmHg during the first 30 minutes of CPB but remained relatively stable for the remaining 24 minutes of observation. Renal medullary hypoxia is an early event during CPB. It starts to develop even before CPB, presumably due to a pressure-dependent decrease in renal blood flow. Medullary hypoxia during CPB appears to be promoted by hypotension and is not ameliorated by increasing blood hemoglobin concentration.

Responses Of Regional Kidney Perfusion To Vasoconstrictors In Anaesthetized Rabbits: Dependence On Agent And Renal Artery Pressure

Publisher: Wiley

Date: 12-2000

DOI: 10.1046/J.1440-1681.2000.03377.X

Abstract: 1. We tested the effects of intravenous infusions of angiotensin II (AngII 300 ng/kg per min) and the vasopressin V1 receptor agonist [Phe2,Ile3,Orn8]-vasopressin (30 ng/kg per min) on regional kidney perfusion in an extracorporeal circuit model in anaesthetized rabbits in which renal artery pressure (RAP) can be set independently of systemic mean arterial pressure. To test whether the level of RAP can influence the renal vascular response to [Phe2,Ile3,Orn8]-vasopressin, we compared its effects when RAP was initially set at approximately 65 mmHg with those when RAP was set at approximately 130 mmHg. 2. When RAP was initially set at approximately 65 mmHg, a 20min infusion of AngII increased RAP (13%) and reduced renal blood flow (RBF 50%) and cortical perfusion (CBF 43%). Medullary perfusion (MBF) transiently increased during the first 10 min of infusion, but was not significantly different from control levels during the final 5 min of infusion. 3. When RAP was initially set at approximately 65 mmHg, a 20 min infusion of [Phe2,Ile3,Orn8]-vasopressin increased RAP (9%) and reduced RBF (21%) MBF was reduced by 57%, but CBF was reduced by only 15%. In contrast, when RAP was initially set at approximately 130 mmHg, infusion of [Phe2,Ile3,Orn8]-vasopressin reduced RAP (7%) and increased RBF (13%). In these experiments, MBF was reduced by 38%, but CBF increased by 6%. 4. Our experiments show that AngII preferentially reduces CBF, while [Phe2,Ile3,Orn8]-vasopressin preferentially reduces MBF. The renal vascular responses to [Phe2,Ile3,Orn8]-vasopressin appear to be profoundly affected by the level of RAP, because increasing RAP from approximately 65 to approximately 130 mmHg transforms its cortical vasoconstrictor effect into cortical vasodilatation while leaving the response of the medullary microvasculature relatively unchanged. Whether renal vascular responses to other vasoactive agents (e.g. AngII) are similarly affected by the level of RAP remains to be determined.

Positive allosteric modulation of GABAA receptors attenuates high blood pressure in Schlager hypertensive mice

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2017

DOI: 10.1097/HJH.0000000000001210

Alterations in regional kidney oxygenation during expansion of extracellular fluid volume in conscious healthy sheep

Publisher: American Physiological Society

Date: 12-2018

DOI: 10.1152/AJPREGU.00247.2018

Abstract: Expansion of extracellular fluid volume with crystalloid solutions is a common medical intervention, but its effects on renal cortical and medullary oxygenation are poorly understood. Therefore, we instrumented sheep under general anesthesia to enable continuous measurement of systemic and renal hemodynamics, global renal oxygen delivery and consumption, and intrarenal tissue perfusion and oxygen tension (Po 2 ) in conscious animals ( n = 7). The effects of three sequential intermittent infusions of 500 ml of compound sodium lactate solution, administered at hourly intervals, were determined. Volume expansion induced transient increases in mean arterial pressure (+7 ± 2%), central venous pressure (+50 ± 19%), and cardiac output (+15 ± 3%). There were sustained increases in renal medullary tissue Po 2 (+35 ± 10%) despite increases in global renal oxygen consumption (+66 ± 18%) and renal oxygen extraction (+64 ± 8%). Volume expansion did not significantly alter renal blood flow, renal oxygen delivery, or medullary perfusion. The sustained increase in medullary Po 2 was paralleled by increased bladder urine Po 2 (34 ± 4%). Cortical perfusion and Po 2 did not change significantly. Our findings indicate that extracellular fluid volume expansion can increase renal medullary oxygenation, providing a potential mechanistic basis for its use as prophylaxis against iatrogenic acute kidney injury. They also indicate that continuous measurement of bladder urine Po 2 could be used to monitor the effects of volume expansion on medullary oxygenation. However, the mechanisms mediating increased medullary oxygenation during volume expansion remain to be determined.

Corrigendum

Publisher: American Physiological Society

Date: 10-2004

DOI: 10.1152/AJPREGU.00468.2004

Clonidine restores pressor responsiveness to phenylephrine and angiotensin II in ovine sepsis

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 07-2015

DOI: 10.1097/CCM.0000000000000963

Compensatory responses to nephron deficiency: adaptive or maladaptive?

Publisher: Wiley

Date: 17-02-2014

DOI: 10.1111/NEP.12198

Abstract: Compensatory renal growth is a characteristic adaptation to reduced renal mass that appears to recapitulate the normal pattern of maturation of the kidney during the postnatal period. Hypertrophy of tubules (predominantly the proximal tubule) and glomeruli is accompanied by increased single nephron glomerular filtration rate and tubular reabsorption of sodium. We propose that the very factors, which contribute to the increase in growth and function of the renal tubular system, are, in the long term, the precursors to the development of hypertension in those with a nephron deficit. The increase in single nephron glomerular filtration rate is dependent on multiple factors, including reduced renal vascular resistance associated with an increased influence of nitric oxide, and a rightward shift in the tubuloglomerular feedback curve, both of which contribute to the normal maturation of renal function. The increased influence of nitric oxide appears to contribute to the reduction in tubuloglomerular feedback sensitivity and facilitate the initial increase in glomerular filtration rate. The increased single-nephron filtered load associated with nephron deficiency may promote hypertrophy of the proximal tubule and so increased reabsorption of sodium, and thus a rightward shift in the pressure natriuresis relationship. Normalization of sodium balance can then only occur at the expense of chronically increased arterial pressure. Therefore, alterations/adaptations in tubules and glomeruli in response to nephron deficiency may increase the risk of hypertension and renal disease in the long-term.

Hypoxia as a novel method for preventing movement-induced mortality during translocation of turtle eggs

Publisher: Elsevier BV

Date: 12-2017

DOI: 10.1016/J.BIOCON.2017.10.009

INTRODUCTION

Publisher: Wiley

Date: 26-09-2006

DOI: 10.1111/J.1440-1681.2006.04471.X

Metalloendopeptidases EC 3.4.24.15 and EC 3.4.24.16 And Bradykinin B₂ Receptors Do Not Play Important Roles In Renal Wrap Hypertension In Rabbits

Publisher: Wiley

Date: 30-10-2001

DOI: 10.1046/J.1440-1681.2001.03532.X

Abstract: 1. The aim of the present study was to determine the effects of the metalloendopeptidase (EP) 24.15 and 24.16 inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA-2) on haemodynamics and renal function in conscious rabbits with two-kidney, two-wrapped hypertension. We have also examined the role of endogenous bradykinin in the maintenance phase of this form of renovascular hypertension and whether inhibition of bradykinin degradation contributes to any potential effects of JA-2. 2. In two preliminary operations, rabbits were equipped with transit-time ultrasound flow probes for measuring cardiac output (CO) and renal blood flow (RBF) and had both kidneys wrapped in cellophane. Starting 4 weeks after the last operation, rabbits underwent four studies (3-5 days apart), during which they were treated with combinations of the bradykinin B2 receptor antagonist icatibant or its vehicle (1 mL/kg bodyweight 0.9% w/v NaCl) and JA-2 or its vehicle (1 mL/kg of a 5% w/v 2-hydroxypropyl-beta-cyclodextrin, 2.5% v/v dimethylsulphoxide solution). Renal function was monitored using standard renal clearance methods. 3. Icatibant (10 microg/kg) had no significant effects on systemic haemodynamic variables (mean arterial pressure, heart rate or CO), renal haemodynamic variables (RBF or glomerular filtration rate), urine flow or sodium excretion. At 5 mg/kg plus 3 mg/kg per h, JA-2 also did not affect any of these variables, either after icatibant vehicle treatment or after icatibant treatment. 4. Our data do not support major roles for endogenous bradykinin or bradykinin degradation by EP 24.15/24.16 in the control of systemic and renal haemodynamics or renal excretory function in two-kidney, two-wrapped hypertension in rabbits.

Multitasking: a challenge for the kidney

Publisher: American Physiological Society

Date: 04-2018

DOI: 10.1152/AJPREGU.00011.2018

Variable responses of regional renal oxygenation and perfusion to vasoactive agents in awake sheep

Publisher: American Physiological Society

Date: 15-11-2015

DOI: 10.1152/AJPREGU.00228.2015

Abstract: Vasoactive agents are used in critical care to optimize circulatory function, but their effects on renal tissue oxygenation in the absence of anesthesia remain largely unknown. Therefore, we assessed the effects of multiple vasoactive agents on regional kidney oxygenation in awake sheep. Sheep were surgically instrumented with pulmonary and renal artery flow probes, and combination fiber-optic probes, in the renal cortex and medulla, comprising a fluorescence optode to measure tissue Po 2 and a laser-Doppler probe to assess tissue perfusion. Carotid arterial and renal venous cannulas enabled measurement of arterial pressure and total renal oxygen delivery and consumption. Norepinephrine (0.1 or 0.8 μg·kg −1 ·min −1 ) dose-dependently reduced cortical and medullary laser Doppler flux (LDF) and Po 2 without significantly altering renal blood flow (RBF), or renal oxygen delivery or consumption. Angiotensin II (9.8 ± 2.1 μg/h) reduced RBF by 21%, renal oxygen delivery by 28%, oxygen consumption by 18%, and medullary Po 2 by 38%, but did not significantly alter cortical Po 2 or cortical or medullary LDF. Arginine vasopressin (3.3 ± 0.5 μg/h) caused similar decreases in RBF and renal oxygen delivery, but did not significantly alter renal oxygen consumption or cortical or medullary LDF or Po 2 . Captopril had no observable effects on cortical or medullary LDF or Po 2 , at a dose that increased renal oxygen delivery by 24%, but did not significantly alter renal oxygen consumption. We conclude that vasoactive agents have erse effects on regional kidney oxygenation in awake sheep that are not predictable from their effects on LDF, RBF, or total renal oxygen delivery and consumption.

Synchronised nesting aggregations are associated with enhanced capacity for extended embryonic arrest in olive ridley sea turtles

Publisher: Springer Science and Business Media LLC

Date: 05-07-2019

DOI: 10.1038/S41598-019-46162-3

Abstract: Sea turtle species in the genus Lepidochelys exhibit an unusual behavioural polymorphism, nesting in both aggregations and solitarily. Aggregated nesting events, termed ‘arribadas’, involve hundreds of thousands of females congregating at a single nesting beach over a few days to oviposit their eggs. Aggregate and solitary nesting behaviours are associated with distinct inter-nesting intervals, three and four weeks for non-arribada and arribada nesters respectively. Consequently, embryos are maintained in pre-ovipositional embryonic arrest in the hypoxic oviduct for different lengths of time depending on the mother’s reproductive behaviour. However, sea turtle embryos are limited in their capacity to remain in arrest and will subsequently die if held in hypoxia too long. Here, we tested whether embryos oviposited during arribada or non-arribada nesting differ in their capacity to be maintained in pre-ovipositional arrest. Olive ridley turtle ( Lepidochelys olivacea ) eggs from eight clutches (four from each nesting tactic) were ided among seven treatments after oviposition normoxia (control 21% O 2 ), or hypoxia (1% O 2 ) for 3, 3.5, 4, 8, 15 or 30 days, before being returned to normoxia. Arribada eggs were capable of extending pre-ovipositional arrest for longer, with some eggs from the 8- and 15-day hypoxia treatment still hatching while no non-arribada eggs hatched after more than four days in hypoxia. This difference in embryonic capacity to survive extended periods of arrest may be an important mechanism facilitating arribada behaviour by allowing longer inter-nesting intervals. Our finding provides an intriguing insight into the physiological mechanisms that are integral to this unique mass-nesting behaviour.

Glomerular surface area is normalized in mice born with a nephron deficit: no role for AT₁receptors

Publisher: American Physiological Society

Date: 03-2009

DOI: 10.1152/AJPRENAL.90359.2008

Abstract: We examined whether deficits in glomerular capillary surface area associated with a congenital nephron deficit could be corrected by glomerular hypertrophy. Using unbiased stereological techniques, we examined the time course and mode of glomerular hypertrophy in mice lacking one allele for glial cell line-derived neurotrophic factor (GDNF). These GDNF heterozygous (Het) mice are born with ∼30% less nephrons than wild-type (WT) littermates. An additional group of GDNF Het mice received the angiotensin type 1 (AT 1 )-receptor antagonist candesartan (Cand 10 mg·kg −1 ·day −1 ) from 5 wk of age to determine the role of AT 1 receptors in the compensatory hypertrophy. At 10 wk of age, the total volume of renal corpuscles, glomerular capillary surface area, and length of glomerular capillaries in the kidneys of GDNF Het mice were all markedly (∼45%) less than that of WT mice ( P 0.001). However, by 30 wk, and persisting at 60 wk of age, GDNF Het and WT mice did not significantly differ in any of these parameters. Furthermore, conscious 24-h mean arterial pressure (MAP) did not differ between GDNF Het and WT mice at any time point. MAP of GDNF Het-Cand mice was 20–30 mmHg less than that of GDNF Het-vehicle mice at all three ages, but Cand treatment did not significantly alter glomerular capillary dimensions. In conclusion, we have demonstrated that the deficit in glomerular capillary surface area associated with a congenital nephron deficit can be corrected for in adulthood by an increase in the total length of glomerular capillaries. This process does not require AT 1 receptor activation.

Structural antioxidant defense mechanisms in the mammalian and nonmammalian kidney: different solutions to the same problem?

Publisher: American Physiological Society

Date: 09-2010

DOI: 10.1152/AJPREGU.00364.2010

Abstract: Tissue oxygen levels are tightly regulated in all organs. This poses a challenge for the kidney, as its function requires blood flow, and thus, oxygen delivery to greatly exceed its metabolic requirements. Because superoxide production in the kidney is dependent on oxygen availability, tissue hyperoxia could drive oxidative stress. In the mammalian renal cortex, this problem may have been solved, in part, through a structural antioxidant defense mechanism. That is, arteries and veins are closely associated in a countercurrent arrangement, facilitating diffusional arterial-to-venous (AV) oxygen shunting. Because of this mechanism, a proportion of the oxygen delivered in the renal artery never reaches kidney tissue but instead diffuses to the closely associated renal veins, thus limiting oxygen transport to tissue. In the nonmammalian kidney, arteries and veins are not arranged in an intimate countercurrent fashion as in mammals thus AV oxygen shunting is likely less important in regulation of kidney oxygenation in these species. Instead, the kidney's blood supply is predominately of venous origin. This likely has a similar impact on tissue oxygenation as AV oxygen shunting, of limiting delivery of oxygen to renal tissue. Thus, we hypothesize the evolution of structural antioxidant mechanisms that are anatomically ergent but functionally homologous in the mammalian and nonmammalian kidney.

Endogenous endothelins and the response to electrical renal nerve stimulation in anaesthetized rabbits

Publisher: Elsevier BV

Date: 03-2007

DOI: 10.1016/J.AUTNEU.2006.08.003

Abstract: The influence of endogenous endothelins on the neural control of renal function is poorly understood. We therefore studied the effects of endothelin blockade (combined ET(A) and ET(B) receptor antagonism using TAK-044) on the acute and prolonged effects of renal nerve stimulation in rabbits, measuring renal blood flow, glomerular filtration rate (GFR), urine flow and sodium excretion. Brief (3 min) stimulation over 0.5-8 Hz produced frequency-dependent reductions in total renal blood flow, cortical blood flow and, less markedly, medullary blood flow. TAK-044 did not significantly alter basal total renal blood flow or cortical blood flow, or their responses to nerve stimulation, but significantly increased basal medullary blood flow (P<0.01) and increased the slope of the stimulation frequency-medullary blood flow relationship (P<0.05). Prolonged (20 min) stimulation at 0, 0.5 and 2 Hz produced frequency-dependent reductions in total renal blood flow, GFR, urine flow and sodium excretion, but not medullary blood flow. Pretreatment with TAK-044 did not significantly alter these responses. Thus, endogenous endothelins do not appear to either augment or lessen the effects of renal nerve activation on total renal blood flow, cortical blood flow, GFR or sodium excretion. The apparent ability of TAK-044 to enhance medullary blood flow responses to renal nerve stimulation may reflect an action of endogenous endothelins to blunt neurally mediated vasoconstriction in the medullary circulation. Alternatively, it may simply be secondary to the effects of endogenous endothelins on basal medullary blood flow.

Chronic treatment with tempol does not significantly ameliorate renal tissue hypoxia or disease progression in a rodent model of polycystic kidney disease

Publisher: Wiley

Date: 29-10-2012

DOI: 10.1111/1440-1681.12013

Abstract: In the present study, we tested whether polycystic kidney disease (PKD) is associated with renal tissue hypoxia and oxidative stress, which, in turn, contribute to the progression of cystic disease and hypertension. Lewis polycystic kidney (LPK) rats and Lewis control (Lewis) rats were treated with tempol (1 mmol/L in drinking water) from 3 to 13 weeks of age or remained untreated. The LPK rats developed polyuria, uraemia and proteinuria. At 13 weeks of age, LPK rats had greater mean arterial pressure (1.5-fold), kidney weight (sixfold) and plasma creatinine (3.5-fold) than Lewis rats. Kidneys from LPK rats were cystic and fibrotic. Renal hypoxia was evidenced by staining for pimonidazole adducts and hypoxia-inducible factor (HIF)-1α in cells lining renal cysts and upregulation of HIF-1α and its downstream targets vascular endothelial growth factor (VEGF), glucose transporter-1 (Glut-1) and heme oxygenase 1 (HO-1). However, total HO activity did not differ greatly between kidney tissue from LPK compared with Lewis rats. Renal oxidative and/or nitrosative stress was evidenced by ninefold greater immunofluorescence for 3-nitrotyrosine in kidney tissue from LPK compared with Lewis rats and a > 10-fold upregulation of mRNA for p47phox and gp91phox. Total renal superoxide dismutase (SOD) activity was sevenfold less and expression of SOD1 mRNA was 70% less in kidney tissue from LPK compared with Lewis rats. In LPK rats, tempol treatment reduced immunofluorescence for 3-nitrotyrosine and HIF1A mRNA while upregulating VEGF and p47phox mRNA expression, but otherwise had little impact on disease progression, renal tissue hypoxia or hypertension. Our findings do not support the hypothesis that oxidative stress drives hypoxia and disease progression in PKD.

Endothelial cationic amino acid transporter-1 overexpression can prevent oxidative stress and increases in arterial pressure in response to superoxide dismutase inhibition in mice

Publisher: Wiley

Date: 16-01-2014

DOI: 10.1111/APHA.12215

Abstract: Oxidative stress may play an important role in the pathogenesis of hypertension. The aim of our study is to examine whether increased expression of the predominant endothelial l-arginine transporter, cationic amino acid transporter-1 (CAT1), can prevent oxidative stress-induced hypertension. Wild-type mice (WT n = 9) and endothelial CAT1 overexpressing (CAT+) mice (n = 6) had telemetry probes implanted for the measurement of mean arterial pressure (MAP), heart rate (HR) and locomotor activity. Minipumps were implanted for infusion of the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA 30 mg kg(-1) day(-1) 14 days) or its saline vehicle. Baseline levels of MAP, HR and locomotor activity were determined before and during chronic DETCA administration. Mice were then killed, and their plasma and kidneys collected for analysis of F2 -isoprostane levels. Basal MAP was less in CAT+ (92 ± 2 mmHg n = 6) than in WT (98 ± 2 mmHg n = 9 P < 0.001). During DETCA infusion, MAP was increased in WT (by 4.2 ± 0.5% P < 0.001) but not in CAT+, when compared to appropriate controls (PDETCA*genotype = 0.006). DETCA infusion increased total plasma F2 -isoprostane levels (by 67 ± 11% P = 0.05) in WT but not in CAT+. Total renal F2 -isoprostane levels were greater during DETCA infusion in WT (by 72% P < 0.001), but not in CAT+, compared to appropriate controls. Augmented endothelial l-arginine transport attenuated the prohypertensive effects of systemic and renal oxidative stress, suggesting that manipulation of endothelial CAT1 may provide a new therapeutic approach for the treatment of cardiovascular disease associated with oxidative stress.

Renal effects of rilmenidine in volume-loaded anaesthetized dogs

Publisher: Wiley

Date: 1997

DOI: 10.1111/J.1440-1681.1997.TB01784.X

Abstract: 1. In anaesthetized, fluid expanded rats rilmenidine has diuretic and natriuretic effects. There is strong evidence that the natriuresis is mediated by putative imidazoline receptors. In contrast, in conscious euvolaemic dogs rilmenidine has a diuretic effect that is entirely attributable to activation of alpha 2-adrenoceptors, but no natriuretic effect. To determine whether the effects of rilmenidine are truly species dependent, or merely dependent upon the influences of anaesthesia and volume status, we tested the effects of rilmenidine in pentobarbitone anaesthetized, volume-loaded dogs. 2. The effects of rilmenidine in anaesthetized, volume-loaded dogs were similar to those found in conscious euvolaemic dogs. Compared with vehicle treatment, levels of glomerular filtration rate, urine flow and haematocrit were increased following rilmenidine treatment. No effect of rilmenidine on sodium excretion was observed. 3. We conclude that the renal responses to rilmenidine in dogs are largely unaffected by anaesthesia and plasma volume status. In particular, the natriuretic effect seen in rats was not observed. We conclude that putative imidazoline receptors do not have a major influence on sodium excretion in dogs.

Role for endothelium‐derived hyperpolarizing factor in vascular tone in rat mesenteric and hindlimb circulations in vivo

Publisher: Wiley

Date: 08-2002

DOI: 10.1113/JPHYSIOL.2002.021030

Abstract: The role of endothelium-derived hyperpolarizing factor (EDHF) in the regulation of blood flow in vivo was examined in the mesenteric and hindlimb circulations of anaesthetized rats. Basal mesenteric conductance decreased from 57 +/- 5 to 20 +/- 6 microl min(-1) mmHg(-1) when nitric oxide (NO) production was inhibited, and combined blockade of intermediate- and small-conductance Ca(2+)-activated K(+) (K(Ca)) channels with charybdotoxin (ChTx) and apamin had no further effect. Basal hindlimb conductance was reduced from 39 +/- 3 to 22 +/- 2 microl min(-1) mmHg(-1) by NO synthesis inhibition, with no effect of the K(Ca) channel blockers. Endothelial stimulation with acetylcholine (ACh) infusion directly into the mesenteric bed increased conductance by 20 +/- 2 microl min(-1) mmHg(-1). Blockade of NO synthesis decreased this conductance to 15 +/- 1 microl min(-1) mmHg(-1), leaving the response attributable to EDHF. This was reduced to 2 +/- 1 microl min(-1) mmHg(-1) by ChTx plus apamin but not by iberiotoxin, which selectively blocks large-conductance K(Ca) channels. Similar results were obtained when bradykinin (BK) was used to stimulate the endothelium. Nitroprusside, which directly relaxes smooth muscle, evoked an increase in conductance that was resistant to all blockers tested. ACh-induced increases in hindlimb conductance were reduced from 19 +/- 1 to 12 +/- 1 microl min(-1) mmHg(-1) by NO synthesis inhibition and further reduced to 2 +/- 2 microl min(-1) mmHg(-1) by ChTx plus apamin. In contrast to NO, ChTx- and apamin-sensitive EDHF appears to contribute little to basal conductance in rat mesenteric and hindlimb beds. However, EDHF accounts for a significant component of the conductance increase during endothelial stimulation by ACh and BK. In these beds, intermediate- and small-conductance K(Ca) channels underpin EDHF-mediated vasodilatation.

Detection of cellular hypoxia by pimonidazole adduct immunohistochemistry in kidney disease: Methodological pitfalls and their solution

Publisher: American Physiological Society

Date: 08-2019

DOI: 10.1152/AJPRENAL.00219.2019

Abstract: Pimonidazole adduct immunohistochemistry is one of the few available methods for assessing renal tissue hypoxia at the cellular level. It appears to be prone to artifactual false positive staining under some circumstances. Here, we assessed the nature of this false positive staining and, having determined how to avoid it, reexamined the nature of cellular hypoxia in rat models of kidney disease. When a mouse-derived anti-pimonidazole primary antibody was used, two types of staining were observed. First, there was diffuse staining of the cytoplasm of tubular epithelial cells, which was largely absent when the primary antibody was omitted from the incubation protocol or in tissues known not to contain pimonidazole adducts. Second, there was staining of the apical membranes of tubular epithelial cells, debris within the lumen of renal tubules, including tubular casts, and the interstitium this latter staining was present even when the primary antibody was omitted from the incubation protocol. Such false positive staining was particularly prominent in acutely injured kidneys. It could not be avoided by preincubation of sections with a mouse IgG blocking reagent. Furthermore, preadsorption of the secondary antibody against rat Ig abolished all staining however, when a rabbit-derived polyclonal anti-pimonidazole primary antibody was used, the false positive staining was largely avoided. Using this method, we confirmed the presence of hypoxia, localized mainly to the tubular epithelium, in the acute phase of severe renal ischemia-reperfusion injury, adenine-induced chronic kidney disease, and polycystic kidney disease. We conclude that this new method provides improved detection of renal cellular hypoxia.

Differential Effects of Acute and Chronic Estrogen Treatment on Thermogenic and Metabolic Pathways in Ovariectomized Sheep

Publisher: The Endocrine Society

Date: 2013

DOI: 10.1210/EN.2012-1758

Abstract: Estrogen is protective against weight gain, but the underlying mechanisms are not fully elucidated. We sought to characterize the effects of estrogen on energy expenditure in skeletal muscle and adipose tissue in ovariectomized sheep. Temperature probes were implanted into sc (gluteal) and visceral (retroperitoneal) fat depots and skeletal muscle of the hind limb (vastus lateralis). Food was available from 1100–1600 h to entrain postprandial thermogenesis. We characterized the effects of single (50 μg estradiol benzoate, im) and repeated (25 μg estradiol-17β, iv) injections as well as chronic (3 × 3 cm estradiol-17β implants for 7 d) treatment on heat production. A single injection of estrogen increased heat production in visceral fat and skeletal muscle, without an effect on food intake. Increased heat production in skeletal muscle was sustained by repeated estradiol-17β injections. On the other hand, continuous treatment reduced food intake but had no effect on thermogenesis. To determine possible mechanisms that underpin estradiol-17β-induced heat production, we measured femoral artery blood flow, the expression of uncoupling protein (UCP) mRNA and the phosphorylation of AMP-activated protein kinase and Akt in fat and muscle. There was little effect of either single or repeated injections of estradiol-17β on the expression of UCP1, -2, or -3 mRNA in visceral fat or skeletal muscle. Acute injection of estradiol-17β increased the phosphorylation of AMP-activated protein kinase and Akt in muscle only. Estradiol-17β treatment did not alter femoral artery blood flow. Thus, the stimulatory effect of estradiol-17β on thermogenesis in female sheep is dependent upon a pulsatile pattern of treatment and not constant continuous exposure.

