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0000-0002-7623-137X
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Baker Heart and Diabetes Institute
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2016
Publisher: Frontiers Media SA
Date: 29-03-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2014
Publisher: Wiley
Date: 06-12-2001
DOI: 10.1046/J.1440-1681.2001.03567.X
Abstract: 1. The purpose of the present study was to assess the changes to renal sympathetic nerve activity (RSNA) baroreflexes during the development of hypertension after renal clipping in conscious rabbits. 2. Rabbits were fitted with a clip on the right renal artery or underwent a sham operation under halothane anaesthesia. A recording electrode was implanted on the left renal nerve 1 week before the experiment, 3 or 6 weeks after the initial operation. During the experiment, drug-induced r rises and falls in mean arterial pressure (MAP) were used to produce RSNA and heart rate (HR) baroreflex curves. The RSNA for each experiment was calibrated against maximum RSNA evoked by stimulation of baroreceptor-independent trigeminal afferents. 3. Mean arterial pressure was 20 and 36% higher 3 and 6 weeks after clip implantation, respectively. Renal sympathetic nerve activity baroreflex curves were reset rightwards accordingly, but the shape of the RSNA curves was differentially affected. 4. At both hypertensive periods, MAP-HR baroreflex gain was markedly reduced due to a reduction in curvature. The HR baroreflex range was increased. The RSNA baroreflex gain was reduced at 3 weeks, which was due to a 35% lower RSNA baroreflex range, but was similar to sham animals at 6 weeks. 5. The results show that, in established two kidney, one clip hypertension in rabbits, the sympathetic baroreflex is relatively well preserved but sensitivity of cardiac baroreflexes is attenuated. Therefore, the short-term inhibition of RSNA baroreflexes is not related to the level of blood pressure or the development of secondary changes, such as cardiac or vascular hypertrophy, but may be related to circulating angiotensin, which is known to increase at this time.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.ATHEROSCLEROSIS.2013.12.026
Abstract: Characteristics of short-term blood pressure (BP) variation may influence cardiovascular disease risk via effects on vascular function. In a cross-sectional study of a group of treated hypertensive and untreated largely normotensive subjects we investigated the relationships of measures of short-term BP variation with brachial artery vasodilator function. A total of 163 treated hypertensive (n = 91) and untreated largely normotensive (n = 72) men and women were recruited from the general population. Measures of systolic and diastolic BP variation were calculated from 24 h ambulatory BP assessments and included: (i) rate of measurement-to-measurement BP variation (SBP-var and DBP-var) and (ii) day-to-night BP dip (SBP-dip and DBP dip). Endothelium-dependent vasodilation was assessed as flow-mediated dilation (FMD) and endothelium-independent vasodilation was assessed in response to glyceryl trinitrate (GTN). Relationships were explored using univariate and multivariate linear regression. The relationships of brachial artery vasodilator function with BP variation were not significantly different between treated hypertensive and untreated subjects, therefore these groups were combined for analysis. In univariate analysis, higher SBP-var (P < 0.001) and lower DBP-dip (P = 0.004) were associated with lower FMD and higher SBP-var (P = 0.002) and lower SBP-dip (P = 0.003) and DBP-dip (P = 0.001) were associated with lower GTN-mediated dilation. In multivariate analysis, lower SBP-dip (P = 0.007) and DBP-dip (P = 0.03) were independently associated with lower GTN response. Our results indicate that a lower day-to-night BP dip is independently associated with impaired smooth muscle cell function. Although rate of BP variation was associated with measures of endothelial and smooth muscle cell function, relationships were attenuated after accounting for age and BP.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2003
DOI: 10.1161/01.HYP.0000064574.29317.45