Association of hypertension with infection and inflammation in a setting of disadvantage in rural India

Publisher: Springer Science and Business Media LLC

Date: 17-09-2022

DOI: 10.1038/S41371-021-00609-1

Abstract: We assessed the association of hypertension with markers of inflammation and infection in a rural and disadvantaged Indian population. In a case-control study, we age- and gender-matched 300 cases with hypertension to 300 controls without hypertension. Blood pressure was measured according to a strict protocol. We measured markers of inflammation and infection including serum high-sensitivity C-reactive protein (hs-CRP), blood lymphocyte count, serum homocysteine, tooth loss, overcrowding and exposure to fecal contamination. Multivariable conditional logistic regression was used to determine their association with hypertension. Median serum hs-CRP was 42% greater in cases than controls, while median serum homocysteine was 10% greater. In multivariable conditional logistic regression, elevated homocysteine (OR 1.75, 95% CI 1.09-2.82), greater lymphocyte count (OR 1.49, 95% CI 1.01-2.01) and exposure to fecal contamination, defined as a distance from the field used for toilet purposes to the household of ≤50 m (OR 2.38, 95% CI 1.07-5.29), were independently associated with hypertension in this rural population. In separate analyses for each gender, elevated hs-CRP (OR 2.62, 95% CI 1.04-6.58) was associated with hypertension in men, whereas edentulism (OR 4.75, 95% CI 1.62-13.96) was associated with greater odds of hypertension in women. Our findings demonstrate specific associations between hypertension and markers of inflammation and infection including hs-CRP, homocysteine, lymphocyte count, edentulism and exposure to fecal contamination. Thus, strategies aimed at reducing inflammation and infection may reduce the burden of hypertension in such settings of disadvantage in rural India.

Blood Flow, Oxygenation, and Oxidative Stress in the Post-stenotic Kidney

Publisher: Springer London

Date: 2014

DOI: 10.1007/978-1-4471-2810-6_9

Effects of renal arterial endothelin-1 and endogenous endothelins on regional kidney blood flow and renal antihypertensive mechanisms in anesthetized rabbits

Publisher: S. Karger AG

Date: 2000

DOI: 10.1159/000025985

Abstract: To determine how endothelins affect regional kidney blood flow and responses to increased renal artery pressure (RAP), an extracorporeal circuit was established to control RAP independent of the mean systemic arterial pressure (MAP). RAP was first set at ∼65 mm Hg, and endothelin-1 (1 ng/kg/min for 30 min then 0.4 ng/kg/min) or vehicle was infused into the renal artery, or the ET sub A /sub /ET sub B /sub antagonist TAK-044 (3 mg/kg plus 3 mg/kg/h) or vehicle was administered intravenously. RAP was then progressively increased in steps from ∼65 to ∼160 mm Hg. When RAP was ∼65 mm Hg, endothelin-1 increased renal vascular resistance (RVR, 72%), and reduced cortical (CBF, 26%) but not medullary blood flow (MBF). TAK-044 reduced MAP (12%) and RVR (15%) and increased CBF (21%) but not MBF. When RAP was increased, renal blood flow (RBF), glomerular filtration rate, and urine and sodium excretion increased, while MAP fell. These responses were unaffected by endothelin-1. TAK-044 potentiated the increases in RBF and reductions in MAP in response to increased RAP, but did not affect urine and sodium excretion. Plasma renin activity was reduced by endothelin-1 and increased by TAK-044. Thus, both exogenous and endogenous endothelins reduce CBF but not MBF, and reduce plasma renin activity, but neither affect pressure natriuresis.

Neurohumoral-renal interactions in blood pressure control

Publisher: Wiley

Date: 20-07-2016

DOI: 10.1111/APHA.12748

Stability of tissue PO₂ in the face of altered perfusion: a phenomenon specific to the renal cortex and independent of resting renal oxygen consumption

Publisher: Wiley

Date: 25-03-2011

DOI: 10.1111/J.1440-1681.2011.05494.X

Abstract: 1. Oxygen tension (PO(2)) in renal cortical tissue can remain relatively constant when renal blood flow changes in the physiological range, even when changes in renal oxygen delivery (DO(2)) and oxygen consumption (VO(2)) are mismatched. In the current study, we examined whether this also occurs in the renal medulla and skeletal muscle, or if it is an unusual property of the renal cortex. We also examined the potential for dysfunction of the mechanisms underlying this phenomenon to contribute to kidney hypoxia in disease states associated with increased renal VO(2) . 2. In both the kidney and hindlimb of pentobarbitone anaesthetized rabbits, whole organ blood flow was reduced by intra-arterial infusion of angiotensin-II and increased by acetylcholine infusion. In the kidney, this was carried out before and during renal arterial infusion of the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), or its vehicle. 3. Angiotensin-II reduced renal (-34%) and hindlimb (-25%) DO(2) , whereas acetylcholine increased renal (+38%) and hindlimb (+66%) DO(2) . However, neither renal nor hindlimb VO(2) were altered. Tissue PO(2) varied with local perfusion in the renal medulla and biceps femoris, but not the renal cortex. DNP increased renal VO(2) (+38%) and reduced cortical tissue PO(2) (-44%), but both still remained stable during subsequent infusion of angiotensin-II and acetylcholine. 4. We conclude that maintenance of tissue PO(2) in the face of mismatched changes in local perfusion and VO(2) is an unusual property of the renal cortex. The underlying mechanisms remain unknown, but our current findings suggest they are not compromised when resting renal VO(2) is increased.

Renal oxygenation in acute renal ischemia-reperfusion injury

Publisher: American Physiological Society

Date: 05-2014

DOI: 10.1152/AJPRENAL.00281.2013

Abstract: Tissue hypoxia has been demonstrated, in both the renal cortex and medulla, during the acute phase of reperfusion after ischemia induced by occlusion of the aorta upstream from the kidney. However, there are also recent clinical observations indicating relatively well preserved oxygenation in the nonfunctional transplanted kidney. To test whether severe acute kidney injury can occur in the absence of widespread renal tissue hypoxia, we measured cortical and inner medullary tissue Po 2 as well as total renal O 2 delivery (Do 2 ) and O 2 consumption (V̇o 2 ) during the first 2 h of reperfusion after 60 min of occlusion of the renal artery in anesthetized rats. To perform this experiment, we used a new method for measuring kidney Do 2 and V̇o 2 that relies on implantation of fluorescence optodes in the femoral artery and renal vein. We were unable to detect reductions in renal cortical or inner medullary tissue Po 2 during reperfusion after ischemia localized to the kidney. This is likely explained by the observation that V̇o 2 (−57%) was reduced by at least as much as Do 2 (−45%), due to a large reduction in glomerular filtration (−94%). However, localized tissue hypoxia, as evidence by pimonidazole adduct immunohistochemistry, was detected in kidneys subjected to ischemia and reperfusion, particularly in, but not exclusive to, the outer medulla. Thus, cellular hypoxia, particularly in the outer medulla, may still be present during reperfusion even when reductions in tissue Po 2 are not detected in the cortex or inner medulla.

Micro‐computed tomographic analysis of the radial geometry of intrarenal artery‐vein pairs in rats and rabbits: Comparison with light microscopy

Publisher: Wiley

Date: 05-09-2017

DOI: 10.1111/1440-1681.12842

Abstract: We assessed the utility of synchrotron-radiation micro-computed tomography (micro-CT) for quantification of the radial geometry of the renal cortical vasculature. The kidneys of nine rats and six rabbits were perfusion fixed and the renal circulation filled with Microfil. In order to assess shrinkage of Microfil, rat kidneys were imaged at the Australian Synchrotron immediately upon tissue preparation and then post fixed in paraformaldehyde and reimaged 24 hours later. The Microfil shrank only 2-5% over the 24 hour period. All subsequent micro-CT imaging was completed within 24 hours of s le preparation. After micro-CT imaging, the kidneys were processed for histological analysis. In both rat and rabbit kidneys, vascular structures identified in histological sections could be identified in two-dimensional (2D) micro-CT images from the original kidney. Vascular morphology was similar in the two sets of images. Radial geometry quantified by manual analysis of 2D images from micro-CT was consistent with corresponding data generated by light microscopy. However, due to limited spatial resolution when imaging a whole organ using contrast-enhanced micro-CT, only arteries ≥100 and ≥60 μm in diameter, for the rat and rabbit respectively, could be assessed. We conclude that it is feasible and valid to use micro-CT to quantify vascular geometry of the renal cortical circulation in both the rat and rabbit. However, a combination of light microscopic and micro-CT approaches are required to evaluate the spatial relationships between intrarenal arteries and veins over an extensive range of vessel size.

Evidence for a renomedullary vasodepressor hormone

Publisher: Wiley

Date: 09-1996

DOI: 10.1111/J.1440-1681.1996.TB01179.X

Abstract: 1. Recent physiological experiments have established that increasing the perfusion pressure of the kidney causes the release of vasodepressor substance from the renal medulla. 2. The substance is not a platelet activating factor, a prostaglandin or nitric oxide and the vasodepressor response to increased renal perfusion is not due simply to inhibition of renin release. 3. The mechanisms by which the renomedullary vasodepressor substance lowers arterial pressure remain to be determined. Sympathoinhibition may account for part of the response, but the hypotension still occurs in autonomic ganglion blocked animals. 4. The source of substance appears to be the renomedullary interstitial cells, though the control of the production and release of the substance remain to be determined. 5. The substance may be a lipid but it is yet to be fully isolated and identified. 6. The threshold for release of the substance appears to be close to normal resting arterial blood pressure. 7. Despite strong evidence that the renal medulla releases a vasodepressor hormone in response to increased renal perfusion pressure, much is still to be determined regarding the physiology of this hormone and its involvement in the aetiology of hypertension.

Cortical and Medullary Tissue Perfusion and Oxygenation in Experimental Septic Acute Kidney Injury

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2015

DOI: 10.1097/CCM.0000000000001198

Renal sympathetic activation from long-term low-dose angiotensin II infusion in rabbits

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2012

DOI: 10.1097/HJH.0B013E328350133A

Eulogy John Ludbrook: Surgeon, physiologist and biostatistician

Publisher: Wiley

Date: 16-10-2017

DOI: 10.1111/1440-1681.12843

Intraoperative hemodynamics and risk of cardiac surgery‐associated acute kidney injury: An observation study and a feasibility clinical trial

Publisher: Wiley

Date: 07-08-2023

DOI: 10.1111/1440-1681.13812

Abstract: Targeting greater pump flow and mean arterial pressure (MAP) during cardiopulmonary bypass (CPB) could potentially alleviate renal hypoxia and reduce the risk of postoperative acute kidney injury (AKI). Therefore, in an observational study of 93 patients undergoing on‐pump cardiac surgery, we tested whether intraoperative hemodynamic management differed between patients who did and did not develop AKI. Then, in 20 patients, we assessed the feasibility of a larger‐scale trial in which patients would be randomized to greater than normal target pump flow and MAP, or usual care, during CPB. In the observational cohort, MAP during hypothermic CPB averaged 68.8 ± 8.0 mmHg (mean ± SD) in the 36 patients who developed AKI and 68.9 ± 6.3 mmHg in the 57 patients who did not ( p = 0.98). Pump flow averaged 2.4 ± 0.2 L/min/m 2 in both groups. In the feasibility clinical trial, compared with usual care, those randomized to increased target pump flow and MAP had greater mean pump flow (2.70 ± 0.23 vs. 2.42 ± 0.09 L/min/m 2 during the period before rewarming) and systemic oxygen delivery (363 ± 60 vs. 281 ± 45 mL/min/m 2 ). Target MAP ≥80 mmHg was achieved in 66.6% of patients in the intervention group but in only 27.3% of patients in the usual care group. Nevertheless, MAP during CPB did not differ significantly between the two groups. We conclude that little insight was gained from our observational study regarding the impact of variations in pump flow and MAP on the risk of AKI. However, a clinical trial to assess the effects of greater target pump flow and MAP on the risk of AKI appears feasible.

New physiological targets within the kidney for antihypertensive therapy

Publisher: Bentham Science Publishers Ltd.

Date: 03-2005

DOI: 10.2174/1567269053202651

Synchrotron-based angiography for investigation of the regulation of vasomotor function in the microcirculation in vivo

Publisher: Wiley

Date: 2009

DOI: 10.1111/J.1440-1681.2008.05073.X

Abstract: 1. Real-time imaging of the vascular networks of any organ system in vivo is possible with synchrotron radiation (SR) angiography. In this review, we discuss the advantages of SR angiography over clinical X-ray imaging and other non-ionizing imaging modalities. Current limitations are also described. 2. The usefulness of dual-energy and temporal subtraction approaches to K-edge iodine imaging are compared. 3. High-resolution images of the microcirculation in small animals are now being collected routinely by multiple research groups through public access research programmes at synchrotrons worldwide. Such images are permitting unrivalled insights into vasomotor regulation deep within intact organ systems, such as the brain, kidney, lung and heart. For ex le, recent observations indicate changes in vascular control mechanisms in pulmonary hypertension that are specific to certain branching segments of the pulmonary circulation. 4. New possibilities for non-iodinated contrast agents in SR angiography are briefly described. 5. High-resolution angiography in vivo using SR will now allow us to identify vessels with localized or non-uniform vasoconstriction in states such as diabetes or to characterize the extent of endothelial dysfunction in the circulation following hypertension or ischaemic-reperfusion injury. In the near future, this research is expected to reveal the contribution of resistance vessel dysfunction to erse pathophysiological states, such as stroke, hypertension and ischaemic heart disease.

Enhanced responses to ganglion blockade do not reflect sympathetic nervous system contribution to angiotensin II-induced hypertension

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 09-2009

DOI: 10.1097/HJH.0B013E32832DD0D8

Renal medullary antihypertensive mechanisms

Publisher: Wiley

Date: 12-1995

DOI: 10.1111/J.1440-1681.1995.TB02329.X

Abstract: 1. Increasing renal perfusion pressure, using an extracorporeal circuit in rabbits and dogs, causes release from the kidney of a vasodepressor substance. 2. The hypotensive response occurs in denervated kidneys, and it is not due to platelet activating factor, nitric oxide, prostanoids or suppression of renin release. 3. In the rabbit, the pressure threshold for release of the hypotensive substance appears to be slightly above normal resting pressures. 4. The source of the hypotensive substance is medullary, since the hypotensive response to increased renal perfusion pressure is abolished in dogs and rabbits whose medullae are damaged by bromoethylamine treatment. 5. The chemical nature of the hypotensive substance remains unknown. 6. Thus the renal medulla appears to possess a hypotensive hormone, released in response to elevation of renal perfusion pressure. Many aspects of the physiology and pathology of the substance and its significance in blood pressure regulation remain to be determined.

Renal hemodynamics and oxygenation during experimental cardiopulmonary bypass in sheep under total intravenous anesthesia

Publisher: American Physiological Society

Date: 02-2020

DOI: 10.1152/AJPREGU.00290.2019

Abstract: Renal medullary hypoxia may contribute to the pathophysiology of acute kidney injury, including that associated with cardiac surgery requiring cardiopulmonary bypass (CPB). When performed under volatile (isoflurane) anesthesia in sheep, CPB causes renal medullary hypoxia. There is evidence that total intravenous anesthesia (TIVA) may preserve renal perfusion and renal oxygen delivery better than volatile anesthesia. Therefore, we assessed the effects of CPB on renal perfusion and oxygenation in sheep under propofol/fentanyl-based TIVA. Sheep ( n = 5) were chronically instrumented for measurement of whole renal blood flow and cortical and medullary perfusion and oxygenation. Five days later, these variables were monitored under TIVA using propofol and fentanyl and then on CPB at a pump flow of 80 mL·kg −1 ·min −1 and target mean arterial pressure of 70 mmHg. Under anesthesia, before CPB, renal blood flow was preserved under TIVA (mean difference ± SD from conscious state: −16 ± 14%). However, during CPB renal blood flow was reduced (−55 ± 13%) and renal medullary tissue became hypoxic (−20 ± 13 mmHg versus conscious sheep). We conclude that renal perfusion and medullary oxygenation are well preserved during TIVA before CPB. However, CPB under TIVA leads to renal medullary hypoxia, of a similar magnitude to that we observed previously under volatile (isoflurane) anesthesia. Thus use of propofol/fentanyl-based TIVA may not be a useful strategy to avoid renal medullary hypoxia during CPB.

When is embryonic arrest broken in turtle eggs?

Publisher: University of Chicago Press

Date: 09-2017

DOI: 10.1086/692630

Abstract: Turtle embryos enter a state of arrested development in the oviduct, allowing the mother greater flexibility in her reproductive schedule. Development recommences once eggs transition from the hypoxic oviduct to the normoxic nest. Significant mortality can occur if turtle eggs are moved between 12 h and 20 d after oviposition, and this is linked to the recommencement of embryonic development. To better understand the timing of developmental arrest and to determine how movement-induced mortality might be avoided, we determined the latency (i.e., time elapsed since oviposition) to recommencement of development following oviposition by exposing the eggs of green turtles (Chelonia mydas) to hypoxia (oxygen tension <8 mmHg) for 3 d, commencing 30 min to 48 h after oviposition. Embryonic development-including development of the characteristic opaque white spot on the eggshell-was halted by hypoxic incubation. When the delay before hypoxic incubation was 12 h or less, hatching success did not differ from a control group. If the hypoxic treatment began after 16 h or more in normoxia, then all embryos died. Thus, by returning eggs to a hypoxic environment before they have broken from arrest (i.e., within 12 h of oviposition), it is possible to extend embryonic arrest for at least 3 d, with no apparent detriment to hatching success. Therefore, hypoxic incubation may provide a new approach for avoidance of movement-induced mortality when conservation or research efforts require the relocation of eggs. Our findings also suggest that movement-induced mortality may have constrained the evolution of viviparity in turtles.

Effects of dietary protein restriction on nephron number in the mouse

Publisher: American Physiological Society

Date: 05-2007

DOI: 10.1152/AJPREGU.00442.2006

Abstract: In rats, maternal protein restriction reduces nephron endowment and often leads to adult hypertension. Sex differences in these responses have been identified. The molecular and genetic bases of these phenomena can best be identified in a mouse model, but effects of maternal protein restriction on kidney development have not been examined in mice. Therefore, we determined how combined prenatal and postnatal protein restriction in mice affects organ weight, glomerular number and dimensions, and renal expression of angiotensin receptor mRNA, in both male and female offspring. C57/BL6/129sv mice received either a normal (20% wt/wt NP) or low (9% wt/wt LP) protein diet during gestation and postnatal life. Offspring were examined at postnatal day 30. Protein restriction retarded growth of the kidney, liver, spleen, heart, and brain. All organs except the brain weighed less in female than male offspring. Protein restriction increased normalized (to body weight) brain weight, with females having relatively heavier brains than males. The effects of protein restriction were not sex dependent, except that normalized liver weight was reduced in males but increased in females. Glomerular volume, but not number, was greater in female than in male mice. Maternal protein restriction reduced nephron endowment similarly in male and female mice. Renal expression of AT 1A receptor mRNA was approximately sixfold greater in female than male NP mice, but similar in male LP and female LP mice. We conclude that maternal protein restriction reduces nephron endowment in mice. This effect provides a basis for future studies of developmental programming in the mouse.

Disparate Roles of AT ₂ Receptors in the Renal Cortical and Medullary Circulations of Anesthetized Rabbits

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-2003

DOI: 10.1161/01.HYP.0000083341.64034.00

Abstract: The contributions of angiotensin II type 1 (AT 1 ) and type 2 (AT 2 ) receptors to the control of regional kidney blood flow were determined in pentobarbital-anesthetized rabbits. Intravenous candesartan (AT 1 antagonist 10 μg/kg plus 10 μg · kg −1 · h −1 ) reduced mean arterial pressure (12%) and increased total renal blood flow (29%) and cortical laser-Doppler flux (18%) but not medullary laser-Doppler flux. Neither intravenous PD123319 (AT 2 antagonist 1 mg/kg plus 1 mg · kg −1 · h −1 ) nor saline vehicle significantly affected these variables, and the responses to candesartan plus PD123319 were indistinguishable from those of candesartan alone. In vehicle-treated rabbits, renal-arterial infusions of angiotensin II (1 to 25 ng · kg −1 · min −1 ) and angiotensin III (5 to 125 ng · kg −1 · min −1 ) dose-dependently reduced renal blood flow (up to 51%) and cortical laser-Doppler flux (up to 50%) but did not significantly affect medullary laser-Doppler flux or arterial pressure. Angiotensin(1–7) (20 to 500 ng · kg −1 · min −1 ) had similar effects but of lesser magnitude. CGP42112A (20 to 500 ng · kg −1 · min −1 ) did not significantly affect these variables. After PD123319 administration, angiotensin II and angiotensin III dose-dependently increased medullary laser-Doppler flux (up to 84%), and reductions in renal blood flow in response to angiotensin II were enhanced. Candesartan abolished renal hemodynamic responses to the angiotensin peptides, even when given in combination with PD123319. We conclude that AT 2 receptor activation counteracts AT 1 -mediated vasoconstriction in the renal cortex but also counteracts AT 1 -mediated vasodilatation in vascular elements controlling medullary perfusion. These mechanisms might have an important effect on the control of medullary perfusion under conditions of activation of the renin-angiotensin system.

RESPONSE TO ‘THE PRESENTATION OF STATISTICS IN CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY’

Publisher: Wiley

Date: 28-08-2008

DOI: 10.1111/J.1440-1681.2008.05023.X

Interactions Between Neural and Hormonal Mediators of Renal Vascular Tone in Anaesthetized Rabbits

Publisher: Wiley

Date: 03-2003

DOI: 10.1113/EPH8802462

Abstract: We investigated how sympathetic nerve activity and vasoactive hormones interact in controlling renal haemodynamics in pentobarbitone-anaesthetized rabbits. Renal blood flow was progressively reduced by electrical stimulation (0.5-3 Hz) of the renal nerves, during renal arterial infusion of saline, vasoconstrictors (angiotensin II and [Phe2,Ile3,Orn8]-vasopressin), or vasodilators (acetylcholine, adrenomedullin and the nitric oxide donor methylamine hexamethylene NONOate (MAHMA NONOate). A frequency-rich stimulus was also applied to test whether the vasoactive agents affect the dynamic control of renal blood flow by sympathetic nerve activity. The vasodilators tended to increase renal blood flow, but only the effect of MAHMA NONOate was statistically significant. [Phe2,Ile3,Orn8]-vasopressin reduced medullary perfusion (by 61 +/- 12 %) but not renal blood flow or cortical perfusion. Angiotensin II reduced renal blood flow (33 +/- 3 %) and cortical perfusion (14 +/- 5 %) but not medullary perfusion. Steady-state responses of renal blood flow and cortical perfusion during renal nerve stimulation were attenuated during infusion of acetylcholine and [Phe2,Ile3,Orn8]-vasopressin, while angiotensin II attenuated responses of medullary perfusion, and MAHMA NONOate and adrenomedullin had no significant effects. The dynamic response to sympathetic nerve activity (renal blood flow responded as a low pass filter with a pure time delay of ~664 ms) was not altered by the vasoactive agents. We conclude that some vasoactive agents can modulate steady-state renal haemodynamic responses to sympathetic nerve activity in a regionally specific manner, independent of their effects on baseline renovascular tone. However, they have little impact on the dynamic response of renal blood flow to sympathetic nerve activity.

Effect of renal perfusion pressure on responses of intrarenal blood flow to renal nerve stimulation in rabbits

Publisher: Wiley

Date: 2004

DOI: 10.1111/J.1440-1681.2004.03947.X

Abstract: 1. We investigated how sympathetic nerve activity and renal perfusion pressure (RPP) interact in controlling renal haemodynamics in pentobarbitone-anaesthetized rabbits. 2. Renal blood flow (RBF) was reduced by electrical renal nerve stimulation (0.5-8 Hz), with RPP set using an extracorporeal circuit to 65, 100 and 135 mmHg. 3. Responses of RBF and cortical laser Doppler flux to renal nerve stimulation were blunted by increased RPP. For ex le, 4 Hz stimulation reduced RBF by 68 +/- 7% with baseline perfusion pressure approximately 65 mmHg, but only by 22 +/- 3% at approximately 135 mmHg. Medullary laser Doppler flux was less responsive than cortical laser Doppler flux to renal nerve stimulation and its response was not dependent on perfusion pressure. 4. When perfusion pressure was cl ed at its baseline level during renal nerve stimulation, responses of RBF and cortical laser Doppler flux, but not medullary laser Doppler flux, were still blunted with increased baseline perfusion pressure. 5. A frequency rich stimulus was applied to assess the effects of perfusion pressure on dynamic neural control of RBF. Renal blood flow responded similarly at each level of perfusion pressure, as a low-pass filter with a pure time delay. 6. Our results suggest that, in the rabbit extracorporeal circuit model, increased RPP blunts the ability of steady state renal nerve stimulation to reduce cortical, but not medullary perfusion. However, in this model the level of RPP appears to have little impact on dynamic neural control of RBF.

Effects of long-term intrarenal angiotensin II infusion on renal vascular responsiveness to vasoactive agents

Publisher: Wiley

Date: 08-1998

DOI: 10.1111/J.1440-1681.1998.TB02267.X

Abstract: 1. We tested whether chronic intrarenal angiotensin II (AngH) infusion altered renal vascular responsiveness to vasoactive agents, which would provide evidence of vascular structural changes. 2. The renal blood flow (RBF) responses to renal arterial administration of bolus doses of acetylcholine, glyceryl trinitrate, AngH and noradrenaline were measured before commencement of and 1 day after cessation of 28 days intrarenal Angll infusion (0.5 ng/kg per min) in chronically instrumented conscious dogs. 3. The RBF responses to these vasoactive agents were unaltered by chronic intrarenal Angll infusion in conscious dogs. 4. These functional studies provide no evidence for renal vascular hypertrophy in response to chronic intrarenal Angll infusion in conscious dogs.

Hypoxia as a biomarker of kidney disease

Publisher: Springer Netherlands

Date: 2016

DOI: 10.1007/978-94-007-7743-9_7-1

Renal hypoxia in kidney disease: Cause or consequence?

Publisher: Wiley

Date: 27-12-2018

DOI: 10.1111/APHA.12999

Abstract: Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute kidney injury (AKI), initiating and propagating a vicious cycle of tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (i) Is kidney disease always associated with tissue hypoxia? (ii) Does tissue hypoxia drive signalling cascades that lead to tissue damage and dysfunction? (iii) Does tissue hypoxia per se lead to kidney disease? (iv) Does tissue hypoxia precede pathology? (v) Does tissue hypoxia colocalize with pathology? (vi) Does prevention of tissue hypoxia prevent kidney disease? We conclude that tissue hypoxia is a common feature of both AKI and CKD. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signalling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. colocalization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a "common pathway" to both AKI and CKD still remains to be adequately tested.

Predicting oxygen tension along the ureter

Publisher: American Physiological Society

Date: 10-2021

DOI: 10.1152/AJPRENAL.00122.2021

Abstract: Measurement of bladder urine oxygen tension has been proposed as a new method to potentially detect the risk of acute kidney injury in patients. A computational model of oxygen exchange between urine bolus and ureteral tissue shows that it may be technically possible to determine the risk of acute kidney injury based on the measurement of bladder urine oxygen tension, provided that the measurement data are properly interpreted via a computational model.