Abstract: In this study, we examined the role of angiotensin type 1 (AT 1 ) receptors in the rostral ventrolateral medulla (RVLM) in mediating the pressor action of emotional stress in conscious rabbits. Rabbits were chronically instrumented with guide cannulas for bilateral microinjections into the RVLM and an electrode for measuring renal sympathetic nerve activity (RSNA). Airjet stress evoked increases in arterial pressure, heart rate, and RSNA, which reached a maximum (+9±1 mm Hg, +20±5 beats/min, and +93±17%, respectively) in the first 2 minutes of stress exposure. Then RSNA rapidly returned to prestress values, while arterial pressure and heart rate remained close to the maximal level until the conclusion of the 7-minute airjet exposure. Microinjections of the nonselective angiotensin receptor antagonist sarile (0.5 nmol, n=8) or AT 1 receptor antagonists losartan (2 nmol, n=6) or candesartan (0.2 nmol, n=6) into the RVLM did not alter resting cardiovascular parameters. By contrast, the antagonists attenuated the sustained phase (4 to 7 minutes) of the pressor stress response by 55% to 89%. However, only sarile decreased the onset of this response. The antagonists affected neither the stress-induced tachycardia nor the pressor response to glutamate microinjections. Microinfusion of angiotensin II (4 pmol/min, n=8) into the RVLM did not change the pressor response to airjet stress but attenuated tachycardic response by 47%. Microinjections of vehicle did not alter the cardiovascular stress response. Sarile, losartan, and angiotensin II did not affect the sympathoexcitatory response to baroreceptor unloading. These results suggest that AT 1 receptors in the RVLM are important in mediating the pressor effects of emotional stress in conscious rabbits.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2009
DOI: 10.1161/HYPERTENSIONAHA.109.136069
Abstract: Early studies indicate that the hypertension observed in the Schlager inbred mouse strain may be attributed to a neurogenic mechanism. In this study, we examined the contribution of the sympathetic nervous system in maintaining hypertension in the BPH/2J mouse and used c-Fos immunohistochemistry to elucidate whether neuronal activation in specific brain regions was associated with waking blood pressure. Male hypertensive (BPH/2J n=14), normotensive (BPN/3J n=18), and C57/Bl6 (n=5) mice were implanted with telemetry devices, and after 10 days of recovery, recordings of blood pressure, heart rate, and locomotor activity were measured to determine circadian variation. Mean arterial pressure was higher in BPH/2J than in BPN/3J or C57/Bl6 mice ( P .001), and BPH/2J animals showed exaggerated day-night differences (17±2 versus 6±1 mm Hg in BPN/3J or +8±2 mm Hg in C57/Bl6 mice P .001). Acute sympathetic blockade with pentolinium (7.5 mg/kg IP) during the active and inactive phases reduced blood pressure to comparable levels in BPH/2J and BPN/3J mice. The number of c-Fos–labeled cells was greater in the amygdala (+180% P .01), paraventricular nucleus (+110% P .001), and dorsomedial hypothalamus (+48% P .001) in the active (hypertensive) phase in BPH/2J compared with BPN/3J mice. The level of neuronal activation was mostly similar in these regions in the inactive phase. Of all of the regions studied, neuronal activation in the medial amygdala, as detected by c-Fos, was highly correlated to mean arterial pressure ( r =0.98). These findings indicate that the hypertension is largely attributable to sympathetic nervous system activity, possibly generated through greater levels of arousal regulated by neurons located in the medial amygdala.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2003
DOI: 10.1097/00004872-200301000-00027
Abstract: To determine the involvement of central imidazoline receptors in the cardiovascular actions of the chronically administered antihypertensive agents moxonidine, rilmenidine and clonidine. In 21 rabbits with implanted fourth-ventricular catheters, we investigated the central effects of three cumulative doses of an I(1)-imidazoline/alpha(2)-adrenoceptor antagonist, efaroxan, and of an alpha(2)-adrenoceptor antagonist, 2-methoxyidazoxan (2-MI), on the changes in blood pressure and heart rate (HR) elicited by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine, after 1 and 3 weeks of treatment. A low, medium and high dose of 2-MI was matched to three doses of efaroxan, such that each produced equal reversal of the hypotension induced by fourth-ventricular alpha-methyldopa and hence produced a similar degree of alpha(2)-adrenoceptor blockade. Clonidine and moxonidine, at doses of 1 mg/kg per day, and rilmenidine at 5 mg/kg per day, produced sustained reductions in mean arterial pressure of 13 +/- 3, 15 +/- 2 and 13 +/- 2 mmHg, respectively over the 3-week treatment period, but did not alter HR. Central administration of efaroxan on day 9 and day 23 of treatment produced a greater increase in blood pressure than did 2-MI with all three antihypertensive agents. Blood pressure reached levels that were significantly above the original control values. By contrast, the alpha(2)-adrenoceptor antagonist 2-MI only induced a rebound blood pressure effect in clonidine- and to a lesser extent in rilmenidine-treated rabbits. Both efaroxan and 2-MI produced a similar degree of tachycardia in moxonidine-, rilmenidine- and clonidine-treated animals.(2) The greater effect of efaroxan compared to the alpha(2)-adrenoceptor antagonist 2-MI suggests that the hypotension induced by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine is mediated predominantly via an action on central imidazoline receptors. Furthermore, all agents showed a propensity to produce rebound hypertension with imidazoline receptor blockade. However, only clonidine showed a rebound phenomenon when challenged by acute central alpha(2)-adrenoceptor blockade
Publisher: Oxford University Press (OUP)
Date: 28-12-2013
DOI: 10.1093/AJH/HPS016
Abstract: Dyslipidemia is one the most well-established risk factors for cardiovascular disease development. Moreover, hypercholesterolemia and plasma cholesterol level in the high to normal range are established triggers for impairment in endothelial function. Evidence indicates that endothelial function is closely linked with sympathetic nervous activity in healthy in iduals. We therefore investigated whether both endothelial and sympathetic functions may be impaired in young females with abnormal plasma cholesterol levels. Baseline endothelial function (digital pulse litude) and muscle sympathetic nervous activity (microneurography) were retrospectively analyzed in 14 young healthy females with dyslipidemia as indicated by total cholesterol ≥197mg/dL, high-density lipoprotein ≤39mg/dL, or low-density lipoprotein >116mg/dL, and in 13 females with lipids in the healthy range. Subjects with dyslipidemia had significantly impaired endothelial function compared to those with a normal cholesterol profile (reactive hyperemia index 1.61±0.10 vs. 2.32±0.14, P < 0.001), increased muscle sympathetic nervous activity (after adjusting for body mass and age, 36±3 vs. 27±3 bursts per 100 heartbeats, P = 0.049) and elevated high-sensitivity C-reactive protein (4.13±0.77 vs. 1.92±0.61mg/L, P = 0.03). Our results indicate that young healthy females with dyslipidemia present with a strong impairment of endothelial function and increased sympathetic drive. The sympathetic activation observed in the subjects with an elevated cholesterol profile may play a role in the development of cardiovascular disease development.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2015
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.
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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
Publisher: Wiley
Date: 28-09-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2022
DOI: 10.1161/HYPERTENSIONAHA.121.18354
Abstract: Majority of patients with hypertension and chronic kidney disease (CKD) undergoing renal denervation (RDN) are maintained on antihypertensive medication. However, RDN may impair compensatory responses to hypotension induced by blood loss. Therefore, continuation of antihypertensive medications in denervated patients may exacerbate hypotensive episodes. This study examined whether antihypertensive medication compromised hemodynamic responses to blood loss in normotensive (control) sheep and in sheep with hypertensive CKD at 30 months after RDN (control-RDN, CKD-RDN) or sham (control-intact, CKD-intact) procedure. CKD-RDN sheep had lower basal blood pressure (BP ≈9 mm Hg) and higher basal renal blood flow (≈38%) than CKD-intact. Candesartan lowered BP and increased renal blood flow in all groups. 10% loss of blood volume alone caused a modest fall in BP (≈6–8 mm Hg) in all groups but did not affect the recovery of BP. 10% loss of blood volume in the presence of candesartan prolonged the time at trough BP by 9 minutes and attenuated the fall in renal blood flow in the CKD-RDN group compared with CKD-intact. Candesartan in combination with RDN prolonged trough BP and attenuated renal hemodynamic responses to blood loss. To minimize the risk of hypotension-mediated organ damage, patients with RDN maintained on antihypertensive medications may require closer monitoring when undergoing surgery or experiencing traumatic blood loss.
Publisher: Oxford University Press (OUP)
Date: 02-2008
DOI: 10.1038/AJH.2007.28
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2001
DOI: 10.1109/51.917723
Publisher: Public Library of Science (PLoS)
Date: 25-03-2014
Publisher: Wiley
Date: 31-03-2015
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2001
DOI: 10.1109/51.917720
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.