Haemodynamic influences on kidney oxygenation: Clinical implications of integrative physiology

Publisher: Wiley

Date: 29-01-2013

DOI: 10.1111/1440-1681.12031

Abstract: Renal blood flow, local tissue perfusion and blood oxygen content are the major determinants of oxygen delivery to kidney tissue. Arterial pressure and segmental vascular resistance influence kidney oxygen consumption through effects on glomerular filtration rate and sodium reabsorption. Diffusive shunting of oxygen from arteries to veins in the cortex and from descending to ascending vasa recta in the medulla limits oxygen delivery to renal tissue. Oxygen shunting depends on the vascular network, renal haemodynamics and kidney oxygen consumption. Consequently, the impact of changes in renal haemodynamics on tissue oxygenation cannot necessarily be predicted intuitively and, instead, requires the integrative approach offered by computational modelling and multiple measuring modalities. Tissue hypoxia is a hallmark of acute kidney injury (AKI) arising from multiple initiating insults, including ischaemia-reperfusion injury, radiocontrast administration, cardiopulmonary bypass surgery, shock and sepsis. Its pathophysiology is defined by inflammation and/or ischaemia resulting in alterations in renal tissue oxygenation, nitric oxide bioavailability and oxygen radical homeostasis. This sequence of events appears to cause renal microcirculatory dysfunction, which may then be exacerbated by the inappropriate use of therapies common in peri-operative medicine, such as fluid resuscitation. The development of new ways to prevent and treat AKI requires an integrative approach that considers not just the molecular mechanisms underlying failure of filtration and tissue damage, but also the contribution of haemodynamic factors that determine kidney oxygenation. The development of bedside monitors allowing continuous surveillance of renal haemodynamics, oxygenation and function should facilitate better prevention, detection and treatment of AKI.

Your fat talks to your brain through your kidneys

Publisher: Wiley

Date: 07-05-2015

DOI: 10.1111/APHA.12513

Usability and acceptability of the software ‘Arogya Sahyog’ to assess non-communicable diseases in rural India

Publisher: Elsevier BV

Date: 12-2022

DOI: 10.1016/J.HLPT.2022.100681

Maximizing Patient Recruitment and Retention in a Secondary Stroke Prevention Clinical Trial: Lessons Learned from the STAND FIRM Study

Publisher: Elsevier BV

Date: 06-2016

DOI: 10.1016/J.JSTROKECEREBROVASDIS.2016.02.020

Abstract: Recruitment and retention of patients in a clinical trial is important for generalizability and robustness of findings. We aimed to investigate features of a study design that were associated with recruitment and retention in a Phase II and Phase III trial of a secondary prevention program for stroke. Following informed consent in hospital, Phase II participants were randomized to intervention or usual care. Baseline clinical assessments were conducted at home approximately 3 months after discharge. In Phase III study, informed consent was obtained at home. We compared the characteristics of participants recruited and retained to 12 months for both phases. Interviews with study nurses were undertaken in order to ascertain their opinions of features of study design. Triangulation was used to identify the features of study design that nurses thought had improved recruitment and retention. All 24 eligible participants were recruited to the Phase II pilot study (100% recruitment), with 67% retention at 12 months. In Phase III study, 570 participants were recruited, and 93% of these participants had reached their 12-month assessment (n = 532) and were still participating. Consistent with the greater patient retention in Phase III study, nurses reported that patients' willingness to participate was greater when consent was obtained at home. Following a change in the consent process from hospital to home, more participants continued participation to 12 months. Pilot studies can provide important data to improve study design and better understand potential barriers to recruitment and retention.

The Global Alliance for Chronic Diseases Supports 15 Major Studies in Hypertension Prevention and Control in Low‐ and Middle‐Income Countries

Publisher: Wiley

Date: 06-2016

DOI: 10.1111/JCH.12835

Multiple mechanisms act to maintain kidney oxygenation during renal ischemia in anesthetized rabbits.

Publisher: American Physiological Society

Date: 05-2010

DOI: 10.1152/AJPRENAL.00647.2009

Abstract: We examined the mechanisms that maintain stable renal tissue Po 2 during moderate renal ischemia, when changes in renal oxygen delivery (Ḋo 2 ) and consumption (V̇o 2 ) are mismatched. When renal artery pressure (RAP) was reduced progressively from 80 to 40 mmHg, V̇o 2 (−38 ± 7%) was reduced more than Ḋo 2 (−26 ± 4%). Electrical stimulation of the renal nerves (RNS) reduced Ḋo 2 (−49 ± 4% at 2 Hz) more than V̇o 2 (−30 ± 7% at 2 Hz). Renal arterial infusion of angiotensin II reduced Ḋo 2 (−38 ± 3%) but not V̇o 2 (+10 ± 10%). Despite mismatched changes in Ḋo 2 and V̇o 2 , renal tissue Po 2 remained remarkably stable at ≥40 mmHg RAP, during RNS at ≤2 Hz, and during angiotensin II infusion. The ratio of sodium reabsorption to V̇o 2 was reduced by all three ischemic stimuli. None of the stimuli significantly altered the gradients in Pco 2 or pH across the kidney. Fractional oxygen extraction increased and renal venous Po 2 fell during 2-Hz RNS and angiotensin II infusion, but not when RAP was reduced to 40 mmHg. Thus reduced renal V̇o 2 can help prevent tissue hypoxia during mild renal ischemia, but when renal V̇o 2 is reduced less than Ḋo 2 , other mechanisms prevent a fall in renal Po 2 . These mechanisms do not include increased efficiency of renal oxygen utilization for sodium reabsorption or reduced washout of carbon dioxide from the kidney, leading to increased oxygen extraction. However, increased oxygen extraction could be driven by altered countercurrent exchange of carbon dioxide and/or oxygen between renal arteries and veins.

Endothelial cationic amino acid transporter-1 overexpression blunts the effects of oxidative stress on pressor responses to behavioural stress in mice

Publisher: Wiley

Date: 12-2014

DOI: 10.1111/1440-1681.12279

Abstract: Observational studies indicate that psychological stress may contribute to the pathogenesis of hypertension and this may be further accentuated by factors such as endothelial dysfunction. On this basis, we aimed to determine whether oxidative stress enhances pressor responses to stressful stimuli and whether augmenting endothelial function by increasing the transport of L-arginine can counter the effects of oxidative stress. Telemetry probes were used to measure mean arterial pressure (MAP) in wild-type (WT n = 6) and endothelial cationic amino acid transporter-1 (CAT-1)-overexpressing (CAT+) mice (n = 6) before and during an aversive (restraint) and non-aversive (almond feeding) stressor. The superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA 30 mg/kg per day 14 days) was then administered via a minipump to induce oxidative stress. Stress responses to feeding and restraint were repeated during Days 11-12 of DETCA infusion. In WT mice, pressor responses to restraint and feeding were augmented during infusion of DETCA (35 ± 1 and 28 ± 1 mmHg, respectively) compared with respective pretreatment responses (28 ± 2 and 24 ± 1 mmHg, respectively P ≤ 0.01). In CAT+ mice, pressor responses to feeding were blunted during DETCA (20 ± 1 mmHg) compared with the control response (23 ± 1 mmHg P = 0.03). In these mice, pressor responses to restraint were similar before (28 ± 1 mmHg) and during (26 ± 1 mmHg) DETCA infusion (P = 0.26). We conclude that endothelial CAT-1 overexpression can counter the ability of oxidative stress to augment pressor responses to behavioural stress.

Reduced sensitivity of the renal vasculature to angiotensin II in young rats: The role of the angiotensin type 2 receptor

Publisher: Springer Science and Business Media LLC

Date: 13-08-2014

DOI: 10.1038/PR.2014.121

Abstract: The angiotensin type-2 receptor (AT2R) opposes the vasoconstrictor actions of angiotensin II (AngII) mediated through the angiotensin type-1 receptor (AT1R). Renal AT2R levels are high during fetal life, but decrease significantly during postnatal maturation. To provide insight into the functional role of the AT2R in the kidney during postnatal development, we investigated the effects of AT2R antagonism on cardiovascular responses to AngII in young and adult male rats. In anesthetized 3- and 6-wk-old male Sprague-Dawley rats, mean arterial pressure (MAP) and renal blood flow (RBF) were measured in response to AngII in the presence of vehicle treatment or AT2R blockade with PD123319. The pressor effect of AngII and associated reduction in RBF were significantly less in 3-wk- than 6-wk-old rats. AT2R blockade potentiated the reduction in RBF in response to AngII in 3-wk-old rats only. In young rats, the AT2R modulates the response to AngII, blunting renal vasoconstriction. This effect is attenuated with age in association with a developmental reduction in renal AT2R expression. These findings may have implications for the development of novel therapies that target the renin-angiotensin system for the improvement of renal function in term and, in particular, preterm infants.

Renal haemodynamics and oxygenation during and after cardiac surgery and cardiopulmonary bypass

Publisher: Wiley

Date: 30-11-2018

DOI: 10.1111/APHA.12995

Abstract: Acute kidney injury (AKI) is a common complication following cardiac surgery performed on cardiopulmonary bypass (CPB) and has important implications for prognosis. The aetiology of cardiac surgery-associated AKI is complex, but renal hypoxia, particularly in the medulla, is thought to play at least some role. There is strong evidence from studies in experimental animals, clinical observations and computational models that medullary ischaemia and hypoxia occur during CPB. There are no validated methods to monitor or improve renal oxygenation during CPB, and thus possibly decrease the risk of AKI. Attempts to reduce the incidence of AKI by early transfusion to ameliorate intra-operative anaemia, refinement of protocols for cooling and rewarming on bypass, optimization of pump flow and arterial pressure, or the use of pulsatile flow, have not been successful to date. This may in part reflect the complexity of renal oxygenation, which may limit the effectiveness of in idual interventions. We propose a multi-disciplinary pathway for translation comprising three components. Firstly, large-animal models of CPB to continuously monitor both whole kidney and regional kidney perfusion and oxygenation. Secondly, computational models to obtain information that can be used to interpret the data and develop rational interventions. Thirdly, clinically feasible non-invasive methods to continuously monitor renal oxygenation in the operating theatre and to identify patients at risk of AKI. In this review, we outline the recent progress on each of these fronts.

Regional vascular responses to ATP and ATP analogues in the rabbit kidney in vivo: roles for adenosine receptors and prostanoids

Publisher: Wiley

Date: 11-2006

DOI: 10.1038/SJ.BJP.0706901

CHARACTERISTICS OF CARDIOVASCULAR REFLEXES ORIGINATING FROM 5‐HT₃ RECEPTORS IN THE HEART AND LUNGS OF UNANAESTHETIZED RABBITS

Publisher: Wiley

Date: 09-1990

DOI: 10.1111/J.1440-1681.1990.TB01367.X

Abstract: 1. When phenylbiguanide (1-PBG) (6.25-400 micrograms) was injected into the left atrium, right atrium or pulmonary artery of unanesthetized rabbits it caused dose-dependent falls of heart rate and arterial pressure, and short-lived hypopnoea or apnoea. The threshold dose was 50-100 micrograms. Maximal falls of heart rate (86-108 beats/min) and arterial pressure (33-35 mmHg) occurred at a dose of 200 micrograms. The latency between injection and onset of the bradycardia was 2.2-2.6 s and did not depend on the route. Cardiac output fell transiently with heart rate, but at the time of the maximal fall of arterial pressure it had returned to normal. All effects were abolished by intrapericardial procaine. The haemodynamic effects were exaggerated by sino-aortic barodenervation. Intrapericardial 1-PBG (200-400 micrograms) was without effect. Injection of 1-PBG (greater than 50-100 micrograms) into the aortic arch caused a variable increase in heart rate and arterial pressure. 2. When both cervical vagus nerves were crushed the depressor effects of atrial 1-PBG were reduced by only 76-84%. 3. The dose-response curves for left atrial and pulmonary artery injection of 1-PBG were shifted successively to the right by intravenous infusion of the 5-HT3 antagonist MDL72222 (0.1 and 1.0 mg/kg). 4. We conclude that in unanesthetized rabbits left atrial 1-PBG selectively excites myocardial afferents, whereas right atrial or pulmonary artery 1-PBG excites afferents that originate close to the pulmonary vasculature. In each case 1-PBG acts through pharmacologically specific 5-HT3 receptors. The afferents run mainly, but not exclusively, in the vagus nerves. The reflex fall of arterial pressure is accounted for almost entirely by a decrease in peripheral resistance.

Heterogeneity of renal cortical oxygenation: seeing is believing

Publisher: Elsevier BV

Date: 06-2018

DOI: 10.1016/J.KINT.2018.01.039

Abstract: The limited spatial and temporal resolution of available methods for quantifying renal tissue oxygen tension is a major impediment to identification of the roles of renal hypoxia in kidney diseases. Intravital phosphorescence lifetime imaging microscopy allows cellular oxygen tension in the renal cortex of live animals to be resolved to the level of in idual tubular cross-sections. This paves the way for future investigations of the spatial relationships between cellular hypoxia and pathophysiological events in kidney disease.

Diffusive shunting of gases and other molecules in the renal vasculature: Physiological and evolutionary significance

Publisher: American Physiological Society

Date: 11-2016

DOI: 10.1152/AJPREGU.00246.2016

Abstract: Countercurrent systems have evolved in a variety of biological systems that allow transfer of heat, gases, and solutes. For ex le, in the renal medulla, the countercurrent arrangement of vascular and tubular elements facilitates the trapping of urea and other solutes in the inner medulla, which in turn enables the formation of concentrated urine. Arteries and veins in the cortex are also arranged in a countercurrent fashion, as are descending and ascending vasa recta in the medulla. For countercurrent diffusion to occur, barriers to diffusion must be small. This appears to be characteristic of larger vessels in the renal cortex. There must also be gradients in the concentration of molecules between afferent and efferent vessels, with the transport of molecules possible in either direction. Such gradients exist for oxygen in both the cortex and medulla, but there is little evidence that large gradients exist for other molecules such as carbon dioxide, nitric oxide, superoxide, hydrogen sulfide, and ammonia. There is some experimental evidence for arterial-to-venous (AV) oxygen shunting. Mathematical models also provide evidence for oxygen shunting in both the cortex and medulla. However, the quantitative significance of AV oxygen shunting remains a matter of controversy. Thus, whereas the countercurrent arrangement of vasa recta in the medulla appears to have evolved as a consequence of the evolution of Henle’s loop, the evolutionary significance of the intimate countercurrent arrangement of blood vessels in the renal cortex remains an enigma.

μ‐ AND K‐OPIATE RECEPTOR AGONISTS REDUCE PLASMA NEUROHYPOPHYSIAL HORMONE CONCENTRATIONS IN WATER‐DEPRIVED AND NORMALLY HYDRATED RATS

Publisher: Wiley

Date: 03-1989

DOI: 10.1111/J.1440-1681.1989.TB01544.X

Abstract: 1. The effects of mu- and K-opiate receptor agonists on plasma concentrations of immunoreactive (ir) oxytocin (OXY) and arginine vasopressin (AVP) in normally hydrated and water-deprived rats were studied. 2. Water-deprivation for 36 h elevated both plasma ir-OXY and ir-AVP concentrations of Long-Evans rats. These elevated levels were lowered in a dose-dependent manner after subcutaneous administration of bremazocine (3-10 micrograms/kg), M320 (10-100 micrograms/kg) or morphine (0.1-10 mg/kg). Comparable reductions of plasma concentrations of ir-AVP and ir-OXY were observed. 3. Plasma concentrations of ir-OXY and ir-AVP of normally hydrated Long-Evans rats were lower after subcutaneous administration of bremazocine (10 micrograms/kg), M320 (10 micrograms/kg) and morphine (1.0 mg/kg). 4. These data suggest that both mu- and K-opiate receptor agonists inhibit both OXY and AVP release from the neurohypophysis of rats.

Autoregulation of renal medullary blood flow in rabbits

Publisher: American Physiological Society

Date: 2003

DOI: 10.1152/AJPREGU.00061.2002

Abstract: We examined the extent of renal medullary blood flow (MBF) autoregulation in pentobarbital-anesthetized rabbits. Two methods for altering renal arterial pressure (RAP) were compared: the conventional method of graded suprarenal aortic occlusion and an extracorporeal circuit that allows RAP to be increased above systemic arterial pressure. Changes in MBF were estimated by laser-Doppler flowmetry, which appears to predominantly reflect erythrocyte velocity, rather than flow, in the kidney. We compared responses using a dual-fiber needle probe held in place by a micromanipulator, with responses from a single-fiber probe anchored to the renal capsule, to test whether RAP-induced changes in kidney volume confound medullary laser-Doppler flux (MLDF) measurements. MLDF responses were similar for both probe types and both methods for altering RAP. MLDF changed little as RAP was altered from 50 to ≥170 mmHg (24 ± 22% change). Within the same RAP range, RBF increased by 296 ± 48%. Urine flow and sodium excretion also increased with increasing RAP. Thus pressure diuresis/natriuresis proceeds in the absence of measurable increases in medullary erythrocyte velocity estimated by laser-Doppler flowmetry. These data do not, however, exclude the possibility that MBF is increased with increasing RAP in this model, because vasa recta recruitment may occur.

Renal medullary and urinary oxygen tension during cardiopulmonary bypass in the rat

Publisher: Oxford University Press (OUP)

Date: 08-06-2016

DOI: 10.1093/IMAMMB/DQW010

Levels of renal and extrarenal sympathetic drive in angiotensin II-induced hypertension

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 04-2008

DOI: 10.1161/HYPERTENSIONAHA.107.100800

Abstract: We examined the contribution of the renal nerves to mean arterial pressure (MAP) during 5-week chronic infusion of angiotensin II (Ang II 50 ng/kg per minute SC) in conscious rabbits. Basal MAP was 68±1 mm Hg, and the maximum depressor response to ganglion blockade was −20±2 mm Hg. MAP increased by 25±2 mm Hg after 1 week and remained stable over the next 4 weeks. Depressor responses to pentolinium (6 mg/kg IV) were similar to control during the first week of hypertension but thereafter became increasingly greater in Ang II–treated rabbits but not vehicle-treated rabbits. After 5 weeks, the fall in MAP was 54% greater in Ang II- than in vehicle-treated rabbits (−34±2 versus −22±2 mm Hg), but renal sympathetic nerve activity was similar in both groups. Renal denervation produced a small fall in MAP in all of the vehicle-treated rabbits after 4 days (−6±2 mm Hg P =0.01), but there was no consistent effect in hypertensive rabbits. The depressor response to ganglion blockade was enhanced in vehicle-treated but not Ang II–treated rabbits. The finding that renal sympathetic nerve activity is not altered by Ang II hypertension nor is the hypertension altered by renal denervation suggests that renal sympathetic nerves do not contribute to the hypertension. The greater depressor effect of acute ganglion blockade in hypertensive rabbits suggests that the sympathetic nervous system exerts increased vasoconstriction in the peripheral vasculature in Ang II–induced hypertension.

Effects of μ‐opioid receptor agonists on circulatory responses to simulated haemorrhage in conscious rabbits

Publisher: Wiley

Date: 07-1990

DOI: 10.1111/J.1476-5381.1990.TB15822.X

Abstract: 1. Cardiac output, arterial pressure, heart rate, systemic vascular conductance, respiratory rate and arterial blood PO2 and PCO2 were measured in unanaesthetized rabbits. Haemorrhage was simulated by inflating a cuff placed around the inferior vena cava so that cardiac output fell at a constant rate of about 8% of its resting value per min. 2. The effects of drug treatments on resting haemodynamic and respiratory variables, and on the haemodynamic response to simulated haemorrhage, were tested. The treatments were 4th ventricular (-)-naloxone HCl (10-100 nmol), 4th ventricular H-Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH (DAMGO 30-300 pmol), and i.v. morphine sulphate (0.5-5.0 mumol kg-1). The interactions of graded 4th ventricular doses of naloxone (3-100 nmol) with the actions of DAMGO (100-300 pmol) on these responses were also assessed. 3. After sham treatments, the circulatory response to simulated haemorrhage had two phases. During the first compensatory phase, systemic vascular conductance fell, heart rate rose, and mean arterial pressure fell by only about 7 mmHg. A second decompensatory phase supervened when cardiac output had fallen by about 50%. At this point systemic vascular conductance rose abruptly and arterial pressure fell to less than or equal to 40 mmHg. 4. Low 4th ventricular doses of naloxone (10-30 nmol) and DAMGO (30-100 pmol) had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of naloxone (30-100 nmol) and DAMGO (100-300 pmol) prevented the decompensatory phase. These high doses of naloxone and DAMGO lowered resting heart rate without affecting the other haemodynamic or respiratory variables. 5. Low doses of i.v. morphine (0.5-1.Spumolkg-1) also had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of morphine (1.5-5.Opmol kg 1) abolished the decompensatory phase. These high doses caused respiratory depression without affecting the resting haemodynamic variables. 6. The prevention of circulatory decompensation by high doses of DAMGO was reversed by 3-10nmol of naloxone in 3 out of 4 rabbits and by 10-30 nmol of naloxone in all 4 rabbits. The decompensatory phase was, however, prevented by the combined high doses of DAMGO (100-300pmol) and naloxone (30-100 nmol). 7. These findings provide strong evidence that activation of mu-opioid receptors in the central nervous system abolishes circulatory decompensation during acute reduction of central blood volume in conscious rabbits. This effect does not appear to be due to activation of arterial chemoreceptors or to a non-specific increase in sympathetic vasoconstrictor drive, since respiratory depression and hypertension were not observed after 4th ventricular doses of DAMGO which abolished circulatory decompensation. Our results also provide indirect confirmation of our previous finding that naloxone acts to prevent circulatory decompensation by an antagonist action at central delta-receptors.

Effects of the Vasopressin V1 Agonist [PHE2,ILE3,ORN8] Vasopressin on Regional Kidney Perfusion and Renal Excretory Function in Anesthetized Rabbits

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-1998

DOI: 10.1097/00005344-199810000-00009

Abstract: To test whether renal V1-receptors selectively influence blood flow in the renal medulla, we compared the effects of infusion of [Phe2,Ile3,Orn8]vasopressin (3-30 ng/kg/min) by the intravenous, renal arterial, and renal medullary interstitial routes in anesthetized rabbits. Intravenous [Phe2,Ile3,Orn8]vasopressin (30 ng/kg/min) reduced renal medullary perfusion (MBF) by 36 +/- 5% but did not significantly affect cortical perfusion (CBF). MBF was also reduced with the renal arterial (35 +/- 5%) and renal medullary interstitial (40 +/- 7%) routes but, in contrast to the intravenous infusion, CBF was also reduced, by 21 +/- 3% and 15 +/- 3%, respectively. Urine flow and sodium excretion were increased by [Phe2,Ile3,Orn8]vasopressin, and with direct intrarenal administration, this effect was similar for both the infused (left) and noninfused (right) kidneys. After a 20-min renal medullary interstitial infusion of [3H]norepinephrine, radiolabel concentration was approximately fivefold greater in the left medulla than in the left cortex. We conclude that [Phe2,Ile3,Orn8]vasopressin acts on V1-receptors to alter regional kidney blood flow and tubular salt and water handling. The V1-receptors involved are almost certainly within the kidney itself, but given the contrasting effects of the different infusion routes on MBF and CBF, we cannot exclude the possibility that some of the observed effects of [Phe2,Ile3,Orn8]vasopressin are mediated by activation of extra-renal V1-receptors.

Initiation and Progression of Chronic Kidney Disease

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 11-2013

DOI: 10.1161/HYPERTENSIONAHA.113.02047

Renal cellular hypoxia in adenine-induced chronic kidney disease

Publisher: Wiley

Date: 09-2016

DOI: 10.1111/1440-1681.12621

Abstract: We determined whether adenine-induced chronic kidney disease (CKD) in rats is associated with renal tissue hypoxia. Adenine (100 mg) or its vehicle was administered to male Sprague-Dawley rats, daily by oral gavage, over a 15-day period. Renal function was assessed before, and 7 and 14 days after, adenine treatment commenced, by collection of a 24-hour urine s le and a blood s le from the tail vein. On day 15, arterial pressure was measured in conscious rats via the tail artery. Renal tissue hypoxia was then assessed by pimonidazole adduct immunohistochemistry and fibrosis was assessed by staining tissue with picrosirius red and Masson's trichrome. CKD was evident within 7 days of commencing adenine treatment, as demonstrated by increased urinary albumin to creatinine ratio (30 ± 12-fold). By day 14 of adenine treatment plasma creatinine concentration was more than 7-fold greater, and plasma urea more than 5-fold greater, than their baseline levels. On day 15, adenine-treated rats had slightly elevated mean arterial pressure (8 mmHg), anaemia and renomegaly. Kidneys of adenine-treated rats were characterised by the presence of tubular casts, dilated tubules, expansion of the interstitial space, accumulation of collagen, and tubulointerstitial hypoxia. Pimonidazole staining (hypoxia) co-localised with fibrosis and was present in both patent and occluded tubules. We conclude that renal tissue hypoxia develops rapidly in adenine-induced CKD. This model, therefore, should prove useful for examination of the temporal and spatial relationships between tubulointerstitial hypoxia and the development of CKD, and thus the testing of the 'chronic hypoxia hypothesis'.

A pseudo-three-dimensional model for quantification of oxygen diffusion from preglomerular arteries to renal tissue and renal venous blood

Publisher: American Physiological Society

Date: 08-2017

DOI: 10.1152/AJPRENAL.00659.2016

Abstract: To assess the physiological significance of arterial-to-venous (AV) oxygen shunting, we generated a new pseudo-three-dimensional computational model of oxygen diffusion from intrarenal arteries to cortical tissue and veins. The model combines the 11 branching levels (known as “Strahler” orders) of the preglomerular renal vasculature in the rat, with an analysis of an extensive data set obtained using light microscopy to estimate oxygen mass transfer coefficients for each Strahler order. Furthermore, the AV shunting model is now set within a global oxygen transport model that includes transport from arteries, glomeruli, peritubular capillaries, and veins to tissue. While a number of lines of evidence suggest AV shunting is significant, most importantly, our AV oxygen shunting model predicts AV shunting is small under normal physiological conditions (~0.9% of total renal oxygen delivery range 0.4–1.4%), but increases during renal ischemia, glomerular hyperfiltration (~2.1% of total renal oxygen delivery range 0.84–3.36%), and some cardiovascular disease states (~3.0% of total renal oxygen delivery range 1.2–4.8%). Under normal physiological conditions, blood Po 2 is predicted to fall by ~16 mmHg from the root of the renal artery to glomerular entry, with AV oxygen shunting contributing ~40% and oxygen diffusion from arteries to tissue contributing ~60% of this decline. Arterial Po 2 is predicted to fall most rapidly from Strahler order 4, under normal physiological conditions. We conclude that AV oxygen shunting normally has only a small impact on renal oxygenation, but may exacerbate renal hypoxia during renal ischemia, hyperfiltration, and some cardiovascular disease states.

Stimulation of erythropoietin release by hypoxia and hypoxemia: similar but different

Publisher: Elsevier BV

Date: 2019

DOI: 10.1016/J.KINT.2018.09.025

Abstract: Erythropoietin is released from the kidney in response to tissue hypoxia. Montero and Lundby found that increases in plasma erythropoietin induced by reducing arterial oxygen content in healthy humans were independent of arterial oxygen tension. Their observations accord with the established physiology of kidney oxygenation and can be predicted by a computational model of renal oxygen transport. However, model simulations indicate that the interpretation implicit in the title of their paper may be an oversimplification.