Publisher: Frontiers Media SA
Date: 16-04-2019
Publisher: Elsevier BV
Date: 02-2020
Publisher: Wiley
Date: 04-09-2021
DOI: 10.1111/BPH.15650
Abstract: Elevated blood pressure (BP), or hypertension, is the main risk factor for cardiovascular disease. As a multifactorial and systemic disease that involves multiple organs and systems, hypertension remains a challenging disease to study. Models of hypertension are invaluable to support the discovery of the specific genetic, cellular and molecular mechanisms underlying essential hypertension, as well as to test new possible treatments to lower BP. Rodent models have proven to be an invaluable tool for advancing the field. In this review, we discuss the strengths and weaknesses of rodent models of hypertension through a systems approach. We highlight the ways how target organs and systems including the kidneys, vasculature, the sympathetic nervous system (SNS), immune system and the gut microbiota influence BP in each rodent model. We also discuss often overlooked hypertensive conditions such as pulmonary hypertension and hypertensive‐pregnancy disorders, providing an important resource for researchers. This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit oi/10.1111/bph.v179.5/issuetoc
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2013
Publisher: Oxford University Press (OUP)
Date: 10-2006
DOI: 10.1016/J.AMJHYPER.2006.03.014
Abstract: We applied a new logistic curve fitting procedure to ambulatory blood pressure (ABP) recordings to determine whether the rate of increase in systolic (SBP), mean (MBP) and diastolic blood pressure (DBP) and heart rate (HR) in the morning is related to the level of BP in subjects. The rate of transition in the morning and evening period was determined using a six-parameter double-logistic equation applied to 528 ABP recordings from a cardiovascular risk assessment clinic. Based on daytime BP (MBP, SBP, or DBP), the upper quartile (UQ, n = 132) and lower quartile (LQ) were compared. Subjects in the UQ of daytime MBP were hypertensive and showed greater day-night differences compared to normotensive subjects in the LQ (29 +/- 1 mm Hg for MBP compared to 20 +/- 1 mm Hg). The rate of morning increase in SBP and DBP was 42% and 30% greater in UQ subjects compared to the LQ subjects (P < .05). The rates of evening decrease in all BPs were 69% to 84% greater in the subjects in the UQ. Similar results were obtained if subjects were ided according to daytime SBP or DBP. The rate of morning increase in MBP was correlated with daytime BP, but not night-time or 24 h MBP. The rate of morning increase in BP is greater in those subjects with the highest daytime BP. The exaggerated rate of morning increase in BP in this group, which were all hypertensive, may also be important for greater cardiovascular risk.
Publisher: AMPCo
Date: 10-2012
DOI: 10.5694/MJA11.11545
Publisher: Wiley
Date: 2010
Publisher: American Physiological Society
Date: 05-2016
DOI: 10.1152/AJPHEART.00866.2015
Abstract: One of the main constraints associated with recording sympathetic nerve activity (SNA) in both humans and experimental animals is that microvolt values reflect characteristics of the recording conditions and limit comparisons between different experimental groups. The nasopharyngeal response has been validated for normalizing renal SNA (RSNA) in conscious rabbits, and in humans muscle SNA is normalized to the maximum burst in the resting period. We compared these two methods of normalization to determine whether either could detect elevated RSNA in hypertensive rabbits compared with normotensive controls. We also tested whether either method eliminated differences based only on different recording conditions by separating RSNA of control (sham) rabbits into two groups with low or high microvolts. Hypertension was induced by 5 wk of renal clipping (2K1C), 3 wk of high-fat diet (HFD), or 3 mo infusion of a low dose of angiotensin (ANG II). Normalization to the nasopharyngeal response revealed RSNA that was 88, 51, and 34% greater in 2K1C, HFD, and ANG II rabbits, respectively, than shams ( P 0.05), but normalization to the maximum burst showed no differences. The RSNA baroreflex followed a similar pattern whether RSNA was expressed in microvolts or normalized. Both methods abolished the difference between low and high microvolt RSNA. These results suggest that maximum burst litude is a useful technique for minimizing differences between recording conditions but is unable to detect real differences between groups. We conclude that the nasopharyngeal reflex is the superior method for normalizing sympathetic recordings in conscious rabbits.
Publisher: Frontiers Media SA
Date: 19-03-2018
Publisher: Springer Singapore
Date: 2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2013
DOI: 10.1161/HYPERTENSIONAHA.113.01474
Abstract: Hypertension contributes to multiple forms of cardiovascular disease and thus morbidity and mortality. The mechanisms inducing hypertension remain unclear although the involvement of homeostatic systems, such as the renin–angiotensin and sympathetic nervous systems, is established. A pivotal role of the angiotensin type 1 receptor in the proximal tubule of the kidney for the development of experimental hypertension is established. Yet, other systems are involved. This study tests whether the expression of angiotensin type 1A receptors in catecholaminergic cells contributes to hypertension development. Using a Cre-lox approach, we deleted the angiotensin type 1A receptor from all catecholaminergic cells. This deletion did not alter basal metabolism or blood pressure but delayed the onset of angiotensin-dependent hypertension and reduced the maximal response. Cardiac hypertrophy was also reduced. The knockout mice showed attenuated activation of the sympathetic nervous system during angiotensin II infusion as measured by spectral analysis of the blood pressure. Increased reactive oxygen species production was observed in forebrain regions, including the subfornical organ, of the knockout mouse but was markedly reduced in the rostral ventrolateral medulla. These studies demonstrate that stimulation of the angiotensin type 1A receptor on catecholaminergic cells is required for the full development of angiotensin-dependent hypertension and support an important role for the sympathetic nervous system in this model.