CURRENT STATUS OF PUTATIVE IMIDAZOLINE (I₁) RECEPTORS AND RENAL MECHANISMS IN RELATION TO THEIR ANTIHYPERTENSIVE THERAPEUTIC POTENTIAL

Publisher: Wiley

Date: 11-1996

DOI: 10.1111/J.1440-1681.1996.TB01132.X

Abstract: 1. A ‘second generation’ of centrally acting antihypertensive agents has recently been developed. Unlike the ‘first generation’ of these agents (e.g. α‐methylodopa, clonidine, guanabenz), which act predominantly by an agonist action at α‐adrenoceptors, these agents (e.g. rilmenidine, moxonidine) are believed to exert their antihypertensive effects chiefly by an interaction at putative imidazoline (I) receptors of the I 1 ‐type, and so have a reduced profile of α‐adrenoceptor‐mediated side effects. There is also evidence from studies in experimental animals that activation of I 1 ‐receptors mediates a natriuretic effect. This review evaluates the evidence that they mediate renal effects different from those of α‐adrenoceptors that could contribute to their long‐term efficacy. 2. Data from binding studies suggest that I 1 ‐binding sites are heterogeneous. There is conflicting evidence concerning whether any of there binding sites are truly receptors. Indeed, the best evidence for the existence of I 1 ‐receptors comes from in vivo experiments receptive sites in the central nervous system to reduce sympathetic drive and blood pressure. 3. There are a wide range of potential sites and mechanisms through which centrally acting antihypetensive agents can affect renal function, including actions mediated within the central nervous system, heart, systemic circulation and within the kidneys themselves. ‘First generation’ centrally acting anti‐hypertensive agents cause diuresis and natriuresis in rats, while in dogs and humans a diuresis is often seen with variable effects on sodium excretion. 4. Evidence from studies in anaesthetized rats indicates that rilmenidine and moxonidine can promote sodium excretion by interacting with both central nervous system and renal putative I 1 ‐receptors. This does not appear to necessarily be the case in other species. At this time there are few or no published data from clinical studies to suggest that ‘second generation’ centrally acting antihypertensive agents affect salt and water balance differently from ‘first generation’ agents.

Renal arterial infusion of tempol prevents medullary hypoperfusion, hypoxia, and acute kidney injury in ovine Gram-negative sepsis

Publisher: Wiley

Date: 07-08-2023

DOI: 10.1111/APHA.14025

Abstract: Renal medullary hypoperfusion and hypoxia precede acute kidney injury (AKI) in ovine sepsis. Oxidative/nitrosative stress, inflammation, and impaired nitric oxide generation may contribute to such pathophysiology. We tested whether the antioxidant and anti‐inflammatory drug, tempol, may modify these responses. Following unilateral nephrectomy, we inserted renal arterial catheters and laser‐Doppler/oxygen‐sensing probes in the renal cortex and medulla. Noanesthetized sheep were administered intravenous (IV) Escherichia coli and, at sepsis onset, IV tempol (IVT 30 mg kg −1 h −1 ), renal arterial tempol (RAT 3 mg kg −1 h −1 ), or vehicle. Septic sheep receiving vehicle developed renal medullary hypoperfusion (76 ± 16% decrease in perfusion), hypoxia (70 ± 13% decrease in oxygenation), and AKI (87 ± 8% decrease in creatinine clearance) with similar changes during IVT. However, RAT preserved medullary perfusion (1072 ± 307 to 1005 ± 271 units), oxygenation (46 ± 8 to 43 ± 6 mmHg), and creatinine clearance (61 ± 10 to 66 ± 20 mL min −1 ). Plasma, renal medullary, and cortical tissue malonaldehyde and medullary 3‐nitrotyrosine decreased significantly with sepsis but were unaffected by IVT or RAT. Consistent with decreased oxidative/nitrosative stress markers, cortical and medullary nuclear factor‐erythroid‐related factor‐2 increased significantly and were unaffected by IVT or RAT. However, RAT prevented sepsis‐induced overexpression of cortical tissue tumor necrosis factor alpha (TNF‐α 51 ± 16% decrease p = 0.003) and medullary Thr‐495 phosphorylation of endothelial nitric oxide synthase (eNOS 63 ± 18% decrease p = 0.015). In ovine Gram‐negative sepsis, renal arterial infusion of tempol prevented renal medullary hypoperfusion and hypoxia and AKI and decreased TNF‐α expression and uncoupling of eNOS. However, it did not affect markers of oxidative/nitrosative stress, which were significantly decreased by Gram‐negative sepsis.

Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury

Publisher: Elsevier BV

Date: 11-2019

DOI: 10.1016/J.KINT.2019.06.013

Abstract: Norepinephrine exacerbates renal medullary hypoxia in experimental septic acute kidney injury. Here we examined whether dexmedetomidine, an α2-adrenergic agonist, can restore vasopressor responsiveness, decrease the requirement for norepinephrine and attenuate medullary hypoxia in ovine gram-negative sepsis. Sheep were instrumented with pulmonary and renal artery flow probes, and laser Doppler and oxygen-sensing probes in the renal cortex and medulla. Conscious sheep received an infusion of live Escherichia coli for 30 hours. Eight sheep in each group were randomized to receive norepinephrine, norepinephrine with dexmedetomidine, dexmedetomidine alone or saline vehicle, from 24-30 hours of sepsis. Sepsis significantly reduced the average mean arterial pressure (84 to 67 mmHg), average renal medullary perfusion (1250 to 730 perfusion units), average medullary tissue pO

In vivo regulation of endothelium-dependent vasodilation in the rat renal circulation and the effect of streptozotocin-induced diabetes

Publisher: American Physiological Society

Date: 09-2008

DOI: 10.1152/AJPREGU.00861.2007

Abstract: We assessed the relative contributions of endothelium-derived relaxing factors to renal vasodilation in vivo and determined whether these are altered in established streptozotocin-induced diabetes. In nondiabetic rats, stimulation of the endothelium by locally administered ACh or bradykinin-induced transient renal hyperemia. Neither basal renal blood flow (RBF) nor renal hyperemic responses to ACh or bradykinin were altered by blockade of prostanoid production (indomethacin) or by administration of charybdotoxin (ChTx) plus apamin to block endothelium-derived hyperpolarizing factor (EDHF). In contrast, combined blockade of nitric oxide (NO) synthase, N ω -nitro-l-arginine methyl ester (l-NAME), and prostanoid production reduced basal RBF and the duration of the hyperemic responses to ACh and bradykinin and revealed a delayed ischemic response to ACh. Accordingly, l-NAME and indomethacin markedly reduced integrated (area under the curve) hyperemic responses to ACh and bradykinin. Peak increases in RBF in response to ACh and bradykinin were not reduced by l-NAME and indomethacin but were reduced by subsequent blockade of EDHF. l-NAME plus indomethacin and ChTx plus apamin altered RBF responses to endothelium stimulation in a qualitatively similar fashion in diabetic and nondiabetic rats. The integrated renal hyperemic responses to ACh and bradykinin were blunted in diabetes, due to a diminished contribution of the component abolished by l-NAME plus indomethacin. We conclude that NO dominates integrated hyperemic responses to ACh and bradykinin in the rat kidney in vivo. After prior inhibition of NO synthase, EDHF mediates transient renal vasodilation in vivo. Renal endothelium-dependent vasodilation is diminished in diabetes due to impaired NO function.

Intracisternal naloxone and cardiac nerve blockade prevent vasodilatation during simulated haemorrhage in awake rabbits.

Publisher: Wiley

Date: 02-1989

DOI: 10.1113/JPHYSIOL.1989.SP017481

Abstract: 1. Acute haemorrhage was simulated in five unanaesthetized rabbits, by inflating a cuff on the inferior vena cava so that cardiac output fell by 8.3% of its resting level per minute. Simulated haemorrhage was performed after sham treatment, after graded doses of intravenous and intracisternal naloxone, and after cardiac nerve blockade with intrapericardial procaine. 2. After sham treatment, the haemodynamic response to simulated haemorrhage was biphasic. During the first phase, systemic vascular conductance fell steadily, heart rate rose steadily, and arterial pressure fell only slightly. A second decompensatory phase began abruptly when cardiac output had fallen to approximately 55% of its resting level. Vascular conductance rose steeply, heart rate fell slowly, and arterial pressure fell precipitately. 3. Treatment with naloxone (intravenous, 0.04-0.4 mg kg-1 intracisternal, 0.2-2 micrograms kg-1) did not affect either phase of the haemodynamic response to simulated haemorrhage. 4. After treatment with larger doses of naloxone (intravenous, 4-8 mg kg-1 intracisternal, 4-69 micrograms kg-1), the first phase was unaffected, but the second phase no longer occurred. Throughout simulated haemorrhage, systemic vascular conductance fell steadily, heart rate rose, and arterial pressure was well maintained. The dose of intracisternal naloxone which prevented the second phase was 90-900 times less than the corresponding intravenous dose. The second phase was also prevented by cardiac nerve blockade. 5. We conclude that an endogenous opiate mechanism is responsible for the haemodynamic decompensation that occurs when cardiac output falls to a critical level. The mechanism is located within the central nervous system. It is triggered by a signal from the heart.

USE OF NICOTINE, BRADYKININ AND VERATRIDINE TO ELICIT CARDIOVASCULAR CHEMOREFLEXES IN UNANAESTHETIZED RABBITS

Publisher: Wiley

Date: 04-1991

DOI: 10.1111/J.1440-1681.1991.TB01438.X

Abstract: 1. We have characterized in unanaesthetized rabbits the reflex effects of injecting nicotine into the pericardial sac or left atrium on heart rate, arterial pressure, systemic vascular resistance and the litude and frequency of respiration. These effects were compared with those of atrial administration of nicotine and veratridine, and intrapericardial administration of veratridine and bradykinin. 2. Injection of nicotine (6.25-400 micrograms) into the pericardial sac caused dose-dependent falls of heart rate and arterial pressure, and a brief period of hypopnoea. The fall in arterial pressure was mainly due to a fall in systemic vascular resistance. The threshold dose was 25 micrograms. Near maximal falls in heart rate (108 beats/min) and arterial pressure (47 mmHg) occurred at a dose of 200-400 micrograms. The latency between injection and the onset of bradycardia was 3.0 s. 3. The effects of intrapericardial nicotine on arterial pressure and respiration were antagonized in a dose-dependent fashion by intrapericardial mecamylamine (1-100 micrograms/kg) but were unaffected by intrapericardial hyoscine methylbromide (10 micrograms/kg) or vecuronium (1-10 micrograms/kg). The haemodynamic and respiratory effects were abolished by intrapericardial procaine. The haemodynamic effects were increased, though not significantly, by sino-aortic baroreceptor denervation. In decerebrate, artificially ventilated rabbits, bilateral cervical vagotomy converted the hypotensive and bradycardic response into a slowly developing tachycardia without change in arterial pressure. 4. Left atrial injection of nicotine (6.25-100 micrograms) caused bradycardia, a rise in arterial pressure, and prolonged hyperpnoea preceded by transient hypopnoea. After sino-aortic barodenervation it caused profound falls in heart rate and arterial pressure and transient hypopnoea, which were abolished by intrapericardial procaine. 5. Intrapericardial injection of veratridine (50-100 micrograms) had no consistent effect under control conditions. After sino-aortic barodenervation it caused falls in heart rate and arterial pressure which were abolished by intrapericardial procaine. Left atrial injection of veratridine caused highly variable haemodynamic effects. 6. Intrapericardial bradykinin (2.5-25 micrograms) caused rises in both arterial pressure and heart rate. These were abolished by intrapericardial procaine. 7. We conclude that when nicotine is injected into the pericardial sac of conscious rabbits the reflex haemodynamic and respiratory effects are due to the selective activation of neuronal-type nicotinic cholinoceptors on vagal afferents that originate in the epicardium. The reflex effects of left atrial nicotine are probably due to the excitation of a combination of carotid chemoreceptors and cardiac receptors. 8. The effects of nicotine, veratridine and bradykinin that we observed in conscious rabbits were profoundly different from those reported in anaesthetized rabbits.

Prolonged and continuous measurement of kidney oxygenation in conscious rats

Publisher: Springer New York

Date: 17-12-2016

DOI: 10.1007/978-1-4939-3353-2_9

Abstract: A relative deficiency in kidney oxygenation, i.e., renal hypoxia, may contribute to the initiation and progression of acute and chronic kidney disease. A critical barrier to investigate this is the lack of methods allowing measurement of the partial pressure of oxygen in kidney tissue for long periods in vivo. We have developed, validated, and tested a novel telemetric method that can do this. Here we provide details on the calibration, implantation, implementation for data recording, and reuse of this telemetry-based technology for measurement of medullary tissue oxygen tension in conscious, unrestrained rats. This technique provides an important additional tool for investigating the impact of renal hypoxia in biology and pathophysiology.

Factors that confound the prediction of renal medullary oxygenation and risk of acute kidney injury from measurement of bladder urine oxygen tension

Publisher: Wiley

Date: 02-06-2019

DOI: 10.1111/APHA.13294

Abstract: Urinary oxygen tension (uPO In 28 sheep urine flow, uPO In conscious sheep breathing room air, uPO uPO

How generalisable is INTERSTROKE?

Publisher: Elsevier BV

Date: 11-2010

DOI: 10.1016/S0140-6736(10)62025-9

Absence of renal hypoxia in the subacute phase of severe renal ischemia-reperfusion injury

Publisher: American Physiological Society

Date: 11-2018

DOI: 10.1152/AJPRENAL.00249.2018

Abstract: Tissue hypoxia has been proposed as an important event in renal ischemia-reperfusion injury (IRI), particularly during the period of ischemia and in the immediate hours following reperfusion. However, little is known about renal oxygenation during the subacute phase of IRI. We employed four different methods to assess the temporal and spatial changes in tissue oxygenation during the subacute phase (24 h and 5 days after reperfusion) of a severe form of renal IRI in rats. We hypothesized that the kidney is hypoxic 24 h and 5 days after an hour of bilateral renal ischemia, driven by a disturbed balance between renal oxygen delivery (Do 2 ) and oxygen consumption (V̇o 2 ). Renal Do 2 was not significantly reduced in the subacute phase of IRI. In contrast, renal V̇o 2 was 55% less 24 h after reperfusion and 49% less 5 days after reperfusion than after sham ischemia. Inner medullary tissue Po 2 , measured by radiotelemetry, was 25 ± 12% (mean ± SE) greater 24 h after ischemia than after sham ischemia. By 5 days after reperfusion, tissue Po 2 was similar to that in rats subjected to sham ischemia. Tissue Po 2 measured by Clark electrode was consistently greater 24 h, but not 5 days, after ischemia than after sham ischemia. Cellular hypoxia, assessed by pimonidazole adduct immunohistochemistry, was largely absent at both time points, and tissue levels of hypoxia-inducible factors were downregulated following renal ischemia. Thus, in this model of severe IRI, tissue hypoxia does not appear to be an obligatory event during the subacute phase, likely because of the markedly reduced oxygen consumption.

Augmented expression and secretion of adipose-derived pigment epithelium-derived factor does not alter local angiogenesis or contribute to the development of systemic metabolic derangements

Publisher: American Physiological Society

Date: 15-06-2014

DOI: 10.1152/AJPENDO.00046.2014

Abstract: Impaired coupling of adipose tissue expansion and vascularization is proposed to lead to adipocyte hypoxia and inflammation, which in turn contributes to systemic metabolic derangements. Pigment epithelium-derived factor (PEDF) is a powerful antiangiogenic factor that is secreted by adipocytes, elevated in obesity, and implicated in the development of insulin resistance. We explored the angiogenic and metabolic role of adipose-derived PEDF through in vivo studies of mice with overexpression of PEDF in adipocytes (PEDF-aP2). PEDF expression in white adipocytes and PEDF secretion from adipose tissue was increased in transgenic mice, but circulating levels of PEDF were not increased. Overexpression of PEDF did not alter vascularization, the partial pressure of O 2 , cellular hypoxia, or gene expression of inflammatory markers in adipose tissue. Energy expenditure and metabolic substrate utilization, body mass, and adiposity were not altered in PEDF-aP2 mice. Whole body glycemic control was normal as assessed by glucose and insulin tolerance tests, and adipocyte-specific glucose uptake was unaffected by PEDF overexpression. Adipocyte lipolysis was increased in PEDF-aP2 mice and associated with increased adipose triglyceride lipase and decreased perilipin 1 expression. Experiments conducted in mice rendered obese by high-fat feeding showed no differences between PEDF-aP2 and wild-type mice for body mass, adiposity, whole body energy expenditure, glucose tolerance, or adipose tissue oxygenation. Together, these data indicate that adipocyte-generated PEDF enhances lipolysis but question the role of PEDF as a major antiangiogenic or proinflammatory mediator in adipose tissue in vivo.

Effects of 5‐HT‐receptor and α₂‐adrenoceptor ligands on the haemodynamic response to acute central hypovolaemia in conscious rabbits

Publisher: Wiley

Date: 05-1993

DOI: 10.1111/J.1476-5381.1993.TB13528.X

Abstract: 1. We set out to elucidate the pharmacological mechanisms by which alpha 2-adrenoceptor and 5-HT-receptor ligands affect the haemodynamic response to acute central hypovolaemia in conscious rabbits. 2. Acute central hypovolaemia was produced by inflating an inferior vena caval cuff so that cardiac output fell at a constant rate of approximately 8.5% of its baseline level per min. 3. Drugs were administered into the fourth cerebral ventricle in either 154 mM NaCl (saline) or 20% w/v 2-hydroxypropyl-beta-cyclodextrin (beta-CDX). After vehicle treatments, the haemodynamic response to acute central hypovolaemia had the usual two phases. During Phase I, systemic vascular conductance fell in proportion to cardiac output so that mean arterial pressure fell by only 8 mmHg. Phase II commenced when cardiac output had fallen to approximately 60% of its baseline level, when vascular conductance rose abruptly and arterial pressure fell to < or = 40 mmHg. The haemodynamic response was not dependent on the vehicle used (saline or beta-CDX). 4. Methysergide delayed the occurrence of Phase II in a dose-dependent manner, and prevented it at a dose of 30- 600 nmol (geometric mean = 186 nmol). The effects and potency of methysergide were not dependent on the vehicle used, indicating that beta-CDX can be used as a vehicle for fourth ventricular administration of lipophilic drugs to conscious rabbits. Clonidine (10 nmol) reversed the effects of a critical dose of methysergide. 5. Phase II was also prevented by 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT1A-selective agonist, geometric mean critical dose (range) = 13.1 (10-30) nmol), sumatriptan (5-HT1D-selective agonist, 72.1 (10-300) nmol), mesulergine (5-HT2/1C-selective antagonist, 173 (30-1000) nmol), idazoxan (alpha 2-adrenoceptor-selective antagonist, 548 (100-3000) nmol), and mianserin (5-HT2/1C-selective antagonist, 548 (100-3000) nmol). It was not affected by MDL 72222 (5-HT3-selective antagonist, 300 nmol) or ketanserin (5-HT2/1C-selective antagonist, 3000 nmol). 6. To characterize the nature of alpha 2-adrenoceptors in rabbit brainstem, we examined the binding of [3H]-rauwolscine to membrane homogenates of whole brainstem. [3H]-rauwolscine bound to a population of sites with the characteristics of alpha 2A-adrenoceptors. 7. From these results we suggest that activation of 5-HT1A receptors in the brainstem can prevent Phase II of the response to acute central hypovolaemia in conscious rabbits. Our results do not support the notion of an endogenous 5-hydroxytryptaminergic mechanism mediating Phase II. The mechanism by which the alpha 2-adrenoceptor antagonists yohimbine and idazoxan prevent Phase II remains to be elucidated. However, their potency relative to other 5-HT-receptor ligands indicates that an agonist action at 5-HT1A-receptors is more likely than an antagonist action at alpha 2-adrenoceptors.

Chronic recurrent dehydration associated with periodic water intake exacerbates hypertension and promotes renal damage in male spontaneously hypertensive rats

Publisher: Springer Science and Business Media LLC

Date: 22-09-2016

DOI: 10.1038/SREP33855

Abstract: Epidemiological evidence links recurrent dehydration associated with periodic water intake with chronic kidney disease (CKD). However, minimal attention has been paid to the long-term impact of periodic water intake on the progression of CKD and underlying mechanisms involved. Therefore we investigated the chronic effects of recurrent dehydration associated with periodic water restriction on arterial pressure and kidney function and morphology in male spontaneously hypertensive rats (SHR). Arterial pressure increased and glomerular filtration rate decreased in water-restricted SHR. This was observed in association with cyclic changes in urine osmolarity, indicative of recurrent dehydration. Additionally, water-restricted SHR demonstrated greater renal fibrosis and an imbalance in favour of pro-inflammatory cytokine-producing renal T cells compared to their control counterparts. Furthermore, urinary NGAL levels were greater in water-restricted than control SHR. Taken together, our results provide significant evidence that recurrent dehydration associated with chronic periodic drinking hastens the progression of CKD and hypertension, and suggest a potential role for repetitive bouts of acute renal injury driving renal inflammatory processes in this setting. Further studies are required to elucidate the specific pathways that drive the progression of recurrent dehydration-induced kidney disease.

Telemetry-based oxygen sensor for continuous monitoring of kidney oxygenation in conscious rats

Publisher: American Physiological Society

Date: 15-06-2013

DOI: 10.1152/AJPRENAL.00662.2012

Abstract: The precise roles of hypoxia in the initiation and progression of kidney disease remain unresolved. A major technical limitation has been the absence of methods allowing long-term measurement of kidney tissue oxygen tension (Po 2 ) in unrestrained animals. We developed a telemetric method for the measurement of kidney tissue Po 2 in unrestrained rats, using carbon paste electrodes (CPEs). After acute implantation in anesthetized rats, tissue Po 2 measured by CPE-telemetry in the inner cortex and medulla was in close agreement with that provided by the “gold standard” Clark electrode. The CPE-telemetry system could detect small changes in renal tissue Po 2 evoked by mild hypoxemia. In unanesthetized rats, CPE-telemetry provided stable measurements of medullary tissue Po 2 over days 5− 19 after implantation. It also provided reproducible responses to systemic hypoxia and hyperoxia over this time period. There was little evidence of fibrosis or scarring after 3 wk of electrode implantation. However, because medullary Po 2 measured by CPE-telemetry was greater than that documented from previous studies in anesthetized animals, this method is presently best suited for monitoring relative changes rather than absolute values. Nevertheless, this new technology provides, for the first time, the opportunity to examine the temporal relationships between tissue hypoxia and the progression of renal disease.

Analysis of the critical determinants of renal medullary oxygenation

Publisher: American Physiological Society

Date: 12-2019

DOI: 10.1152/AJPRENAL.00315.2019

Abstract: We have previously developed a three-dimensional computational model of oxygen transport in the renal medulla. In the present study, we used this model to quantify the sensitivity of renal medullary oxygenation to four of its major known determinants: medullary blood flow (MBF), medullary oxygen consumption rate (V̇o 2,M ), hemoglobin (Hb) concentration in the blood, and renal perfusion pressure. We also examined medullary oxygenation under special conditions of hydropenia, extracellular fluid volume expansion by infusion of isotonic saline, and hemodilution during cardiopulmonary bypass. Under baseline (normal) conditions, the average medullary tissue Po 2 predicted for the whole renal medulla was ~30 mmHg. The periphery of the interbundle region in the outer medulla was identified as the most hypoxic region in the renal medulla, which demonstrates that the model prediction is qualitatively accurate. Medullary oxygenation was most sensitive to changes in renal perfusion pressure followed by Hb, MBF, and V̇o 2,M , in that order. The medullary oxygenation also became sensitized by prohypoxic changes in other parameters, leading to a greater fall in medullary tissue Po 2 when multiple parameters changed simultaneously. Hydropenia did not induce a significant change in medullary oxygenation compared with the baseline state, while volume expansion resulted in a large increase in inner medulla tissue Po 2 (by ~15 mmHg). Under conditions of cardiopulmonary bypass, the renal medulla became severely hypoxic, due to hemodilution, with one-third of the outer stripe of outer medulla tissue having a Po 2 of mmHg.

Benefits and Challenges in Stroke Research in Developing Countries

Publisher: Cambridge University Press (CUP)

Date: 09-2008

DOI: 10.1375/BRIM.9.2.198

Abstract: Stroke is one of the leading causes of death worldwide. Currently more than two thirds of the burden of stroke occurs in developing countries. Development of strategies for prevention and management of stroke in these countries requires data on incidence, risk factors and management practices that are relevant to the specific socioeconomic and cultural factors present in these populations. Yet currently available data come almost exclusively from developed countries. Herein, we aim to discuss some of the issues, impediments and opportunities faced by researchers undertaking population-based studies on the burden of stroke in developing countries. Important criteria to be addressed include the establishment of productive working relationships with both local collaborators and the community the identification of an appropriate population group and development of a working protocol which takes into account potential language barriers and the need for cultural sensitivity. When possible the protocol should include similar methods to studies conducted elsewhere so that comparisons can be made between regions. Furthermore, the results of such studies should be disseminated in an appropriate and timely manner to the local community and appropriate government and nongovernment organisations. This will enable the development and implementation of prevention and intervention programs to reduce the impact of stroke in these nations.

Introduction

Publisher: Wiley

Date: 19-01-2010

DOI: 10.1111/J.1440-1681.2009.05341.X

Influence of moderate hypothermia on renal and cerebral haemodynamics and oxygenation during experimental cardiopulmonary bypass in sheep

Publisher: Wiley

Date: 29-07-2022

DOI: 10.1111/APHA.13860

Abstract: Cardiac surgery requiring cardiopulmonary bypass (CPB) can result in renal and cerebral injury. Intraoperative tissue hypoxia could contribute to such organ injury. Hypothermia, however, may alleviate organ hypoxia. Therefore, we tested whether moderate hypothermia (30°C) improves cerebral and renal tissue perfusion and oxygenation during ovine CPB. Ten sheep were studied while conscious, under stable anesthesia, and during 3 h of CPB. In a randomized within‐animal cross‐over design, five sheep commenced CPB at a target body temperature of 30°C (moderate hypothermia). After 90 min, the body temperature was increased to 36°C (standard procedure). The remaining five sheep were randomized to the opposite order of target body temperature. Compared with the standard procedure, moderately hypothermic CPB reduced renal oxygen delivery (−34.8% ± 19.6%, P = 0.003) and renal oxygen consumption (−42.7% ± 35.2%, P = 0.04). Nevertheless, moderately hypothermic CPB did not significantly alter either renal cortical or medullary tissue PO 2 . Moderately hypothermic CPB also did not significantly alter cerebral perfusion, cerebral tissue PO 2 , or cerebral oxygen saturation compared with the standard procedure. Compared with the anesthetized state, the standard procedure reduced renal medullary PO 2 (−21.0 ± 13.8 mmHg, P = 0.014) and cerebral oxygen saturation (65.0% ± 7.0% to 55.4% ± 9.6%, P = 0.022) but did not significantly alter either renal cortical or cerebral PO 2 . Ovine experimental CPB leads to renal medullary tissue hypoxia. Moderately hypothermic CPB did not improve cerebral or renal tissue oxygenation. In the kidney, this is probably because renal tissue oxygen consumption is matched by reduced renal oxygen delivery.

A model of oxygen transport in the rat renal medulla

Publisher: American Physiological Society

Date: 12-2018

DOI: 10.1152/AJPRENAL.00363.2018

Abstract: The renal medulla is prone to hypoxia. Medullary hypoxia is postulated to be a leading cause of acute kidney injury, so there is considerable interest in predicting the oxygen tension in the medulla. Therefore we have developed a computational model for blood and oxygen transport within a physiologically normal rat renal medulla, using a multilevel modeling approach. For the top-level model we use the theory of porous media and advection-dispersion transport through a realistic three-dimensional representation of the medulla’s gross anatomy to describe blood flow and oxygen transport throughout the renal medulla. For the lower-level models, we employ two-dimensional reaction-diffusion models describing the distribution of oxygen through tissue surrounding the vasculature. Steady-state model predictions at the two levels are satisfied simultaneously, through iteration between the levels. The computational model was validated by simulating eight sets of experimental data regarding renal oxygenation in rats (using 4 sets of control groups and 4 sets of treatment groups, described in 4 independent publications). Predicted medullary tissue oxygen tension or microvascular oxygen tension for control groups and for treatment groups that underwent moderate perturbation in hemodynamic and renal functions is within ±2 SE values observed experimentally. Diffusive shunting between descending and ascending vasa recta is predicted to be only 3% of the oxygen delivered. The validation tests confirm that the computational model is robust and capable of capturing the behavior of renal medullary oxygenation in both normal and early-stage pathological states in the rat.

Ecological and evolutionary significance of a lack of capacity for extended developmental arrest in crocodilian eggs

Publisher: The Royal Society

Date: 12-2017

DOI: 10.1098/RSOS.171439

Abstract: Hypoxia within the oviducts maintains embryonic arrest in turtles at the pre-ovipositional stage, which expands the timeframe over which nesting can occur without compromising embryo survival. The arrest can be extended post-oviposition through incubation of eggs in hypoxia. We determined whether crocodilian embryos have this same capacity. We also tested whether increased oxygen availability during incubation alters hatching success. We incubated freshly laid saltwater crocodile ( Crocodylus porosus ) eggs ( N = 83) at 32°C in one of five treatments control (normoxia 21% O 2 ), 3-day and 6-day hypoxia (1% O 2 ), or 3-day and 6-day hyperoxia (42% O 2 ). Incubation (approx. 82 days) was then completed in normoxia. There was a significant effect of treatment on survival of embryos through to hatching ( p 0.001). The hypoxic treatments resulted in almost no hatching (6.7% and 0% survival for the 3- and 6-day treatments, respectively), while the hyperoxic and control treatments resulted in normal to high hatching success (86.6%, 100% and 64.2% for the control, 3- and 6-day hyperoxic treatments, respectively). Unlike turtles, hypoxic incubation of crocodile eggs failed to delay development. Our results provide the first experimental evidence that, unlike turtles, crocodiles do not exhibit embryonic arrest when incubated under hypoxic conditions immediately following oviposition. An absence of embryonic arrest is of ecological and evolutionary significance, as it implies that crocodilians lack an ability to avoid adverse environmental conditions through delayed nesting and that, unlike turtles, embryonic arrest may not be a potential explanation for the lack of viviparity in the order Crocodylia .

Nitric oxide in responses of regional kidney perfusion to renal nerve stimulation and renal ischaemia

Publisher: Springer Science and Business Media LLC

Date: 11-2003

DOI: 10.1007/S00424-003-1149-1

Abstract: The mechanisms underlying the relative insensitivity of medullary blood flow (MBF) to sympathetic drive remain unknown. We tested the effects of nitric oxide synthase blockade on regional kidney perfusion responses to electrical renal nerve stimulation (RNS) in pentobarbitone-anaesthetized rabbits. Under control conditions, RNS reduced renal blood flow (RBF), cortical blood flow (CBF) and MBF in a frequency-dependent manner. MBF was always reduced less than CBF or RBF. NG-nitro-L-arginine increased mean arterial pressure (31+/-3 mmHg), reduced RBF (-8+/-1 ml/min) and MBF (-33+/-6 units), enhanced responses to RNS of RBF (from -48+/-6% to -58+/-6% at 2 Hz), CBF (from -38+/-6% to -43+/-4% at 2 Hz) and, particularly at low frequencies, MBF (from +1+/-18% to -32+/-11% at 2 Hz) and potentiated the RBF hyperaemic response following RNS (by 27+/-6% at 4 Hz). When glyceryl trinitrate was co-infused with NG-nitro-L-arginine to restore basal nitrergic tone, responses to RNS and the subsequent hyperaemia were indistinguishable from control. Since resting renovascular tone or perfusion pressure has little impact on MBF responses to RNS, these present observations suggest that NO contributes to the blunted MBF response to RNS. Paradoxically, NO seems to blunt renal hyperaemia following acute RNS-induced ischaemia.

Modulation of V₁-receptor-mediated renal vasoconstriction by epoxyeicosatrienoic acids

Publisher: American Physiological Society

Date: 07-2004

DOI: 10.1152/AJPREGU.00555.2002

Abstract: This study examined the effects of renal arterial infusion of a selective cytochrome P-450 epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH 2 mg/kg plus 1.5 mg·kg −1 ·h −1 ), on renal hemodynamic responses to infusions of [Phe 2 ,Ile 3 ,Orn 8 ]vasopressin and ANG II into the renal artery of anesthetized rabbits. MS-PPOH did not affect basal renal blood flow (RBF) or cortical or medullary blood flow measured by laser-Doppler flowmetry (CLDF/MLDF). In vehicle-treated rabbits, [Phe 2 ,Ile 3 ,Orn 8 ]vasopressin (30 ng·kg −1 ·min −1 ) reduced MLDF by 62 ± 7% but CLDF and RBF were unaltered. In MS-PPOH-treated rabbits, RBF and CLDF fell by 51 ± 8 and 59 ± 13%, respectively, when [Phe 2 ,Ile 3 ,Orn 8 ]vasopressin was infused. MS-PPOH had no significant effects on the MLDF response to [Phe 2 ,Ile 3 ,Orn 8 ]vasopressin (43 ± 9% reduction). ANG II (20 ng·kg −1 ·min −1 ) reduced RBF by 45 ± 10% and CLDF by 41 ± 14%, but MLDF was not significantly altered. MS-PPOH did not affect blood flow responses to ANG II. Formation of epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DiHETEs) was 49% lower in homogenates prepared from the renal cortex of MS-PPOH-treated rabbits than from vehicle-treated rabbits. MS-PPOH had no effect on the renal formation of 20-hydroxyeicosatetraenoic acid (20-HETE). Incubation of renal cortical homogenates from untreated rabbits with [Phe 2 ,Ile 3 ,Orn 8 ]vasopressin (0.2–20 ng/ml) did not affect formation of EETs, DiHETEs, or 20-HETE. These results do not support a role for de novo EET synthesis in modulating renal hemodynamic responses to ANG II. However, EETs appear to selectively oppose V 1 -receptor-mediated vasoconstriction in the renal cortex but not in the medullary circulation and contribute to the relative insensitivity of medullary blood flow to V 1 -receptor activation.

Vascular geometry and oxygen diffusion in the vicinity of artery-vein pairs in the kidney

Publisher: American Physiological Society

Date: 15-11-2014

DOI: 10.1152/AJPRENAL.00382.2014

Abstract: Renal arterial-to-venous (AV) oxygen shunting limits oxygen delivery to renal tissue. To better understand how oxygen in arterial blood can bypass renal tissue, we quantified the radial geometry of AV pairs and how it differs according to arterial diameter and anatomic location. We then estimated diffusion of oxygen in the vicinity of arteries of typical geometry using a computational model. The kidneys of six rats were perfusion fixed, and the vasculature was filled with silicone rubber (Microfil). A single section was chosen from each kidney, and all arteries ( n = 1,628) were identified. Intrarenal arteries were largely isible into two “types,” characterized by the presence or absence of a close physical relationship with a paired vein. Arteries with a close physical relationship with a paired vein were more likely to have a larger rather than smaller diameter, and more likely to be in the inner-cortex than the mid- or outer cortex. Computational simulations indicated that direct diffusion of oxygen from an artery to a paired vein can only occur when the two vessels have a close physical relationship. However, even in the absence of this close relationship oxygen can diffuse from an artery to periarteriolar capillaries and venules. Thus AV oxygen shunting in the proximal preglomerular circulation is dominated by direct diffusion of oxygen to a paired vein. In the distal preglomerular circulation, it may be sustained by diffusion of oxygen from arteries to capillaries and venules close to the artery wall, which is subsequently transported to renal veins by convection.

Renal haemodynamic effects of endothelin-1 and the ET(A)/ET(B) antagonist TAK-044 in anaesthetized rabbits

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 12-1998

DOI: 10.1097/00004872-199816121-00008

Abstract: The aim of this study was to test the effects of exogenous endothelin-1 (ET-1) on regional kidney blood flow and renal function, and the renal haemodynamic effects of endogenous ET, in anaesthetized rabbits. ET-1 was infused into the left renal artery at 2 ng/kg/min for 30 min, then at 1 ng/kg/min. Cumulative doses of TAK-044 (0.1-3 mg/kg, i.v.) or its vehicle were given at 30-min intervals. In other rabbits, an extracorporeal circuit was established to adjust renal arterial pressure (RAP) independently of systemic arterial pressure (MAP). RAP was set at 65 mmHg, and either TAK-044 (3 mg/kg, i.v.) or its vehicle was administered. In the infused kidney ET-1 (2 ng/kg/min) reduced renal blood flow (RBFprobe 52+/-8%), cortical perfusion (37+/-7%), glomerular filtration rate (GFR 49+/-8%), urine flow (47+/-14%) and sodium excretion (49+/-13%), but not medullary perfusion (5+/-6%). No effects of ET-1 on MAP or on the contralateral kidney were observed. TAK-044 dose-dependently reversed the effects of ET-1 on RBFprobe and cortical perfusion. TAK-044 also reduced MAP (by up to 11+/-3%) and increased effective renal blood flow in the contralateral kidney (by up to 46+/-27%). In the extracorporeal circuit model, TAK-044 decreased MAP by 12+/-2% and RAP by 10+/-3%, and increased RBF by 9+/-3%. Exogenous ET-1 reduces cortical more than medullary perfusion, and reduces GFR without affecting net tubular sodium and fluid reabsorption. TAK-044 antagonizes local renal vascular responses to ET-1. Endogenous ETs appear to contribute markedly to resting renal vasomotor tone and MAP.

Effect of endothelin-1 on regional kidney blood flow and renal arteriole calibre in rabbits

Publisher: Wiley

Date: 08-2004

DOI: 10.1111/J.1440-1681.2004.04036.X

Effects of activation of vasopressin-V₁-receptors on regional kidney blood flow and glomerular arteriole diameters

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2001

DOI: 10.1097/00004872-200103001-00019

Abstract: We tested whether vasoconstriction of juxtamedullary glomerular arterioles contributes to vasopressin V1 -receptor-mediated reductions in medullary perfusion (MBF). The left kidney of pentobarbitone anaesthetized rabbits was denervated, a perivascular flow probe placed around the renal artery and laser-Doppler flow probes positioned in the inner medulla and on the cortical surface. Rabbits then received a 30 min intravenous infusion of [Phe2,Ile3,Orn8]vasopressin (V1 -AG 30 ng/kg per min n = 7) or its vehicle (n = 7). Kidneys were perfusion fixed at the final recorded mean arterial pressure (MAP) and filled with methacrylate casting material. Diameters of afferent and efferent arterioles were determined by scanning electron microscopy. V1 -AG increased MAP (19 +/- 3%) and reduced MBF (30 +/- 8%) but not cortical perfusion or total renal blood flow. Vehicle-treatment did not significantly affect these variables. After vehicle- and V1-AG-treatment, juxtamedullary afferent arteriole luminal diameter averaged 15.35 +/- 1.31 and 15.88 +/- 1.86 microm, respectively (P= 0.92), while juxtamedullary efferent arteriole luminal diameter averaged 17.75 +/- 1.86 and 18.36 +/- 2.24 microm, respectively (P= 0.93). V1-AG reduced MBF but did not significantly affect juxtamedullary arteriolar diameter. Our results therefore do not support a role for juxtamedullary arterioles in producing V1-receptor-mediated reductions in MBF, suggesting that downstream vascular elements (e.g. outer medullary descending vasa recta) might be involved.

Potential roles of high salt intake and maternal malnutrition in the development of hypertension in disadvantaged populations

Publisher: Wiley

Date: 19-01-2010

DOI: 10.1111/J.1440-1681.2009.05266.X

Abstract: 1. It has been argued that all major risk factors for cardiovascular disease have been identified. Yet, epidemiological studies undertaken to identify risk factors have largely focused on populations in developed nations or on the urban or relatively affluent rural populations of developing countries. Poor rural populations are seldom studied. 2. Somewhat different risk factors may operate in poor rural populations. Evidence for this is provided by the finding that, in disadvantaged rural India, the prevalence of hypertension is greater than would be expected based on established risk factors in these populations. One risk factor to be considered is a poor intrauterine environment. 3. In animals, maternal macro- and micronutrient malnutrition can lead to reduced nephron endowment. Nephron deficiency, in turn, can render blood pressure salt sensitive. The combination of nephron deficiency and excessive salt intake will predispose to hypertension. 4. Human malnutrition may have similar effects, particularly in regions of the world where malnutrition is endemic and where women are disadvantaged by existing social practices. 5. Moreover, high salt intake is endemic in many parts of Asia, including India. Therefore, we propose that maternal malnutrition (leading to reduced nephron endowment), when combined with excessive salt intake postnatally, will account, at least in part, for the unexpectedly high prevalence of hypertension in disadvantaged rural communities in India and elsewhere.

Three-dimensional morphometric analysis of the renal vasculature.

Publisher: American Physiological Society

Date: 05-2018

DOI: 10.1152/AJPRENAL.00339.2017

Abstract: Vascular topology and morphology are critical in the regulation of blood flow and the transport of small solutes, including oxygen, carbon dioxide, nitric oxide, and hydrogen sulfide. Renal vascular morphology is particularly challenging, since many arterial walls are partially wrapped by the walls of veins. In the absence of a precise characterization of three-dimensional branching vascular geometry, accurate computational modeling of the intrarenal transport of small diffusible molecules is impossible. An enormous manual effort was required to achieve a relatively precise characterization of rat renal vascular geometry, highlighting the need for an automated method for analysis of branched vasculature morphology to allow characterization of the renal vascular geometry of other species, including humans. We present a semisupervised method for three-dimensional morphometric analysis of renal vasculature images generated by computed tomography. We derive quantitative vascular attributes important to mass transport between arteries, veins, and the renal tissue and present methods for their computation for a three-dimensional vascular geometry. To validate the algorithm, we compare automated vascular estimates with subjective manual measurements for a portion of rabbit kidney. Although increased image resolution can improve outcomes, our results demonstrate that the method can quantify the morphological characteristics of artery-vein pairs, comparing favorably with manual measurements. Similar to the rat, we show that rabbit artery-vein pairs become less intimate along the course of the renal vasculature, but the total wrapped mass transfer coefficient increases and then decreases. This new method will facilitate new quantitative physiological models describing the transport of small molecules within the kidney.

The effects of recruitment of renal functional reserve on renal cortical and medullary oxygenation in non‐anesthetized sheep

Publisher: Wiley

Date: 12-01-2023

DOI: 10.1111/APHA.13919

Abstract: Recruitment of renal functional reserve (RFR) with amino acid loading increases renal blood flow and glomerular filtration rate. However, its effects on renal cortical and medullary oxygenation have not been determined. Accordingly, we tested the effects of recruitment of RFR on renal cortical and medullary oxygenation in non‐anesthetized sheep. Under general anesthesia, we instrumented 10 sheep to enable subsequent continuous measurements of systemic and renal hemodynamics, renal oxygen delivery and consumption, and cortical and medullary tissue oxygen tension (PO 2 ). We then measured the effects of recruitment of RFR with an intravenous infusion of 500 ml of a clinically used amino acid solution (10% Synthamin® 17) in the non‐anesthetized state. Compared with baseline, Synthamin® 17 infusion significantly increased renal oxygen delivery mean ± SD maximum increase: (from 0.79 ± 0.17 to 1.06 ± 0.16 ml/kg/min, p 0.001), renal oxygen consumption (from 0.08 ± 0.01 to 0.15 ± 0.02 ml/kg/min, p 0.001), and glomerular filtration rate (+45.2 ± 2.7%, p 0.001). Renal cortical tissue PO 2 increased by a maximum of 26.4 ± 1.1% ( p = 0.001) and medullary tissue PO 2 increased by a maximum of 23.9 ± 2.8% ( p = 0. 001). In non‐anesthetized healthy sheep, recruitment of RFR improved renal cortical and medullary oxygenation. These observations might have implications for the use of recruitment of RFR for diagnostic and therapeutic purposes.

Effects of tempol and candesartan on neural control of the kidney

Publisher: Elsevier BV

Date: 05-2012

DOI: 10.1016/J.AUTNEU.2012.01.007

Abstract: We compared the effects of tempol (300 μmol kg(-1) plus 300 μmol kg(-1) h(-1), n=14) and candesartan (10 μg kg(-1) plus 10 μg kg(-1) h(-1), n=14) on renal haemodynamics, excretory function, and responses to electrical stimulation of the renal nerves (RNS) in lean and obese rabbits under pentobarbitone anaesthesia. Depressor responses to tempol (-16 ± 2 mmHg) and candesartan (-12 ± 1 mmHg) were similar. Candesartan, but not tempol, significantly increased basal renal blood flow (RBF +36 ± 7%). Tempol, but not candesartan, significantly reduced glomerular filtration rate (GFR -30 ± 10%) and sodium excretion (U(Na)V -44 ± 14%). RNS induced frequency-dependent reductions in RBF (-20 ± 3% at 1 Hz), GFR (-28 ± 6% at 1 Hz) and U(Na)V (-55 ± 6% at 1 Hz). Candesartan blunted these responses. Tempol did not significantly alter RBF and GFR responses to RNS but blunted the U(Na)V response. Responses to RNS, and the effects of tempol and candesartan, were similar in lean compared with obese rabbits. Unlike candesartan, tempol did not induce renal vasodilatation, maintain GFR and U(Na)V during reductions in arterial pressure, or blunt neurally-mediated vasoconstriction. In conclusion, unlike the AT(1)-receptor antagonist candesartan, tempol does not blunt the effects of RNS on renal haemodynamic function. Furthermore, under the current experimental conditions superoxide appears to make little contribution to the actions of endogenous angiotensin II on baseline renal haemodynamics or excretory function, or their responses to RNS.

Oxygen regulation in biological systems

Publisher: American Physiological Society

Date: 15-04-2016

DOI: 10.1152/AJPREGU.00004.2016

Cellular adaptive changes in AKI: mitigating renal hypoxic injury

Publisher: Oxford University Press (OUP)

Date: 30-04-2012

DOI: 10.1093/NDT/GFS100

Abstract: Hypoxia plays a role in ischemic, toxic and sepsis-induced acute kidney injury. Evolving hypoxia triggers renal adaptive responses that may mitigate the insult, leading to sublethal forms of cell injury. The unique capability of the kidney to downregulate oxygen consumption for tubular transport could represent one such adaptive response which promotes maintenance of renal oxygenation, thereby preserving cellular integrity. Tran et al. recently explored a novel mechanism that might prevent tubular damage by downregulation of mitochondrial biogenesis and oxygen consumption. Using expression profiling of kidney RNA in endotoxemic rodents and complementary studies in vitro and in PGC-1α knockout mice, they found a sepsis-related decline in PPARγ coactivator-1α (PGC-1α) expression and of PGC-1α-dependent genes involved in oxidative phosphorylation. This response may explain their observation of a paradoxical preservation of kidney oxygenation and structural integrity in sepsis, despite reduced renal blood flow and oxygen delivery. Thus, resetting of mitochondrial respiration and oxygen consumption during sepsis might be added to the growing list of adaptive responses that occur during hypoxic stress. This review will focus on these mechanisms that mitigate evolving hypoxic injury, even at the expense of transient renal dysfunction.

Role of central opiate receptor subtypes in the circulatory responses of awake rabbits to graded caval occlusions.

Publisher: Wiley

Date: 12-1989

DOI: 10.1113/JPHYSIOL.1989.SP017858

Abstract: 1. In unanaesthetized rabbits, haemorrhage was simulated by inflating a cuff placed round the inferior vena cava so that cardiac output fell at a constant rate of approximately 8% of its resting value per minute. The circulatory responses were measured after injections into the fourth ventricle of saline vehicle, selective opioid antagonists, selective opioid agonists, and agonist-antagonist mixtures. Three sets of experiments were done to determine if a specific subtype of opiate receptor within the central nervous system is responsible for the circulatory decompensation that occurs during simulated haemorrhage. 2. In six rabbits the effects of ascending doses of the antagonists naloxone (mu-selective), Mr 2266 (kappa- and mu-selective), ICI 174864 (delta-selective) and nor-binaltorphimine (kappa-selective) were tested. In three rabbits the effects of the antagonist naloxone, the agonists HTyr-D-Ala-Gly-MePhe-NH(CH2)2OH (DAGO, mu-selective), U 50488H (kappa-selective), and [D-Pen2,D-Pen5]-enkephalin (DPDPE, delta-selective), and combinations of these agonists with naloxone were tested. In four rabbits the dose-related effects of DAGO on respiratory, as well as circulatory, functions were examined. 3. After injecting saline vehicle, the circulatory response to simulated haemorrhage had two phases. During the first phase, systemic vascular conductance fell, heart rate rose, and mean arterial pressure fell by only approximately 10 mmHg. A second, decompensatory, phase began when cardiac output had fallen to approximately 50% of its resting level. At this point, there was an abrupt rise in systemic vascular conductance and a fall in mean arterial pressure to less than or equal to 40 mmHg. 4. The lower range of doses of naloxone (3-30 nmol), Mr 2266 (10-100 nmol), ICI 174864 (10-30 nmol), and all doses of nor-binaltorphimine (1-100 nmol), were without effect on the circulatory response to stimulated haemorrhage. Higher doses of naloxone (30-100 nmol), Mr 2266 (100-300 nmol) and ICI 174864 (30-100 nmol) abolished the decompensatory phase. The relative order of antagonist potency was ICI 174864 greater than or equal to naloxone greater than Mr 2266 greater than or equal to nor-binaltorphimine. 5. In the second set of experiments, the critical dose of naloxone necessary to prevent circulatory decompensation during simulated haemorrhage was 30-150 nmol. The delta-agonist DPDPE (50 nmol) did not affect the haemodynamic response to simulated haemorrhage, but it did block the effect of naloxone on the response.(ABSTRACT TRUNCATED AT 400 WORDS)

Exploring Barriers to and Enablers of the Adoption of Information and Communication Technology for the Care of Older Adults With Chronic Diseases: Scoping Review

Publisher: JMIR Publications Inc.

Date: 07-01-2022

DOI: 10.2196/25251

Abstract: Information and communication technology (ICT) offers considerable potential for supporting older adults in managing their health, including chronic diseases. However, there are mixed opinions about the benefits and effectiveness of ICT interventions for older adults with chronic diseases. We aim to map the use of ICT interventions in health care and identified barriers to and enablers of its use among older adults with chronic disease. A scoping review was conducted using 5 databases (Ovid MEDLINE, Embase, Scopus, PsycINFO, and ProQuest) to identify eligible articles from January 2000 to July 2020. Publications incorporating the use of ICT interventions, otherwise known as eHealth, such as mobile health, telehealth and telemedicine, decision support systems, electronic health records, and remote monitoring in people aged ≥55 years with chronic diseases were included. We conducted a strengths, weaknesses, opportunities, and threats framework analysis to explore the implied enablers of and barriers to the use of ICT interventions. Of the 1149 identified articles, 31 (2.7% n=4185 participants) met the inclusion criteria. Of the 31 articles, 5 (16%) mentioned the use of various eHealth interventions. A range of technologies was reported, including mobile health (8/31, 26%), telehealth (7/31, 23%), electronic health record (2/31, 6%), and mixed ICT interventions (14/31, 45%). Various chronic diseases affecting older adults were identified, including congestive heart failure (9/31, 29%), diabetes (7/31, 23%), chronic respiratory disease (6/31, 19%), and mental health disorders (8/31, 26%). ICT interventions were all designed to help people self-manage chronic diseases and demonstrated positive effects. However, patient-related and health care provider–related challenges, in integrating ICT interventions in routine practice, were identified. Barriers to using ICT interventions in older adults included knowledge gaps, a lack of willingness to adopt new skills, and reluctance to use technologies. Implementation challenges related to ICT interventions such as slow internet connectivity and lack of an appropriate reimbursement policy were reported. Advantages of using ICT interventions include their nonpharmacological nature, provision of health education, encouragement for continued physical activity, and maintenance of a healthy diet. Participants reported that the use of ICT was a fun and effective way of increasing their motivation and supporting self-management tasks. It gave them reassurance and peace of mind by promoting a sense of security and reducing anxiety. ICT interventions have the potential to support the care of older adults with chronic diseases. However, they have not been effectively integrated with routine health care. There is a need to improve awareness and education about ICT interventions among those who could benefit from them, including older adults, caregivers, and health care providers. More sustainable funding is required to promote the adoption of ICT interventions. We recommend involving clinicians and caregivers at the time of designing ICT interventions.

Renal responses to acute reflex activation of renal sympathetic nerve activity and renal denervation in secondary hypertension

Publisher: American Physiological Society

Date: 09-2007

DOI: 10.1152/AJPREGU.00217.2007

Abstract: We tested whether the responsiveness of the kidney to basal renal sympathetic nerve activity (RSNA) or hypoxia-induced reflex increases in RSNA, is enhanced in angiotensin-dependent hypertension in rabbits. Mean arterial pressure, measured in conscious rabbits, was similarly increased (+16 ± 3 mmHg) 4 wk after clipping the left ( n = 6) or right ( n = 5) renal artery or commencing a subcutaneous ANG II infusion ( n = 9) but was not increased after sham surgery ( n = 10). Under pentobarbital sodium anesthesia, reflex increases in RSNA (51 ± 7%) and whole body norepinephrine spillover (90 ± 17%), and the reductions in glomerular filtration rate (−27 ± 5%), urine flow (−43 ± 7%), sodium excretion (−40 ± 7%), and renal cortical perfusion (−7 ± 3%) produced by hypoxia were similar in normotensive and hypertensive groups. Hypoxia-induced increases in renal norepinephrine spillover tended to be less in hypertensive (1.1 ± 0.5 ng/min) than normotensive (3.7 ± 1.2 ng/min) rabbits, but basal overflow of endogenous and exogenous dihydroxyphenolglycol was greater. Renal plasma renin activity (PRA) overflow increased less in hypertensive (22 ± 29 ng/min) than normotensive rabbits (253 ± 88 ng/min) during hypoxia. Acute renal denervation did not alter renal hemodynamics or excretory function but reduced renal PRA overflow. Renal vascular and excretory responses to reflex increases in RSNA induced by hypoxia are relatively normal in angiotensin-dependent hypertension, possibly due to the combined effects of reduced neural norepinephrine release and increased postjunctional reactivity. In contrast, neurally mediated renin release is attenuated. These findings do not support the hypothesis that enhanced neural control of renal function contributes to maintenance of hypertension associated with activation of the renin-angiotensin system.

Diffusive oxygen shunting between vessels in the preglomerular renal vasculature: anatomic observations and computational modeling

Publisher: American Physiological Society

Date: 09-2012

DOI: 10.1152/AJPRENAL.00186.2012

Abstract: To understand how geometric factors affect arterial-to-venous (AV) oxygen shunting, a mathematical model of diffusive oxygen transport in the renal cortex was developed. Preglomerular vascular geometry was investigated using light microscopy (providing vein shape, AV separation, and capillary density near arteries) and published micro-computed tomography (CT) data (providing vessel size and AV separation Nordsletten DA, Blackett S, Bentley MD, Ritman EL, Smith NP. IUPS Physiome Project. www.physiome.org.nz ublications/nordsletten_blackett_ritman_bentley_smith_2005/folder_contents ). A “U-shaped” relationship was observed between the arterial radius and the distance between the arterial and venous lumens. Veins were found to partially wrap around the artery more consistently for larger rather than smaller arteries. Intrarenal arteries were surrounded by an area of fibrous tissue, lacking capillaries, the thickness of which increased from ∼5 μm for the smallest arteries ( -μm diameter) to ∼20 μm for the largest arteries ( -μm diameter). Capillary density was greater near smaller arteries than larger arteries. No capillaries were observed between wrapped AV vessel pairs. The computational model comprised a single AV pair in cross section. Geometric parameters critical in renal oxygen transport were altered according to variations observed by CT and light microscopy. Lumen separation and wrapping of the vein around the artery were found to be the critical geometric factors determining the amount of oxygen shunted between AV pairs. AV oxygen shunting increases both as lumen separation decreases and as the degree of wrapping increases. The model also predicts that capillaries not only deliver oxygen, but can also remove oxygen from the cortical parenchyma close to an AV pair. Thus the presence of oxygen sinks (capillaries or tubules) near arteries would reduce the effectiveness of AV oxygen shunting. Collectively, these data suggest that AV oxygen shunting would be favored in larger vessels common to the cortical and medullary circulations (i.e., arcuate and proximal interlobular arteries) rather than the smaller vessels specific to the cortical circulation (distal interlobular arteries and afferent arterioles).

Mechanisms underlying the antihypertensive functions of the renal medulla

Publisher: Wiley

Date: 29-07-2004

DOI: 10.1111/J.1365-201X.2004.01321.X

Sex differences in the renal vascular response to angiotensin II involves the Mas receptor

Publisher: Wiley

Date: 11-08-2012

DOI: 10.1111/J.1748-1716.2012.02468.X

Abstract: The renin-angiotensin system (RAS) depressor arm, particularly renal angiotensin type 2 receptor (AT(2) R) and Mas receptor (masR) expression, is enhanced in females, which may contribute to renal and cardiovascular protection. We examined the hypotheses that masR activation increases renal blood flow (RBF) at rest and attenuates the reduction in RBF in response to angiotensin II (AngII) infusion in female rats. Furthermore, we postulated that combined activation of the AT(2) R and masR would produce a greater response than masR activation alone. In anaesthetized male and female Wistar rats, mean arterial pressure (MAP) and RBF responses during graded AngII infusion (30-1000 ng kg(-1) min(-1) i.v.) were assessed following pre-treatment with vehicle, the masR antagonist A779, or A779 plus the AT(2) R antagonist PD123319. Basal MAP was not altered by any pre-treatment. Basal RBF decreased approx. 20% in female (P < 0.05), but not male rats in response to A779. However, basal RBF was not altered by A779 + PD123319. AngII infusion reduced RBF in a dose-related fashion (P(dose) < 0.0001) and masR blockade did not alter the RBF response to AngII infusion in male or female rats. However, A779 + PD123319 attenuated the reduction in RBF response to AngII in females (P(group) < 0.005), but not males. The impact of the masR on renal haemodynamics appears to be sexually dimorphic, with greater effects in female than male rats. However, the paradoxical effects of dual AT(2) R and masR blockade suggest that a greater understanding of the complex interactions between RAS components is required before the therapeutic opportunities of AT(2) R and/or masR stimulation can be advanced.

Role of vagal afferents in the haemodynamic response to acute central hypovolaemia in unanaesthetized rabbits

Publisher: Elsevier BV

Date: 03-1994

DOI: 10.1016/0165-1838(94)90042-6

Abstract: In unanaesthetized mammals, including rabbits, the response to acute central hypovolaemia is biphasic. An initial phase of baroreflex-mediated systemic vasoconstriction is succeeded by an abrupt failure of sympathetic vasoconstrictor drive and haemodynamic decompensation. We have tested whether a signal travelling in the cervical vagus nerves is responsible for the second phase. An inflatable vena caval cuff, an ascending aortic flow probe, and diaphragmatic electrodes were chronically implanted into 7 rabbits. Haemorrhage was simulated by gradual caval constriction so cardiac index (CI) fell linearly at 9% per minute. In Study 1, caval constriction was performed under control conditions, after muscarinic cholinoceptor blockade (MCB), and was repeated twice under MCB after a sham operation. In Study 2, the steps were identical but bilateral cervical vagotomy plus tracheostomy was substituted for sham operation. With or without MCB, caval constriction caused a progressive fall of systemic vascular conductance index (SVCI), and a small decline in mean arterial pressure (MAP) (Phase I). When CI had fallen by approximately 40%, there was an abrupt rise of SVCI and fall of MAP (Phase II). Sham operation had no effect on either phase. Vagotomy had no effect on Phase I, but the onset of Phase II was delayed until CI had fallen by approximately 53% in 6 rabbits. In 1 rabbit, Phase II did not occur, even though CI had fallen by 67%. We conclude that an afferent vagal signal does not contribute to the compensatory Phase I, and is not essential for the occurrence of the decompensatory Phase II, of acute central hypovolaemia in unanaesthetized rabbits.

Reversal of renal tissue hypoxia during experimental cardiopulmonary bypass in sheep by increased pump flow and arterial pressure

Publisher: Wiley

Date: 22-12-2021

DOI: 10.1111/APHA.13596

Editors’ Picks for 2018 demonstrate the diversity of research in regulatory, integrative, and comparative physiology

Publisher: American Physiological Society

Date: 07-2019

DOI: 10.1152/AJPREGU.00151.2019

The chronic hypoxia hypothesis: The search for the smoking gun goes on

Publisher: American Physiological Society

Date: 15-01-2015

DOI: 10.1152/AJPRENAL.00587.2014

Combined prenatal and postnatal protein restriction influences adult kidney structure, function, and arterial pressure

Publisher: American Physiological Society

Date: 2007

DOI: 10.1152/AJPREGU.00079.2006

Abstract: The effects of prenatal protein restriction on adult renal and cardiovascular function have been studied in considerable detail. However, little is known about the effects of life-long protein restriction, a common condition in the developing world. Therefore, we determined in rats the effects of combined pre- and postnatal protein restriction on adult arterial pressure and renal function and responses to increased dietary sodium. Nephron number was also determined. Male Sprague-Dawley rats were born to mothers fed a low [8% (wt/wt), LP] or normal [20% (wt/wt), NP] isocaloric protein diet throughout pregnancy and maintained on these diets after birth. At postnatal day 135, nephron number, mean arterial pressure (MAP), and renal function were determined. A high-NaCl [8.0% (wt/wt), high-salt] diet was fed to a subset of rats from weaning. MAP was less in LP than in NP rats (120 ± 2 vs. 128 ± 2 mmHg, P 0.05) and was not significantly altered by increased salt intake. Nephron number was 31% less in LP than in NP rats ( P 0.001). The volume of in idual glomeruli was also less in LP than in NP rats, as were calculated effective renal plasma flow and glomerular filtration rate. Glomerular filtration rate, but not effective renal plasma flow, appeared to be increased by high salt intake, particularly in LP rats. In conclusion, protein restriction induced a severe nephron deficit, but MAP was lower, rather than higher, in protein-restricted than in control rats in adulthood. These findings indicate that the postnatal environment plays a key role in determining the outcomes of developmental programming.

Factors that render the kidney susceptible to tissue hypoxia in hypoxemia

Publisher: American Physiological Society

Date: 04-2011

DOI: 10.1152/AJPREGU.00552.2010

Abstract: To better understand what makes the kidney susceptible to tissue hypoxia, we compared, in the rabbit kidney and hindlimb, the ability of feedback mechanisms governing oxygen consumption (V̇o 2 ) and oxygen delivery (Do 2 ) to attenuate tissue hypoxia during hypoxemia. In the kidney (cortex and medulla) and hindlimb (biceps femoris muscle), we determined responses of whole organ blood flow and V̇o 2 , and local perfusion and tissue Po 2 , to reductions in Do 2 mediated by graded systemic hypoxemia. Progressive hypoxemia reduced tissue Po 2 similarly in the renal cortex, renal medulla, and biceps femoris. Falls in tissue Po 2 could be detected when arterial oxygen content was reduced by as little as 4–8%. V̇o 2 remained stable during progressive hypoxemia, only tending to fall once arterial oxygen content was reduced by 55% for the kidney or 42% for the hindlimb. Even then, the fall in renal V̇o 2 could be accounted for by reduced oxygen demand for sodium transport rather than limited oxygen availability. Hindlimb blood flow and local biceps femoris perfusion increased progressively during graded hypoxia. In contrast, neither total renal blood flow nor cortical or medullary perfusion was altered by hypoxemia. Our data suggest that the absence in the kidney of hyperemic responses to hypoxia, and the insensitivity of renal V̇o 2 to limited oxygen availability, contribute to kidney hypoxia during hypoxemia. The susceptibility of the kidney to tissue hypoxia, even in relatively mild hypoxemia, may have important implications for the progression of kidney disease, particularly in patients at high altitude or with chronic obstructive pulmonary disease.

Intrarenal and urinary oxygenation during norepinephrine resuscitation in ovine septic acute kidney injury

Publisher: Elsevier BV

Date: 07-2016

DOI: 10.1016/J.KINT.2016.02.017

Abstract: Norepinephrine is the principal vasopressor used to restore blood pressure in sepsis, but its effects on intrarenal oxygenation are unknown. To clarify this, we examined renal cortical, medullary, and urinary oxygenation in ovine septic acute kidney injury and the response to resuscitation with norepinephrine. A renal artery flow probe and fiberoptic probes were placed in the cortex and medulla of sheep to measure tissue perfusion and oxygenation. A probe in the bladder catheter measured urinary oxygenation. Sepsis was induced in conscious sheep by infusion of Escherichia coli for 32 hours. At 24 to 30 hours of sepsis, either norepinephrine, to restore mean arterial pressure to preseptic levels or vehicle-saline was infused (8 sheep per group). Septic acute kidney injury was characterized by a reduction in blood pressure of ∼12 mm Hg, renal hyperperfusion, and oliguria. Sepsis reduced medullary perfusion (from an average of 1289 to 628 blood perfusion units), medullary oxygenation (from 32 to 16 mm Hg), and urinary oxygenation (from 36 to 24 mm Hg). Restoring blood pressure with norepinephrine further reduced medullary perfusion to an average of 331 blood perfusion units, medullary oxygenation to 8 mm Hg and urinary oxygenation to 18 mm Hg. Cortical perfusion and oxygenation were preserved. Thus, renal medullary hypoxia caused by intrarenal blood flow redistribution may contribute to the development of septic acute kidney injury, and resuscitation of blood pressure with norepinephrine exacerbates medullary hypoxia. The parallel changes in medullary and urinary oxygenation suggest that urinary oxygenation may be a useful real-time biomarker for risk of acute kidney injury.

The effects of N‐(cyclopropylmethyl)‐19‐isopentyl‐nororvinol (M320), a potent agonist at k‐ and μ‐ opiate receptors, on urine excretion of rats

Publisher: Wiley

Date: 12-1986

DOI: 10.1111/J.1476-5381.1986.TB11180.X

Abstract: The effects of N-(cyclopropylmethyl)-19-isopentylnororvinol hydrochloride (M320) on urine excretion by rats were investigated. Further studies, using rabbit isolated vas deferens, investigated its interactions with kappa-opiate receptors. The output of urine for a 2 h period after M320, administered subcutaneously to normally hydrated Long Evans rats, showed a bell-shaped dose-response relationship, the maximum effect occurring after 10 micrograms kg-1. Urinary retention contributed to but did not fully account for the weaker diuresis after high doses. Attenuation of the ascending portion of the dose-response curve to M320 occurred after 1 and 10 mg kg-1 but not 0.1 mg kg-1 of naltrexone intraperitoneally. M320 in low doses (3-10 micrograms kg-1) caused a small but significant increase in sodium excretion. M320 (30 micrograms kg-1) reduced both sodium and potassium excretion. M320 (10 micrograms kg-1 s.c.) did not increase the volume of urine voided in 2 h by Brattleboro rats showing diabetes insipidus, even when urine excretion was reduced to normal by 1 week of vasopressin replacement. The volume of urine voided in 4 h by Brattleboro rats was progressively reduced to zero by M320 (10-100 micrograms kg-1 s.c.). Urinary retention contributed to but did not account for this reduction. Plasma levels of immunoreactive arginine vasopressin (ir-AVP) were reduced in both normal and dehydrated Long Evans rats after doses greater than 1 microgram kg-1 M320 s.c. In vitro, M320 caused persistent inhibition of twitches of the electrically stimulated rabbit vas deferens (IC50 1.7 nM). 8 These data suggest that M320 has potent opioid agonist activity at K-receptors and at higher concentrations stimulates mu- receptors. In the rat, its activity on K-receptors is associated with diuresis and suppression of plasma vasopressin levels. The antidiuresis seen after high doses may be due to its activity on mu-receptors, possibly at a central site.

Erratum

Publisher: Springer Science and Business Media LLC

Date: 17-03-2015

DOI: 10.1038/PR.2015.17

α-Adrenoceptor subtypes mediating regional kidney blood flow responses to renal nerve stimulation

Publisher: Elsevier BV

Date: 05-2004

DOI: 10.1016/J.AUTNEU.2004.03.001

TISSUE HYPOXIA AS A THERAPEUTIC TARGET IN ACUTE KIDNEY INJURY

Publisher: Wiley

Date: 30-08-2009

DOI: 10.1111/J.1440-1681.2009.05217.X

INTERACTIONS BETWEEN THE CIRCULATORY EFFECTS OF CENTRAL HYPOVOLAEMIA AND ARTERIAL HYPOXIA IN CONSCIOUS RABBITS

Publisher: Wiley

Date: 05-1994

DOI: 10.1111/J.1440-1681.1994.TB02531.X

Abstract: 1. Eight conscious rabbits were repeatedly subjected to progressive reduction in central blood volume by gradually inflating a thoracic inferior vena caval-cuff so cardiac index (CI) fell at a constant 8.5% of baseline/min. 2. Caval-cuff inflations were performed after 10 min exposure to 100, 21, 12-14 and 8-10% O2, with and without the addition of 3-4% CO2, in randomized order. 3. The haemodynamic response to progressive reduction in central blood volume was biphasic. In Phase I, systemic vascular conductance index (SVCI) fell linearly, supporting mean arterial pressure (MAP). When CI had fallen to a critical level, Phase II occurred in which SVCI rose abruptly, MAP plummeted and respiratory drive progressively increased. 4. During Phase I, there were independent linear relationships between PaCO2 (but not PaO2) and the rates at which SVCI and MAP changed during the progressive fall of CI. The higher the level of PaCO2, the greater was the rate of fall of SVCI and the less the rate of fall of MAP. 5. There was an inverted U-shaped effect of PaO2 on the level of CI at which Phase II occurred: (a) during hyperoxia (100% O2), Phase II occurred later than during normoxia (21% O2) and (b) across the normoxic and hypoxic gas mixtures (21-8% O2, with and without added CO2), there was an independent linear relationship between PaO2 (but not PaCO2 or PaO2 x PaCO2) and the level of CI at which Phase II occurred. That is, the lower the level of PaO2, the later was the onset of Phase II. This interaction is best explained by an increased level of central sympathetic vasoconstrictor drive during hypoxia.

Regional responsiveness of renal perfusion to activation of the renal nerves

Publisher: American Physiological Society

Date: 11-2002

DOI: 10.1152/AJPREGU.00151.2002

Abstract: We tested for regional differences in perfusion responses, within the renal medulla and cortex, to renal nerve stimulation in pentobarbital sodium-anesthetized rabbits. Laser-Doppler flux (LDF) was monitored at various depths below the cortical surface (1–15 mm). Basal cortical LDF (1–3 mm, ∼200–450 U) was greater than medullary LDF (5–15 mm, ∼70–160 U), but there were no statistically significant differences in basal LDF within these regions. The background LDF signal during aortic occlusion was similar in the cortex (2 mm, 31 U) and outer medulla (7 mm, 31 U), but slightly greater in the inner medulla (12 mm, 44 U). During electrical stimulation of the renal nerves (0.5–8 Hz), cortical LDF and total renal blood flow were similarly progressively reduced with increasing stimulus frequency. Medullary LDF (measured between 5 and 15 mm) was overall less responsive than cortical LDF. For ex le, 4-Hz stimulation reduced inner medullary LDF (9 mm) by 19 ± 6% but reduced cortical LDF (1 mm) by 54 ± 11%. However, medullary LDF responses to nerve stimulation were similar at all depths measured. Our results indicate that while the vascular elements controlling medullary perfusion are less sensitive to the effects of electrical stimulation of the renal nerves than are those controlling cortical perfusion, sensitivity within these vascular territories appears to be relatively homogeneous.

Effects of the ETA/ETB antagonist, TAK-044, on blood pressure and renal excretory function after unclipping of conscious one-kidney–one-clip hypertensive rats

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2001

DOI: 10.1097/00004872-200103001-00020

Abstract: Restoring renal perfusion pressure (unclipping) of one-kidney-one-clip renal hypertensive (1 K1C) rats normalizes mean arterial pressure (MAP) rapidly. This has been attributed to salt/volume losses or release of the putative renal medullary depressor hormone (RMDH). To investigate the effects of endothelin receptor A and B (ET(A)/ET(B)) antagonism on unclipping. Telemetric devices were implanted in male Wistar 1K1C rats for measurement of conscious MAP. Hypertension was reversed by unclipping with the animal under brief anaesthesia. Seven rats were treated with the ET(A)/ET(B) antagonist, TAK-044 (two doses of 10 mg/kg intraperitoneally in 24 h), and eight rats received its vehicle. In order to investigate whether endothelin receptor antagonism could release RMDH under resting conditions, TAK-044 was administered to telemetered non-clipped intact and chemically renal medullectomized rats (BEA treatment). TAK-044 did not affect resting MAP, urine flow or sodium excretion in 1K1C rats. However, after unclipping, the TAK-044-treated group showed a more marked reduction in MAP during the first 24 h after unclipping (P< 0.01). TAK-044 also reduced urine flow and sodium excretion during the first 8 h after unclipping (P< 0.05). TAK-044 reduced resting MAP (P< 0.05) to a similar extent in intact and BEA rats. TAK-044 potentiated the reduction in MAP after unclipping, independently of changes in urine flow and sodium excretion. It also reduced MAP in normotensive rats--an effect that was not dependent on an intact renal medulla. Potentiation of the depressor response to unclipping by TAK-044 could be the result of an interaction of endogenous endothelin receptors with renal depressor mechanisms--possibly, the release, actions, or both, of the putative RMDH.

Normotension, hypertension and body fluid regulation: brain and kidney

Publisher: Wiley

Date: 19-06-2016

DOI: 10.1111/APHA.12718

Abstract: The fraction of hypertensive patients with essential hypertension (EH) is decreasing as the knowledge of mechanisms of secondary hypertension increases, but in most new cases of hypertension the pathophysiology remains unknown. Separate neurocentric and renocentric concepts of aetiology have prevailed without much interaction. In this regard, several questions regarding the relationships between body fluid and blood pressure regulation are pertinent. Are all forms of EH associated with sympathetic overdrive or a shift in the pressure-natriuresis curve? Is body fluid homoeostasis normally driven by the influence of arterial blood pressure directly on the kidney? Does plasma renin activity, driven by renal nerve activity and renal arterial pressure, provide a key to stratification of EH? Our review indicates that (i) a narrow definition of EH is useful (ii) in EH, indices of cardiovascular sympathetic activity are elevated in about 50% of cases (iii) in EH as in normal conditions, mediators other than arterial blood pressure are the major determinants of renal sodium excretion (iv) chronic hypertension is always associated with a shift in the pressure-natriuresis curve, but this may be an epiphenomenon (v) plasma renin levels are useful in the analysis of EH only after metabolic standardization and then determination of the renin function line (plasma renin as a function of sodium intake) and (vi) angiotensin II-mediated hypertension is not a model of EH. Recent studies of baroreceptors and renal nerves as well as sodium intake and renin secretion help bridge the gap between the neurocentric and renocentric concepts.

What Do BOLD MR Imaging Changes in Donors’ Remaining Kidneys Tell Us?

Publisher: Radiological Society of North America (RSNA)

Date: 11-2016

DOI: 10.1148/RADIOL.2016160411

α₂ Adrenoceptor‐ and Imidazoline‐Preferring Binding Sites in the Dog Kidney

Publisher: Wiley

Date: 07-1995

DOI: 10.1111/J.1749-6632.1995.TB32423.X

Evidence that renal arterial-venous oxygen shunting contributes to dynamic regulation of renal oxygenation

Publisher: American Physiological Society

Date: 06-2007

DOI: 10.1152/AJPRENAL.00436.2006

Abstract: Renal blood flow (RBF) can be reduced in rats and rabbits by up to 40% without significant changes in renal tissue Po 2 . We determined whether this occurs because renal oxygen consumption changes with RBF or due to some other mechanism. The relationships between RBF and renal cortical and medullary tissue Po 2 and renal oxygen metabolism were determined in the denervated kidneys of anesthetized rabbits under hypoxic, normoxic, and hyperoxic conditions. During artificial ventilation with 21% oxygen (normoxia), RBF increased 32 ± 8% during renal arterial infusion of acetylcholine and reduced 31 ± 5% during ANG II infusion. Neither infusion significantly altered arterial pressure, tissue Po 2 in the renal cortex or medulla, nor renal oxygen consumption. However, fractional oxygen extraction fell as RBF increased and the ratio of oxygen consumption to sodium reabsorption increased during ANG II infusion. Ventilation with 10% oxygen (hypoxia) significantly reduced both cortical and medullary Po 2 (60–70%), whereas ventilation with 50% and 100% oxygen (hyperoxia) increased cortical and medullary Po 2 (by 62–298 and 30–56%, respectively). However, responses to altered RBF under hypoxic and hyperoxic conditions were similar to those under normoxic conditions. Thus renal tissue Po 2 was relatively independent of RBF within a physiological range (±30%). This was not due to RBF-dependent changes in renal oxygen consumption. The observation that fractional extraction of oxygen fell with increased RBF, yet renal parenchymal Po 2 remained unchanged, supports the hypothesis that preglomerular diffusional shunting of oxygen from arteries to veins increases with increasing RBF, and so contributes to dynamic regulation of intrarenal oxygenation.

Effects of Renal Medullary and Intravenous Norepinephrine on Renal Antihypertensive Function

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 04-2000

DOI: 10.1161/01.HYP.35.4.965

Abstract: Abstract —Increasing renal arterial pressure activates at least 3 antihypertensive mechanisms: reduced renin release, pressure natriuresis, and release of a putative renal medullary depressor hormone. To examine the role of renal medullary perfusion in these mechanisms, we tested the effects of the infusion of norepinephrine, either infusion into the renal medullary interstitium or intravenous infusion, on responses to increased renal arterial pressure in pentobarbital-anesthetized rabbits. We used an extracorporeal circuit, which allows renal arterial pressure to be set to any level above or below systemic arterial pressure. With renal arterial pressure initially set at 65 mm Hg, intravenous and medullary interstitial norepinephrine (300 ng · kg −1 · min −1 ) similarly increased mean arterial pressure (by 12% to 17% of baseline) and reduced total renal blood flow (by 16% to 17%) and cortical perfusion (by 13% to 19%), but only medullary norepinephrine reduced medullary perfusion (by 28%). When renal arterial pressure was increased to ≈160 mm Hg, in steps of ≈65 mm Hg, urine output and sodium excretion increased exponentially, and plasma renin activity and mean arterial pressure fell. Medullary interstitial but not intravenous norepinephrine attenuated the increased diuresis and natriuresis and the depressor response to increased renal arterial pressure. This suggests that norepinephrine can act within the renal medulla to inhibit these renal antihypertensive mechanisms, perhaps by reducing medullary perfusion. These observations support the concept that medullary perfusion plays a critical role in the long-term control of arterial pressure by its influence on pressure diuresis/natriuresis mechanisms and also by affecting the release of the putative renal medullary depressor hormone.

From the editors-in-chief

Publisher: Wiley

Date: 27-02-2008

DOI: 10.1111/J.1440-1681.2008.04877.X

Mechanisms underlying the diffential control of blood flow in the renal medulla and cortex

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-2004

DOI: 10.1097/01.HJH.0000133744.85490.9D

Abstract: There is much evidence that the medullary circulation plays a key role in regulating renal salt and water handling and, accordingly, the long-term level of arterial pressure. It has also recently become clear that various regulatory factors can affect medullary blood flow (MBF) differently from cortical blood flow (CBF). It appears likely that the influence of hormonal and neural factors on the control of arterial pressure is mediated partly through their impact on MBF. In this review, we focus on the mechanisms underlying the differential control of MBF and CBF, particularly the relative insensitivity of MBF to vasoconstrictors such as angiotensin II, endothelin-1 and the sympathetic nerves. The vascular architecture of the kidney appears to be arranged in a way that protects the renal medulla from ischaemic insults, with juxtamedullary arterioles, the source of MBF, having larger calibre than their counterparts in other kidney regions. Indeed, recent studies using vascular casting methodology suggest that juxtamedullary glomerular arterioles are not the chief regulators of MBF, which is consistent with the idea that outer medullary descending vasa recta play a key role in MBF control. Release of vasoactive paracrine factors such as nitric oxide and various eicosanoids from the vascular endothelium, and probably also from the tubular epithelium, appear to differentially modulate responses of MBF and CBF to hormonal and neural factors. The prevailing intrarenal hormonal milieu and existing haemodynamic conditions also appear to strongly modulate these responses, indicating that multiple control systems interact to regulate regional kidney blood flow at an integrative level.

Role of bradykinin receptors in the renal effects of inhibition of angiotensin converting enzyme and endopeptidases 24.11 and 24.15 in conscious rabbits

Publisher: Wiley

Date: 09-1996

DOI: 10.1111/J.1476-5381.1996.TB15995.X

Abstract: 1. We tested the effects on systemic haemodynamics and renal function, of inhibition of endopeptidase (EP) 24.15 (E.C. 3.4.24.15), in conscious uninephrectomized rabbits in which the activities of angiotensin converting enzyme (ACE, E.C. 3.4.15.1) and neutral endopeptidase (EP 24.11, E.C. 3.4.24.11) were already inhibited. To test the role of bradykinin B2-receptors in mediating the effects following inhibition of these enzymes, the antagonist Hoe 140 was used. 2. Hoe 140 (0.1 mg kg-1, i.v.) did not affect resting mean arterial pressure or heart rate, but antagonized the depressor effect of right atrial administration of bradykinin. The dose-response curve for bradykinin was shifted more than 1000 fold to the right for more than 4 h. Hoe 140 approximately doubled resting urine flow and increased fractional Na+ excretion from 4.2 to 6.0% consistent with the hypothesis that it exerts a partial agonist effect on the kidney. 3. Combined inhibition of ACE (captopril 0.25 mg kg-1 plus 0.2 mg kg-1h-1) and EP 24.11 (SCH 39370 3 mg kg-1 plus 3 mg kg-1h-1) was followed by a sustained reduction in arterial pressure (-6 +/- 2 mmHg) and increase in heart rate (35 +/- 7 beats min-1). There was a small increase in renal blood flow (by 6.5 +/- 3.2% relative to vehicle-treatment) without a change in glomerular filtration rate, and about a 150% increase in Na+ excretion. Hoe 140 (0.1 mg kg-1, i.v.) pretreatment did not influence the renal effects of captopril and SCH 39370, although it did appear to blunt their hypotensive and tachycardic effects. 4. When EP 24.15 was inhibited with N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB 5 mg kg-1 plus 3 mg kg-1h-1, i.v.) in rabbits pretreated with captopril and SCH 39370, no changes in systemic haemodynamics or renal function were observed. 5. We concluded that in conscious uninephrectomized rabbits, EP 24.15 does not play a major role in modulating renal function, at least under conditions where ACE and EP 24.11 are already inhibited. In contrast, ACE and/or EP 24.11 do modulate renal function in this model, but their influences are mediated chiefly through metabolism of peptides other than bradykinin.

ET-Receptor Subtypes: Roles in Regional Renal Vascular Actions of Exogenous and Endogenous Endothelins in Anesthetized Rabbits

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-2000

DOI: 10.1097/00005344-200005000-00001

Abstract: The roles of endothelin (ET)-receptor subtypes, in the regional renal vascular effects of exogenous and endogenous ETs, were examined in pentobarbitone-anesthetized rabbits. The effects of renal arterial infusion of ET-1 (0.05-12.8 ng/kg/min) and the ET(B)-agonist [Ala1,3,11,15]-ET-1 (12.5-800 ng/kg/min) were compared. We then tested the effects of the ET(A)-antagonist BQ610 and the ET(B)-antagonist BQ788 (both 200 microg/kg plus 100 microg/kg/h, i.v.) on basal hemodynamics and on responses to renal arterial ET-1. Both ET-1 and [Ala1,3,11,15]-ET-1 dose-dependently reduced total renal blood flow (RBF) and cortical blood flow (CBF), but not medullary blood flow (MBF). ET-1 was 34-fold more potent than [Ala1,3,11,15-ET-1. BQ610 reduced mean arterial pressure (MAP 14%), and increased RBF (21%) and CBF (12%), but not MBF. BQ788 increased MAP (13%), and reduced RBF (29%) and CBF (15%) but not MBF. Coadministration of both agents increased RBF (18%) and CBF (9%), without significantly affecting MAP. Neither antagonist (alone or combined) significantly affected responses to renal arterial ET-1. We conclude that the predominant renal vascular effects of exogenous and endogenous ETs are cortical vasoconstriction, but not at vascular sites controlling MBF. ET(A)-receptors contribute to the renal vasoconstrictor effects of endogenous ETs. ET(B2)-like receptors appear to contribute to the vasoconstrictor effects of [Ala1,3,11,15]-ET-1.

Evolution of the glomerulus in a marine environment and its implications for renal function in terrestrial vertebrates

Publisher: American Physiological Society

Date: 02-2023

DOI: 10.1152/AJPREGU.00210.2022

Abstract: Nearly a century ago, Homer Smith proposed that the glomerulus evolved to meet the challenge of excretion of water in freshwater vertebrates. This hypothesis has been repeatedly restated in the nephrology and renal physiology literature, even though we now know that vertebrates evolved and ersified in marine (saltwater) environments. A more likely explanation is that the vertebrate glomerulus evolved from the meta-nephridium of marine invertebrates, with the driving force for ultrafiltration being facilitated by the apposition of the filtration barrier to the vasculature (in vertebrates) rather than the coelom (in invertebrates) and the development of a true heart and the more complex vertebrate vascular system. In turn, glomerular filtration aided in idual regulation of alent ions like magnesium, calcium, and sulfate compatible with the function of cardiac and skeletal muscle required for mobile predators. The metabolic cost, imposed by reabsorption of the small amounts of sodium required to drive secretion of these over-abundant alent ions, was small. This innovation, developed in a salt-water environment, provided a preadaptation for life in freshwater, in which the glomerulus was co-opted to facilitate water excretion, albeit with the additional metabolic demand imposed by the need to reabsorb the majority of filtered sodium. The evolution of the glomerulus in saltwater also provided preadaptation for terrestrial life, where the imperative is conservation of both water and electrolytes. The historical contingencies of this scenario may explain why the mammalian kidney is so metabolically inefficient, with ∼80% of oxygen consumption being used to drive reabsorption of filtered sodium.

Intra‐operative and early post‐operative prediction of cardiac surgery‐associated acute kidney injury: Urinary oxygen tension compared with plasma and urinary biomarkers

Publisher: Wiley

Date: 02-11-2022

DOI: 10.1111/1440-1681.13603

Abstract: Acute kidney injury (AKI) is a common and serious post‐operative complication of cardiac surgery. The value of a predictive biomarker is determined not only by its predictive efficacy, but also by how early this prediction can be made. For a biomarker of cardiac surgery‐associated AKI, this is ideally during the intra‐operative period. Therefore, in 82 adult patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB), we prospectively compared the predictive efficacy of various blood and urinary biomarkers with that of continuous measurement of urinary oxygen tension (UPO 2 ) at pre‐determined intra‐ and post‐operative time‐points. None of the blood or urine biomarkers we studied showed predictive efficacy for post‐operative AKI when measured intra‐operatively. When treated as a binary variable (≤ or median for the whole cohort), the earliest excess risk of AKI was predicted by an increase in urinary neutrophil gelatinase‐associated lipocalin (NGAL) at 3 h after entry into the intensive care unit (odds ratio [95% confidence limits], 2.86 [1.14–7.21], p = 0.03). Corresponding time‐points were 6 h for serum creatinine (3.59 [1.40–9.20], p = 0.008), and 24 h for plasma NGAL (4.54 [1.73–11.90], p = 0.002) and serum cystatin C (6.38 [2.35–17.27], p = 0.001). In contrast, indices of intra‐operative urinary hypoxia predicted AKI after weaning from CPB, and in the case of a fall in UPO 2 to ≤10 mmHg, during the rewarming phase of CPB (3.00 [1.19–7.56], p = 0.02). We conclude that continuous measurement of UPO 2 predicts AKI earlier than plasma or urinary NGAL, serum cystatin C, or early post‐operative changes in serum creatinine.

Association Between Changes in Norepinephrine Infusion Rate and Urinary Oxygen Tension After Cardiac Surgery

Publisher: Elsevier BV

Date: 02-2023

DOI: 10.1053/J.JVCA.2022.11.008

Abstract: To determine if the administration of norepinephrine to patients recovering from on-pump cardiac surgery is associated with changes in urinary oxygen tension (PO Single center, prospective observational study. Surgical intensive care unit (ICU). A nonconsecutive s le of 93 patients recovering from on-pump cardiac surgery. In the ICU, norepinephrine was the most commonly used vasopressor agent (90% of patients, 84/93), with fewer patients receiving epinephrine (48%, 45/93) or vasopressin (4%, 4/93). During the 30-to-60-minute period after increasing the infused dose of norepinephrine (n = 89 instances), urinary PO In patients recovering from on-pump cardiac surgery, changes in norepinephrine dose are associated with reciprocal changes in urinary PO

MECHANISMS MEDIATING PRESSURE NATRIURESIS: WHAT WE KNOW and WHAT WE NEED TO FIND OUT

Publisher: Wiley

Date: 22-04-2005

DOI: 10.1111/J.1440-1681.2005.04202.X

Abstract: 1. It is well established that pressure natriuresis plays a key role in long‐term blood pressure regulation, but our understanding of the mechanisms underlying this process is incomplete. 2. Pressure natriuresis is chiefly mediated by inhibition of tubular sodium reabsorption, because both total renal blood flow and glomerular filtration rate are efficiently autoregulated. Inhibition of active sodium transport within both the proximal and distal tubules likely makes a contribution. Increased renal interstitial hydrostatic pressure (RIHP) likely inhibits sodium reabsorption by altering passive diffusion through paracellular pathways in ‘leaky’ tubular elements. 3. Nitric oxide and products of cytochrome P450‐dependent arachidonic acid metabolism are key signalling mechanisms in pressure natriuresis, although their precise roles remain to be determined. 4. The key unresolved question is, how is increased renal artery pressure ‘sensed’ by the kidney? One proposal rests on the notion that blood flow in the renal medulla is poorly autoregulated, so that increased renal artery pressure leads to increased renal medullary blood flow (MBF), which, in turn, leads to increased RIHP. An alternative proposal is that the process of autoregulation of renal blood flow leads to increased shear stress in the preglomerular vasculature and, so, release of nitric oxide and perhaps products of cytochrome P450‐dependent arachidonic acid metabolism, which, in turn, drive the cascade of events that inhibit sodium reabsorption. 5. Central to the arguments underlying these opposing hypotheses is the extent to which MBF is autoregulated. This remains highly controversial, largely because of the limitations of presently available methods for measurement of MBF.

Authors’ Response to: Data sources for measuring the socioeconomic gradient of hypertension in rural populations of low- and middle-income countries

Publisher: Oxford University Press (OUP)

Date: 14-08-2015

DOI: 10.1093/IJE/DYV160

Sex-and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor

Publisher: American Physiological Society

Date: 15-10-2014

DOI: 10.1152/AJPRENAL.00288.2014

Abstract: Sex hormones regulate the renin-angiotensin system. For ex le, estrogen enhances expression of the angiotensin type 2 receptor. We hypothesized that activation of the angiotensin type 2 receptor shifts the chronic pressure-natriuresis relationship leftward in females compared with males and that this effect is lost with age. Mean arterial pressure was measured by radiotelemetry in adult (4 mo old) and aged (14 mo old) wild-type and angiotensin type 2 receptor knockout male and female mice. Chronic pressure-natriuresis curves were constructed while mice were maintained on a normal-salt (0.26%) diet and following 6 days of high salt (5.0%) diet. Mean arterial pressure was lower in adult wild-type females than males (88 ± 1 and 97 ± 1 mmHg, respectively), a difference that was maintained with age, but was absent in adult knockout mice. In wild-type females, the chronic pressure-natriuresis relationship was shifted leftward compared with knockout females, an effect that was lost with age. In males, the chronic pressure-natriuresis relationship was not influenced by angiotensin type 2 receptor deficiency. Compared with age-matched females, the chronic pressure-natriuresis relationships in male mice were shifted rightward. Renal expression of the angiotensin type 2 receptor was fourfold greater in adult wild-type females than males. With age, the angiotensin type 2 receptor-to-angiotensin type 1 receptor balance was reduced in females. Conversely, in males, angiotensin receptor expression did not vary significantly with age. In conclusion, the angiotensin type 2 receptor modulates the chronic pressure-natriuresis relationship in an age- and sex-dependent manner.

DOES THE HAEMODYNAMIC RESPONSE TO ACUTE CENTRAL HYPOVOLAEMIA DEPEND ON THE RATE OF FALL OF CARDIAC OUTPUT?

Publisher: Wiley

Date: 09-1992

DOI: 10.1111/J.1440-1681.1992.TB00518.X

Abstract: 1. In published studies of the effects of acute blood loss in conscious rabbits, the rates of haemorrhage have ranged for 3-9% of blood volume/min. This is potentially a confounding factor when it comes to comparing the results of different studies. We have therefore tested whether the haemodynamic response to acute central hypovolaemia depends on the rate of fall of cardiac output. 2. Cardiac output in six conscious rabbits was reduced by 4, 8 and 12% of baseline levels per min by gradual inflation of a cuff around the thoracic inferior vena cava. These rates correspond approximately to blood loss at rates of 3, 6 and 9% of blood volume/min. 3. The haemodynamic responses were biphasic. In Phase I (compensatory) there was progressive systemic vasoconstriction and tachycardia, and only a small fall in blood pressure. In Phase II (decompensatory), systemic vasoconstriction failed abruptly, arterial pressure plummeted and heart rate declined. 4. We could detect no effect of rate of fall of cardiac output on the pattern of the haemodynamic responses in either Phase I or Phase II. 5. We conclude that the rate of blood loss in different studies of haemorrhage in conscious rabbits, within the range 3 to 9 per cent of blood volume per minute, need not be regarded as a confounding factor when it comes to interpreting the results. It is likely that this conclusion can be generalized to studies of haemorrhage in other mammalian species.

Bladder urine oxygen tension for assessing renal medullary oxygenation in rabbits: Experimental and modeling studies

Publisher: American Physiological Society

Date: 09-2016

DOI: 10.1152/AJPREGU.00195.2016

Abstract: Oxygen tension (Po 2 ) of urine in the bladder could be used to monitor risk of acute kidney injury if it varies with medullary Po 2 . Therefore, we examined this relationship and characterized oxygen diffusion across walls of the ureter and bladder in anesthetized rabbits. A computational model was then developed to predict medullary Po 2 from bladder urine Po 2 . Both intravenous infusion of [Phe 2 ,Ile 3 ,Orn 8 ]-vasopressin and infusion of N G -nitro-l-arginine reduced urinary Po 2 and medullary Po 2 (8–17%), yet had opposite effects on renal blood flow and urine flow. Changes in bladder urine Po 2 during these stimuli correlated strongly with changes in medullary Po 2 (within-rabbit r 2 = 0.87–0.90). Differences in the Po 2 of saline infused into the ureter close to the kidney could be detected in the bladder, although this was diminished at lesser ureteric flow. Diffusion of oxygen across the wall of the bladder was very slow, so it was not considered in the computational model. The model predicts Po 2 in the pelvic ureter (presumed to reflect medullary Po 2 ) from known values of bladder urine Po 2 , urine flow, and arterial Po 2 . Simulations suggest that, across a physiological range of urine flow in anesthetized rabbits (0.1–0.5 ml/min for a single kidney), a change in bladder urine Po 2 explains 10–50% of the change in pelvic urine/medullary Po 2 . Thus, it is possible to infer changes in medullary Po 2 from changes in urinary Po 2 , so urinary Po 2 may have utility as a real-time biomarker of risk of acute kidney injury.

Angiotensin II Type 1 Receptors and Systemic Hemodynamic and Renal Responses to Stress and Altered Blood Volume in Conscious Rabbits

Publisher: Frontiers Media SA

Date: 2011

DOI: 10.3389/FPHYS.2011.00040

Renal hemodynamic responses to intrarenal infusion of ligands for the putative angiotensin IV receptor in anesthetized rats.

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-1999

DOI: 10.1097/00005344-199908000-00005

Abstract: Angiotensin IV, a hexapeptide fragment (3-8) of angiotensin II metabolism, has been reported to produce vasodilatation within the renal vasculature by activation of the putative AT4 receptor. However, there are conflicting findings, with previous in vivo studies providing evidence for and against a renal vasodilator action of angiotensin IV. In this study, the renal hemodynamic responses to activation of the putative AT4 receptor were studied in anesthetized rats by left renal arterial infusion of two endogenous ligands, angiotensin IV and LVV-hemorphin-7. Angiotensin IV (10, 100, and 1,000 pmol/min) infusion caused dose-dependent reductions in blood flow to the infused kidney, which were abolished by pretreatment with losartan. In respect to this effect, angiotensin IV was approximately 300-fold less potent than angiotensin II. There were no significant effects of angiotensin IV on mean arterial pressure, heart rate, or blood flow to the noninfused kidney. Intrarenal infusion of LVV-hemorphin-7 (10, 100, and 1,000 pmol/min) had no significant effect on renal blood flow in the infused and noninfused kidneys, or on mean arterial pressure or heart rate. These results provide no evidence for a renal vasodilatory action of angiotensin IV or LVV-hemorphin-7. On the contrary, intrarenal angiotensin IV infusion produced vasoconstriction of the renal vasculature, mediated by activation of AT1 receptors. These observations provide evidence against a vasodilatory role of putative AT4 receptors in the rat kidney.

A mathematical model of diffusional shunting of oxygen from arteries to veins in the kidney

Publisher: American Physiological Society

Date: 06-2011

DOI: 10.1152/AJPRENAL.00544.2010

Abstract: To understand how arterial-to-venous (AV) oxygen shunting influences kidney oxygenation, a mathematical model of oxygen transport in the renal cortex was created. The model consists of a multiscale hierarchy of 11 countercurrent systems representing the various branch levels of the cortical vasculature. At each level, equations describing the reactive-advection-diffusion of oxygen are solved. Factors critical in renal oxygen transport incorporated into the model include the parallel geometry of arteries and veins and their respective sizes, variation in blood velocity in each vessel, oxygen transport (along the vessels, between the vessels and between vessel and parenchyma), nonlinear binding of oxygen to hemoglobin, and the consumption of oxygen by renal tissue. The model is calibrated using published measurements of cortical vascular geometry and microvascular Po 2 . The model predicts that AV oxygen shunting is quantitatively significant and estimates how much kidney V̇o 2 must change, in the face of altered renal blood flow, to maintain cortical tissue Po 2 at a stable level. It is demonstrated that oxygen shunting increases as renal V̇o 2 or arterial Po 2 increases. Oxygen shunting also increases as renal blood flow is reduced within the physiological range or during mild hemodilution. In severe ischemia or anemia, or when kidney V̇o 2 increases, AV oxygen shunting in proximal vascular elements may reduce the oxygen content of blood destined for the medullary circulation, thereby exacerbating the development of tissue hypoxia. That is, cortical ischemia could cause medullary hypoxia even when medullary perfusion is maintained. Cortical AV oxygen shunting limits the change in oxygen delivery to cortical tissue and stabilizes tissue Po 2 when arterial Po 2 changes, but renders the cortex and perhaps also the medulla susceptible to hypoxia when oxygen delivery falls or consumption increases.

Effectiveness of a scalable group-based education and monitoring program, delivered by health workers, to improve control of hypertension in rural India: A cluster randomised controlled trial

Publisher: Public Library of Science (PLoS)

Date: 02-01-2020

DOI: 10.1371/JOURNAL.PMED.1002997

Urinary oxygen tension: A clinical window on the health of the renal medulla?

Publisher: American Physiological Society

Date: 2014

DOI: 10.1152/AJPREGU.00437.2013

Abstract: We describe the determinants of urinary oxygen tension (Po 2 ) and the potential for use of urinary Po 2 as a “physiological biomarker” of the risk of acute kidney injury (AKI) in hospital settings. We also identify knowledge gaps required for clinical translation of bedside monitoring of urinary Po 2 . Hypoxia in the renal medulla is a hallmark of AKI of erse etiology. Urine in the collecting ducts would be expected to equilibrate with the tissue Po 2 of the inner medulla. Accordingly, the Po 2 of urine in the renal pelvis changes in response to stimuli that would be expected to alter oxygenation of the renal medulla. Oxygen exchange across the walls of the ureter and bladder will confound measurement of the Po 2 of bladder urine. Nevertheless, the Po 2 of bladder urine also changes in response to stimuli that would be expected to alter renal medullary oxygenation. If confounding influences can be understood, urinary bladder Po 2 may provide prognostically useful information, including for prediction of AKI after cardiopulmonary bypass surgery. To translate bedside monitoring of urinary Po 2 into the clinical setting, we require 1) a more detailed knowledge of the relationship between renal medullary oxygenation and the Po 2 of pelvic urine under physiological and pathophysiological conditions 2) a quantitative understanding of the impact of oxygen transport across the ureteric epithelium on urinary Po 2 measured from the bladder and 3) a simple, robust medical device that can be introduced into the bladder via a standard catheter to provide reliable and continuous measurement of urinary Po 2 .

Sepsis‐induced acute kidney injury: A disease of the microcirculation

Publisher: Wiley

Date: 18-07-2018

DOI: 10.1111/MICC.12483

Abstract: AKI is a common complication of sepsis and is significantly associated with mortality. Sepsis accounts for more than 50% of the cases of AKI, with a mortality rate of up to 40%. The pathogenesis of septic AKI is complex, but there is emerging evidence that, at least in the first 48 hours, the defects may be functional rather than structural in nature. For ex le, septic AKI is associated with an absence of histopathological changes, but with microvascular abnormalities and tubular stress. In this context, renal medullary hypoxia due to redistribution of intra-renal perfusion is emerging as a critical mediator of septic AKI. Clinically, vasopressor drugs remain the cornerstone of therapy for maintenance of blood pressure and organ perfusion. However, in septic AKI, there is insensitivity to vasopressors such as norepinephrine, leading to persistent hypotension and organ failure. Vasopressin, angiotensin II, and, paradoxically, α

CHARACTERIZATION OF BINDING SITES FOR [³H]‐IDAZOXAN, [³H]‐P‐AMINOCLONIDINE AND [³H]‐RAUWOLSCINE IN THE KIDNEY OF THE DOG

Publisher: Wiley

Date: 08-1994

DOI: 10.1111/J.1440-1681.1994.TB02566.X

Abstract: 1. We characterized the binding of [3H]-rauwolscine, [3H]-p-aminoclonidine and [3H]-idazoxan in a dog kidney membrane preparation. Our aim was to determine the pharmacological nature of the alpha 2-adrenoceptor- and imidazoline-preferring binding sites in this organ. 2. [3H]-Rauwolscine bound to an apparent single site with an affinity (KD) of 2.2 nmol/L and a maximum density (Bmax) of 58.5 fmol/mg protein, when 10 mumol/L idazoxan defined non-specific binding. However displacement studies demonstrated that a number of compounds, including prazosin, inhibited [3H]-rauwolscine binding in a complex manner consistent with displacement from two distinct binding sites. The majority (69%) of the [3H]-rauwolscine binding sites had a relatively low affinity for prazosin (KI = 398 nmol/L), while the remainder had a relatively high affinity for prazosin (KI = 7.9 nmol/L). 3. [3H]-p-Aminoclonidine bound to an apparent single site (KD = 5.2 nmol/L Bmax = 72.4 fmol/mg protein), when 10 mumol/L phentolamine defined non-specific binding. When 1 mumol/L of the potent and selective alpha 2-adrenoceptor antagonist 2-methoxyidazoxan was included in the incubate, no specific binding was detected. We therefore conclude that under the conditions of this experiment [3H]-p-aminoclonidine binds only to alpha 2-adrenoceptors in the dog kidney. 4. [3H]-Idazoxan bound to two sites, with a higher (KD = 0.95 nmol/L Bmax = 43.9 fmol/mg protein) and lower (KD = 9.1 nmol/L Bmax = 93.8 fmol/mg protein) affinity, respectively, when 1 mmol/L phentolamine defined non-specific binding. When 10 mumol/L GTP gamma S was included in the incubate, the low affinity site was unaffected but the maximum binding at the higher affinity site was reduced by 79%. 2-Methoxyidazoxan displaced [3H]-idazoxan in a monophasic manner and with low potency (IC50 = 11.5 mumol/L). Yohimbine, efaroxan, clonidine, rilmenidine, guanabenz and idazoxan itself displaced [3H]-idazoxan in a complex manner the slope of the displacement curves being less than unity. 5. We conclude that the dog kidney contains a heterogeneous population of alpha 2-adrenoceptors that can be labelled either with [3H]-rauwolscine or [3H]-p-aminoclonidine. The dog kidney also contains a heterogeneous population of non-adrenoceptor imidazoline-preferring binding sites of the I2-subtype, that can be labelled with [3H]-idazoxan. The binding site for which [3H]-idazoxan has the highest affinity appears to be coupled to a guanine nucleotide binding regulatory protein.

Modelling The Neural Control Of Intrarenal Blood Flow

Publisher: Wiley

Date: 14-08-2000

DOI: 10.1046/J.1440-1681.2000.03298.X

Abstract: 1. The aim of the present study was to produce a mathematical model that describes the way dynamic changes in renal sympathetic nerve activity affect renal, cortical and medullary blood flow. 2. Cortical blood flow (CBF) and medullary blood flow (MBF) were measured using laser-Doppler flowmetry and (total) renal blood flow (RBF) was measured by transit-time flowmetry in six pentobarbitone-anaesthetized rabbits. The renal nerves were stimulated with rectangular pulses of 2 msec width and constant voltage at frequencies of 0.5, 1, 1.5, 2 and 3 Hz. 3. An exponential function with two parameters was applied steady state gain and a dynamic constant for the blood flow reduction with stimulation. The steady state gain coefficients were similar for RBF and CBF, but significantly less for MBF. The time taken to reach minimum flow was less for MBF than for RBF and CBF. 4. The model parameters indicate that there is differential neural control of CBF and MBF.

Amygdala–hippocampal shape and cortical thickness abnormalities in first-episode schizophrenia and mania

Publisher: Cambridge University Press (CUP)

Date: 28-11-2012

DOI: 10.1017/S0033291712002218

Abstract: Abnormalities in cortical thickness and subcortical structures have been studied in schizophrenia but little is known about corresponding changes in mania and brain structural differences between these two psychiatric conditions, especially early in the stage of the illness. In this study we aimed to compare cortical thickness and shape of the amygdala–hippoc al complex in first-episode schizophrenia (FES) and mania (FEM). Structural magnetic resonance imaging (MRI) was performed on 28 FES patients, 28 FEM patients and 28 healthy control subjects who were matched for age, gender and handedness. Overall, the shape of the amygdala was deformed in both patient groups, relative to controls. Compared to FEM patients, FES patients had significant inward shape deformation in the left hippoc al tail, right hippoc al body and a small region in the right amygdala. Cortical thinning was more widespread in FES patients, with significant differences found in the temporal brain regions when compared with FEM and controls. Significant differences were observed between the two groups of patients with FES and FEM in terms of the hippoc al shape and cortical thickness in the temporal region, highlighting that distinguishable brain structural changes are present early in the course of schizophrenia and mania.

Role of the kidney in the pathogenesis of hypertension: time for a neo-Guytonian paradigm or a paradigm shift?

Publisher: American Physiological Society

Date: 02-2016

DOI: 10.1152/AJPREGU.00254.2015

Abstract: The “Guytonian paradigm” places the direct effect of arterial pressure, on renal excretion of salt and water, at the center of long-term control of blood pressure, and thus the pathogenesis of hypertension. It originated in the sixties and remains influential within the field of hypertension research. However, the concept of one central long-term feedback loop, through which arterial pressure is maintained by its influence on renal function, has been questioned. Furthermore, some concepts in the paradigm are undermined by experimental observations. For ex le, volume retention and increased cardiac output induced by high salt intake do not necessarily lead to increased arterial pressure. Indeed, in multiple models of salt-sensitive hypertension the major abnormality appears to be failure of the vasodilator response to increased cardiac output, seen in salt-resistant animals, rather than an increase in cardiac output itself. There is also evidence that renal control of extracellular fluid volume is driven chiefly by volume-dependent neurohumoral control mechanisms rather than through direct or indirect effects of changes in arterial pressure, compatible with the concept that renal sodium excretion is controlled by parallel actions of different feedback systems, including hormones, reflexes, and renal arterial pressure. Moreover, we still do not fully understand the sequence of events underlying the phenomenon of “whole body autoregulation.” Thus the events by which volume retention may develop to hypertension characterized by increased peripheral resistance remain enigmatic. Finally, by definition, animal models of hypertension are not “essential hypertension ” progress in our understanding of essential hypertension depends on new results on system functions in patients.

NEURAL, HORMONAL and RENAL INTERACTIONS IN LONG‐TERM BLOOD PRESSURE CONTROL

Publisher: Wiley

Date: 22-04-2005

DOI: 10.1111/J.1440-1681.2005.04198.X

Nitric Oxide in Responses of Regional Kidney Blood Flow to Vasoactive Agents in Anesthetized Rabbits

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-2002

DOI: 10.1097/00005344-200208000-00006

Abstract: To determine whether differential release of nitric oxide underlies the ersity of regional kidney blood flow responses to vasoactive agents, this study examined how nitric oxide synthase blockade with IV N(G)-nitro-L-arginine (L-NNA), and also IV L-NNA plus co-infusion of glyceryl trinitrate, affected responses to renal arterial boluses and infusions of vasoactive agents. L-NNA, but not vehicle, or L-NNA plus glyceryl trinitrate, increased mean arterial pressure (35%) and reduced renal blood flow (20%), cortical perfusion (11%), and medullary perfusion (54%). L-NNA plus glyceryl trinitrate, but not L-NNA alone, blunted renal vasodilatation in response to boluses of bradykinin and acetylcholine, abolished increased medullary perfusion after bolus angiotensin II, and enhanced reductions in medullary perfusion, and to a lesser extent those in renal blood flow and cortical perfusion, during norepinephrine infusion. Neither L-NNA, nor L-NNA plus glyceryl trinitrate, affected responses to infusions of angiotensin II, [Phe(2),Ile(3),Orn(8)]-vasopressin, or endothelin-1. The data indicate roles for nitric oxide in angiotensin II-induced increases in medullary perfusion and in protecting medullary perfusion from norepinephrine-induced vasoconstriction. However, differential engagement of nitric oxide synthase cannot completely account for the ersity of responses of regional kidney perfusion to vasoactive agents. Effects of nitric oxide synthase blockade on renal vascular responses to vasoactive agents were revealed only when glyceryl trinitrate was co-infused to restore resting nitrergic vasodilator tone. This may reflect interactions between nitric oxide and other vasodilator mediators, in modulating renal hemodynamic responses to vasoactive agents.

Hypoxic signaling: some organs are more equal than others. Focus on “Differential HIF and NOS responses to acute anemia: defining organ-specific hemoglobin thresholds for tissue hypoxia”

Publisher: American Physiological Society

Date: 07-2014

DOI: 10.1152/AJPREGU.00524.2013

Measurement of renal tissue oxygen tension: Systematic differences between fluorescence optode and microelectrode recordings in anaesthetized rabbits

Publisher: S. Karger AG

Date: 28-01-2008

DOI: 10.1159/000114203

Abstract: i Background/Aims: /i The validity of fluorescence optodes for measurement of renal cortical tissue oxygen tension was tested by comparison with Clark electrodes. i Methods: /i We varied renal blood flow and inspired O sub /sub content in anaesthetized rabbits while simultaneously measuring cortical tissue oxygen tension. i Results: /i Cortical oxygen tension varied with inspired O sub /sub content. Fluorescence optode measurements were more tightly distributed than those from a Clark electrode. Cumulative frequency distributions for fluorescence optodes were shifted to the left of those for Clark electrodes. The slope of the relationship between oxygen tension in arterial blood and cortical tissue was less for the fluorescence optode than the Clark electrode. Cortical tissue oxygen tension measurements by these two methods were correlated (r sup /sup = 0.32 p 0.001), with no fixed bias but considerable proportional bias. Thus, the slope of the relationship between the two measurements was less than unity (0.57 [0.50–0.69]). i Conclusion: /i Cortical oxygen tension values from fluorescence optodes are less variable but proportionally less than those from Clark electrodes. Theoretical considerations suggest that true interstitial oxygen tension lies somewhere between values provided by the two techniques. Nevertheless, the lesser variability of the fluorescence optode technique may aid detection of physiologically significant changes in intrarenal oxygenation.

The Effects of Targeted Changes in Systemic Blood Flow and Mean Arterial Pressure on Urine Oximetry During Cardiopulmonary Bypass

Publisher: Elsevier BV

Date: 09-2022

DOI: 10.1053/J.JVCA.2022.05.023

Abstract: Poor medullary oxygenation is implicated in the evolution of acute kidney injury. The authors sought to determine if increasing systemic flow and mean arterial pressure could improve urine oxygen tension (PuO Randomized crossover study. University-affiliated hospital. Twenty adult patients undergoing cardiopulmonary bypass (CPB) with expected cross-cl time of >60 minutes and estimated glomerular filtration rate of >30 mL/min/1.73m Sequential 20-minute periods of 2 interventions: Intervention H ("High") or Intervention N ("Normal"). The order of interventions was determined by randomization. Intervention H: targeted CPB flow 3.0 L/min/m PuO PuO

AN UPDATE FROM THE EDITORS OF CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY

Publisher: Wiley

Date: 2009

DOI: 10.1111/J.1440-1681.2008.05093.X

Renal Decapsulation to Treat Ischemic Acute Kidney Injury: A New Twist in an Old Tale*

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 02-2018

DOI: 10.1097/CCM.0000000000002861

Furosemide reverses medullary tissue hypoxia in ovine septic acute kidney injury.

Publisher: American Physiological Society

Date: 08-2019

DOI: 10.1152/AJPREGU.00371.2018

Abstract: In experimental sepsis, the rapid development of renal medullary hypoxia precedes the development of acute kidney injury (AKI) and may contribute to its pathogenesis. We investigated whether inhibiting active sodium transport and oxygen consumption in the medullary thick ascending limb with furosemide attenuates the medullary hypoxia in experimental septic AKI. Sheep were instrumented with flow probes on the pulmonary and renal arteries and fiber optic probes to measure renal cortical and medullary perfusion and oxygen tension (Po

Chronic renal blood flow measurement in dogs by transit-time ultrasound flowmetry.

Publisher: Elsevier BV

Date: 09-1997

DOI: 10.1016/S1056-8719(97)00046-4

Abstract: To test the validity of transit-time ultrasound flowmetry for chronic measurement of renal blood flow in dogs, we compared this method with the renal clearance of para-aminohippuric acid (CPAH) (corrected for hematocrit), and with direct volumetric measurements. When flow-probes were implanted without silastic sheeting to stabilize the implant, there was significant disparity between the (within-dog) mean levels of renal blood flow estimated by flow-probe and CPAH. In contrast, when the flow-probe implants were stabilized with silicone sheeting, there was close agreement in each dog between the flow rates measured by the two methods. When flow-probes were calibrated volumetrically in situ, there was a close linear relationship between flow derived from the flow-probe and that measured volumetrically (r = 0.98 +/- 0.02). We conclude that valid, chronic measurement of renal blood flow in dogs can be achieved using transit-time ultrasound flowmetry, provided the implant is stabilized with silicone sheeting.

Contributions of endothelium-derived relaxing factors to control of hindlimb blood flow in the mouse in vivo

Publisher: American Physiological Society

Date: 08-2007

DOI: 10.1152/AJPHEART.00072.2007

Abstract: We determined the contributions of various endothelium-derived relaxing factors to control of basal vascular tone and endothelium-dependent vasodilation in the mouse hindlimb in vivo. Under anesthesia, catheters were placed in a carotid artery, jugular vein, and femoral artery (for local hindlimb circulation injections). Hindlimb blood flow (HBF) was measured by transit-time ultrasound flowmetry. N ω -nitro-l-arginine methyl ester (l-NAME, 50 mg/kg plus 10 mg·kg −1 ·h −1 ), to block nitric oxide (NO) production, altered basal hemodynamics, increasing mean arterial pressure (30 ± 3%) and reducing HBF (−30 ± 12%). Basal hemodynamics were not significantly altered by indomethacin (10 mg·kg −1 ·h −1 ), charybdotoxin (ChTx, 3 × 10 −8 mol/l), apamin (2.5 × 10 −7 mol/l), or ChTx plus apamin (to block endothelium-derived hyperpolarizing factor EDHF). Hyperemic responses to local injection of acetylcholine (2.4 μg/kg) were reproducible in vehicle-treated mice and were not significantly attenuated by l-NAME alone, indomethacin alone, l-NAME plus indomethacin with or without co-infusion of diethlyamine NONOate to restore resting NO levels, ChTx alone, or apamin alone. Hyperemic responses evoked by acetylcholine were reduced by 29 ± 11% after combined treatment with apamin plus charybdotoxin, and the remainder was virtually abolished by additional treatment with l-NAME but not indomethacin. None of the treatments altered the hyperemic response to sodium nitroprusside (5 μg/kg). We conclude that endothelium-dependent vasodilation in the mouse hindlimb in vivo is mediated by both NO and EDHF. EDHF can fully compensate for the loss of NO, but this cannot be explained by tonic inhibition of EDHF by NO. Control of basal vasodilator tone in the mouse hindlimb is dominated by NO.

Effects of naloxone on the haemodynamic and renal functional responses to plasma volume expansion in conscious rabbits

Publisher: Springer Science and Business Media LLC

Date: 15-11-1999

DOI: 10.1007/S004240051139

Angiotensin II and neurohumoral control of the renal medullary circulation

Publisher: Wiley

Date: 19-01-2010

DOI: 10.1111/J.1440-1681.2009.05233.X

Abstract: 1. Angiotensin (Ang) II has multiple actions in the renal medullary circulation. It can induce vasodilatation and blunt the response of medullary blood flow (MBF) to renal nerve activation through AT(1) receptor-mediated release of nitric oxide (NO) and/or vasodilator prostaglandins. These actions require high intravascular and/or intratubular AngII concentrations, so are not apparent under physiological conditions. 2. Nevertheless, these mechanisms blunt the responsiveness of MBF to AT(1) receptor-mediated vasoconstriction. When these protective mechanisms fail, as when oxidative stress reduces NO bioavailability in the medullary circulation, AngII reduces MBF. If sustained, reduced MBF leads to the development of hypertension. 3. Chronic activation of the renin-angiotensin system (RAS) induces oxidative stress in the kidney. Therefore, MBF may be reduced in models of hypertension associated with RAS activation both because AngII levels per se are increased and because of increased responsiveness of MBF to AngII-induced vasoconstriction. 4. Endogenous AngII enhances the responsiveness of MBF to renal nerve stimulation, whereas NO blunts it. Chronic RAS activation and/or oxidative stress should therefore be expected to enhance MBF responses to renal nerve stimulation. Consistent with this, reductions in MBF induced by renal nerve stimulation are enhanced in rabbits with AngII-induced hypertension, renovascular hypertension or after 9 weeks of fat feeding. 5. We conclude that the ability of endogenous AngII to reduce MBF and enhance the response of MBF to activation of the renal nerves could contribute to the development of hypertension under conditions of RAS activation, especially if accompanied by increased renal sympathetic nerve activity.

Effects of α-adrenoceptor antagonists and clonidine on the haemodynamic response to acute hypovolaemia in conscious rabbits

Publisher: Elsevier BV

Date: 06-1992

DOI: 10.1016/0014-2999(92)90369-F

Abstract: In conscious rabbits an inferior vena caval cuff was progressively inflated so cardiac output fell at a constant approximately 8% of its baseline value. There was a biphasic haemodynamic response, consisting of an initial compensatory phase during which there was progressive systemic vasoconstriction and tachycardia, followed by a decompensatory phase in which systemic vasoconstriction failed abruptly, blood pressure plummeted and heart rate declined. We tested the effects on the haemodynamic response of prior 4th ventricular, and in some cases intravenous, infusions of saline, yohimbine, clonidine, yohimbine plus clonidine, and bunazosin. From the results we conclude that a yohimbine-sensitive mechanism in the brainstem, possibly alpha 2-adrenoceptor-mediated, may be an essential element of the cardiac receptor-mediated decompensatory phase of acute central hypovolaemia, but does not contribute to the arterial baroreflex-mediated compensatory phase.

Accounting for oxygen in the renal cortex: A computational study of factors that predispose the cortex to hypoxia

Publisher: American Physiological Society

Date: 08-2017

DOI: 10.1152/AJPRENAL.00657.2016

Abstract: We develop a pseudo-three-dimensional model of oxygen transport for the renal cortex of the rat, incorporating both the axial and radial geometry of the preglomerular circulation and quantitative information regarding the surface areas and transport from the vasculature and renal corpuscles. The computational model was validated by simulating four sets of published experimental studies of renal oxygenation in rats. Under the control conditions, the predicted cortical tissue oxygen tension ([Formula: see text]) or microvascular oxygen tension (µPo 2 ) were within ±1 SE of the mean value observed experimentally. The predicted [Formula: see text] or µPo 2 in response to ischemia-reperfusion injury, acute hemodilution, blockade of nitric oxide synthase, or uncoupling mitochondrial respiration, were within ±2 SE observed experimentally. We performed a sensitivity analysis of the key model parameters to assess their in idual or combined impact on the predicted [Formula: see text] and µPo 2 . The model parameters analyzed were as follows: 1) the major determinants of renal oxygen delivery ([Formula: see text]) (arterial blood Po 2 , hemoglobin concentration, and renal blood flow) 2) the major determinants of renal oxygen consumption (V̇o 2 ) [glomerular filtration rate (GFR) and the efficiency of oxygen utilization for sodium reabsorption (β)] and 3) peritubular capillary surface area (PCSA). Reductions in PCSA by 50% were found to profoundly increase the sensitivity of [Formula: see text] and µPo 2 to the major the determinants of [Formula: see text] and V̇o 2 . The increasing likelihood of hypoxia with decreasing PCSA provides a potential explanation for the increased risk of acute kidney injury in some experimental animals and for patients with chronic kidney disease.

Augmented endothelial-specific L-arginine transport blunts the contribution of the sympathetic nervous system to obesity induced hypertension in mice

Publisher: Public Library of Science (PLoS)

Date: 17-07-2015

DOI: 10.1371/JOURNAL.PONE.0131424

Gender-specific effects of caste and salt on hypertension in poverty: a population-based study

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2011

DOI: 10.1097/HJH.0B013E328341888C

Lipoxygenase and cyclo‐oxygenase products in the control of regional kidney blood flow in rabbits

Publisher: Wiley

Date: 11-2003

DOI: 10.1046/J.1440-1681.2003.03916.X

Abstract: 1. The aim of the present study was to examine the roles of cyclo-oxygenase (COX)- and lipoxygenase (LOX)-dependent arachidonate signalling cascades in the control of regional kidney blood flow. 2. In pentobarbitone-anaesthetized rabbits treated with NG-nitro-l-arginine and glyceryl trinitrate to 'cl ' nitric oxide, we determined the effects of ibuprofen (a COX inhibitor) and esculetin (a LOX inhibitor) on resting systemic and renal haemodynamics and responses to renal arterial infusions of vasoconstrictors. 3. Ibuprofen increased mean arterial pressure (14 +/- 5%) and reduced medullary laser Doppler flux (MLDF 26 +/- 6%) when administered with esculetin. A similar pattern of responses was observed when ibuprofen was given alone, although the reduction in MLDF was not statistically significant. Esculetin tended to increase renal blood flow (RBF 16 +/- 7%) and MLDF (28 +/- 13%) when given alone, but not when combined with ibuprofen. 4. After vehicle, renal arterial infusions of noradrenaline, angiotensin II and endothelin-1 reduced RBF and cortical laser Doppler flux (CLDF), but not MLDF. In contrast, renal arterial [Phe2,Ile3,Orn8]-vasopressin reduced MLDF but not RBF or CLDF. Ibuprofen alone did not significantly affect these responses. Esculetin, when given alone, but not when combined with ibuprofen, enhanced noradrenaline-induced renal vasoconstriction. In contrast, esculetin did not significantly affect responses to [Phe2,Ile3,Orn8]-vasopressin, angiotensin II or endothelin-1. 5. We conclude that COX products contribute to the maintenance of arterial pressure and renal medullary perfusion under 'nitric oxide cl ' conditions, but not to renal haemodynamic responses to the vasoconstrictors we tested. Lipoxygenase products may blunt noradrenaline-induced vasoconstriction, but our observations may, instead, reflect LOX-independent effects of esculetin.

Oxygen, Free Radicals, and the Kidney

Publisher: Springer Berlin Heidelberg

Date: 2014

DOI: 10.1007/978-3-642-30018-9_112

Low Dose Angiotensin II Infusions into the Renal Artery Induce Chronic Hypertension in Conscious Dogs

Publisher: Informa UK Limited

Date: 1997

DOI: 10.3109/08037059709086446

Abstract: Angiotensin II was infused at 0.5 ng/kg/min either directly into the left renal artery (n = 5) or intravenously (n = 4) for 28 days in conscious dogs. Renal artery infusion of angiotensin II had no significant effect on mean arterial pressure after 1 and 24 h, but pressure had increased by 12 +/- 2, 12 +/- 4, 8 +/- 3 and 13 +/- 3 mmHg on days 7, 14, 21 and 28, respectively, during infusion. Renal blood flow decreased significantly at 24 hours (p = 0.02) but was not significantly reduced subsequently. Over days 7-28, central venous pressure and haematocrit rose significantly but body weight did not change significantly. During intravenous infusion of angiotensin II, arterial pressure increased (5 +/- 4, 7 +/- 5 and 5 +/- 3 mmHg on days 7, 14 and 21, respectively), body weight rose and haematocrit fell significantly, but central venous pressure did not change. Thus, angiotensin II infused into the renal artery, at a dose which had no initial pressor effect, produced chronic, stable hypertension, with equivocal evidence of renal fluid retention. We conclude that elevated levels of angiotensin II in the kidney alone can cause chronic hypertension.

Nitric oxide and superoxide in the renal medulla: a delicate balancing act

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 2005

DOI: 10.1097/00041552-200501000-00003

Abstract: Endothelial nitric oxide synthase (eNOS) and nicotinamide adenine dinucleotide (phosphate) oxidase [NAD(P)H oxidase] are both expressed in tubular epithelial cells within the renal medulla, particularly the thick ascending limb of the loop of Henle (mTALH). Thick ascending limbs contribute to long-term blood pressure control, both because they reabsorb approximately 30% of filtered sodium, and because they produce paracrine factors like nitric oxide (NO) that control medullary blood flow (MBF), which in turn has a major impact on tubular sodium reabsorption. Herein, we review recent evidence for roles of NO and superoxide (O2*-) in autocrine control of tubular sodium reabsorption, and in paracrine control of MBF. O2*- can have a direct action to reduce MBF, and to enhance sodium reabsorption from mTALH. These actions oppose those of NO produced in mTALH, which inhibits tubular sodium reabsorption (autocrine) and increases MBF (paracrine). NO and O2*- also oppose each other's actions through chemical combination to produce peroxynitrite. Thus, interactions between NO and O2*-, at both the chemical and cellular levels, likely contribute to long-term blood pressure control. This hypothesis is supported by recent data showing that sodium retention and hypertension can develop when the balance of production of these free radicals is tipped towards O2*-, such as in diabetes, atherosclerosis and renin-angiotensin-system activation. Interactions between O2*- and NO produced within the mTALH regulate tubular and vascular function in the renal medulla. Dysregulation of these systems in states of oxidative stress likely promotes salt and water retention, and thus hypertension.

Chronic intermittent hypoxia accelerates coronary microcirculatory dysfunction in insulin-resistant Goto-Kakizaki rats

Publisher: American Physiological Society

Date: 08-2016

DOI: 10.1152/AJPREGU.00112.2016

Abstract: Chronic intermittent hypoxia (IH) induces oxidative stress and inflammation, which impair vascular endothelial function. Long-term insulin resistance also leads to endothelial dysfunction. We determined, in vivo, whether the effects of chronic IH and insulin resistance on endothelial function augment each other. Male 12-wk-old Goto-Kakizaki (GK) and Wistar control rats were subjected to normoxia or chronic IH (90-s N 2 , 5% O 2 at nadir, 90-s air, 20 cycles/h, 8 h/day) for 4 wk. Coronary endothelial function was assessed using microangiography with synchrotron radiation. Imaging was performed at baseline, during infusion of acetylcholine (ACh, 5 μg·kg −1 ·min −1 ) and then sodium nitroprusside (SNP, 5 μg·kg −1 ·min −1 ), after blockade of both nitric oxide (NO) synthase (NOS) with N ω -nitro-l-arginine methyl ester (l-NAME, 50 mg/kg) and cyclooxygenase (COX, meclofenamate, 3 mg/kg), and during subsequent ACh. In GK rats, coronary vasodilatation in response to ACh and SNP was blunted compared with Wistar rats, and responses to ACh were abolished after blockade. In Wistar rats, IH blunted the ability of ACh or SNP to increase the number of visible vessels. In GK rats exposed to IH, neither ACh nor SNP were able to increase visible vessel number or caliber, and blockade resulted in marked vasoconstriction. Our findings indicate that IH augments the deleterious effects of insulin resistance on coronary endothelial function. They appear to increase the dependence of the coronary microcirculation on NO and/or vasodilator prostanoids, and greatly blunt the residual vasodilation in response to ACh after blockade of NOS/COX, presumably mediated by endothelium-derived hyperpolarizing factors.

Rejoinder: Socioeconomic gradients and hypertension in low- and middle-income countries: A straw man and no solutions

Publisher: Oxford University Press (OUP)

Date: 18-08-2014

DOI: 10.1093/IJE/DYU171

High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT₂-Receptor Dependent Mechanism

Publisher: Hindawi Limited

Date: 2015

DOI: 10.1155/2015/682745

Abstract: Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT 2 R-) mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week) for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min) were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT 2 R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF) decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For ex le, at 300 ng kg −1 min −1 , Ang II reduced RBF by 45.7 ± 1.9 % in estradiol-treated rats but only by 27.3 ± 5.1 % in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT 2 R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.

Chemosensitive cardiopulmonary afferents and the haemodynamic response to simulated haemorrhage in conscious rabbits

Publisher: Wiley

Date: 02-1991

DOI: 10.1111/J.1476-5381.1991.TB12206.X

Abstract: 1. We set out to test whether the signal from the heart that initiates the decompensatory phase of acute central hypovolaemia in conscious rabbits is conveyed by chemosensitive afferents. 2. Haemorrhage was simulated by inflating an inferior vena caval cuff so that cardiac output fell at a constant rate of 8% of its baseline level per min. After sham or vehicle treatments the haemodynamic response had two phases. In the first, sympathoexcitatory, phase systemic vascular conductance fell in proportion to cardiac output so that mean arterial pressure fell by only 13 mmHg. When cardiac output had fallen by approximately 50% a second, sympathoinhibitory, phase supervened. There was an abrupt rise of systemic vascular conductance and an abrupt fall of mean arterial pressure, to approximately 40 mmHg. 3. The sympathoinhibitory phase was prevented by injection of the delta-opioid antagonist ICI 174864 (100-300 nmol) or the mu-opioid agonist H-Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH (DAMGO) (100-300 pmol) into the fourth cerebral ventricle. 4. 5-HT3 receptors on myocardial or pulmonary afferents were excited by injection of ascending doses of phenylbiguanide (6.25-400 micrograms) into the left or right atrium respectively. Neuronal-type nicotinic cholinoceptors in the epicardium were excited by injecting ascending doses of nicotine bitartrate (6.25-400 micrograms) into the pericardial sac. Each of these treatment regimens caused a reproducible, dose-dependent, fall in mean arterial pressure. Intravenous injection of the 5-HT3 antagonist MDL 72222 (1.0 mg kg-1) markedly attenuated the responses to phenylbiguanide. Intrapericardial injection of the neuronal-type nicotinic cholinoceptor antagonist mecamylamine HCl (0.1 mgkg- ') abolished the effects of intrapericardial nicotine. Neither of these treatments affected the haemodynamic response to simulated haemorrhage. 5. Injection into the fourth ventricle of ICI 174864 (100-300nmol) or DAMGO (100-300pmol) had no effects on the dose-response relationships for phenylbiguanide or nicotine. 6. We conclude that the cardiac afferents responsible for initiating the sympathoinhibitory phase of simulated haemorrhage in conscious rabbits do not correspond to the populations of phenylbiguanidesensitive cardiopulmonary afferents, nor to the population of nicotine-sensitive epicardial afferents. We also conclude that the reflex haemodynamic responses to atrial phenylbiguanide and intrapericardial nicotine do not depend on an endogenous delta-opioid receptor mechanism in the brainstem, and are not affected by exposure of the brainstem to exogeneous DAMGO.

Excitation of 5-hydroxytryptamine3 receptors and nicotinic ganglionic cholinoceptors on vagal cardiopulmonary afferents in rabbits

Publisher: Elsevier BV

Date: 07-1990

DOI: 10.1016/0014-2999(90)92979-S

Long-term measurement of renal cortical and medullary tissue oxygenation and perfusion in unanesthetized sheep

Publisher: American Physiological Society

Date: 15-05-2015

DOI: 10.1152/AJPREGU.00515.2014

Abstract: The role of renal cortical and medullary hypoxia in the development of acute kidney injury is controversial, partly due to a lack of techniques for the long-term measurement of intrarenal oxygenation and perfusion in conscious animals. We have, therefore, developed a methodology to chronically implant combination probes to chronically measure renal cortical and medullary tissue perfusion and oxygen tension (tPo 2 ) in conscious sheep and evaluated their responsiveness and reliability. A transit-time flow probe and a vascular occluder were surgically implanted on the left renal artery. At the same operation, dual fiber-optic probes, comprising a fluorescence optode to measure tPo 2 and a laser-Doppler probe to assess tissue perfusion, were inserted into the renal cortex and medulla. In recovered conscious sheep ( n = 8) breathing room air, mean 24-h cortical and medullary tPo 2 were similar (31.4 ± 0.6 and 29.7 ± 0.7 mmHg, respectively). In the renal cortex and medulla, a 20% reduction in renal blood flow (RBF) decreased perfusion (14.6 ± 8.6 and 41.2 ± 8.5%, respectively) and oxygenation (48.1 ± 8.5 and 72.4 ± 8.5%, respectively), with greater decreases during a 50% reduction in RBF. At autopsy, minimal fibrosis was observed around the probes. In summary, we have developed a technique to chronically implant fiber-optic probes in the renal cortex and medulla for recording tissue perfusion and oxygenation over many days. In normal resting conscious sheep, cortical and medullary tPo 2 were similar. The responses to and recovery from renal artery occlusion, together with the consistent measurements over a 24-h period, demonstrate the responsiveness and stability of the probes.

Monash University

Location: Australia

View Organisation

Discovery Projects - Grant ID: DP140103045

Start Date: 2014

End Date: 06-2017

Amount: $505,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0877327

Start Date: 01-2008

End Date: 06-2011

Amount: $350,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0555897

Start Date: 2005

End Date: 04-2008

Amount: $338,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP180103039

Start Date: 2018

End Date: 12-2021

Amount: $392,664.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0561229

Start Date: 03-2005

End Date: 08-2007

Amount: $518,427.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0668435

Start Date: 2006

End Date: 03-2007

Amount: $1,300,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989341

Start Date: 10-2009

End Date: 12-2010

Amount: $690,000.00

Funder: Australian Research Council