Publisher: American Physiological Society
Date: 04-2005
DOI: 10.1152/JAPPLPHYSIOL.00647.2004
Abstract: We developed an asymmetric double logistic curve-fitting procedure for circadian analysis that can determine the rate of change in variables during the day-to-night separately from the night-to-day transition for use in animal studies. We now have applied this procedure to 24-h systolic (SAP) and diastolic arterial pressure (DAP) and heart rate ambulatory recordings from 302 patients. In 292 cases, all parameters showed a pattern of higher day and lower night values. In men there was a similar rate of transition between day and night or from night to day for both SAP and DAP that lasted 3–4 h, indicating a symmetrical diurnal pattern. By contrast, women showed a faster rate of decrease in mean arterial pressure in the evening compared with men ( P 0.05) and therefore showed an asymmetric diurnal SAP pattern. For both men and women, there was a markedly greater rate of morning increase in heart rate compared with the rate of evening decrease (2.2- and 1.9-fold, respectively, P 0.001). The logistic method provided a better fit than the square-wave or the cosinor method ( P 0.001) and more appropriately detected nondippers. We conclude that analysis of ambulatory recordings by a new logistic curve-fitting method reveals more rapid reductions in evening SAP in women than men but both have two- to threefold more rapid morning rates of tachycardia. The ability of the double logistic method to determine the diurnal blood pressure rates of change independently is key to determining new markers for cardiovascular risk.
Publisher: Elsevier BV
Date: 2000
DOI: 10.1016/S0014-2999(99)00835-3
Abstract: Intravenous administration of 0.3 mg/kg of quinpirole to conscious rabbits that had been pretreated with domperidone caused a marked increase in blood pressure and renal sympathetic nerve activity with a peak at 5-10 min after injection (25% and 3-fold increase, respectively). Spectral analysis of the blood pressure-renal sympathetic nerve activity relationship in the 0.2-0.4 Hz domain showed that baroreflex gain was markedly increased at 5-10 min (4-fold) and at 20-25 min after injection (3.7-fold). These results show that administration of the dopamine D(2)/D(3) receptor agonist quinpirole causes profound and long-lasting changes in the central integration of the sympathetic baroreceptor-vasomotor reflex.
Publisher: Springer Science and Business Media LLC
Date: 03-2011
DOI: 10.1007/S11906-011-0196-9
Abstract: The importance of the sympathetic nervous system in the pathophysiology of human and experimental models of hypertension is well established. Underpinning recent advances has been direct recording from sympathetic nerves via implanted electrodes in animals or microneurography in human subjects. However, the limited life of a recording electrode and the prolonged nature of the development of hypertension bring with it the difficulty of comparing sympathetic nerve activity between groups. New developments in high-frequency radiotelemetry in animals have heralded a new age in long-term sympathetic recordings ideal for hypertension research. Standard multifiber recordings in human and animal studies have provided information about the frequency and litude of sympathetic bursts. Characterization of sympathetic output is now possible from new techniques of determining single-unit firing frequency, firing probability, and the number of spikes generated per cardiac interval. These have led to a better understanding of sympathoactivation in hypertension and its underlying mechanisms.
Publisher: Wiley
Date: 07-2018
DOI: 10.1111/JCH.13295
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2012
DOI: 10.1161/HYPERTENSIONAHA.111.190413
Abstract: Hypertension and elevated sympathetic drive result from consumption of a high-calorie diet and deposition of abdominal fat, but the etiology and temporal characteristics are unknown. Rabbits instrumented for telemetric recording of arterial pressure and renal sympathetic nerve activity (RSNA) were fed a high-fat diet for 3 weeks then control diet for 1 week or control diet for 4 weeks. Baroreflexes and responses to air-jet stress and hypoxia were determined weekly. After 1 week of high-fat diet, caloric intake increased by 62%, accompanied by elevated body weight, blood glucose, plasma insulin, and leptin (8%, 14%, 134%, and 252%, respectively). Mean arterial pressure, heart rate, and RSNA also increased after 1 week (6%, 11%, and 57%, respectively). Whereas mean arterial pressure and body weight continued to rise over 3 weeks of high-fat diet, heart rate and RSNA did not change further. The RSNA baroreflex was attenuated from the first week of the diet. Excitatory responses to air-jet stress diminished over 3 weeks of high-fat diet, but responses to hypoxia were invariant. Resumption of a normal diet returned glucose, insulin, leptin, and heart rate to control levels, but body weight, mean arterial pressure, and RSNA remained elevated. In conclusion, elevated sympathetic drive and impaired baroreflex function, which occur within 1 week of consumption of a high-fat, high-calorie diet, appear integral to the rapid development of obesity-related hypertension. Increased plasma leptin and insulin may contribute to the initiation of hypertension but are not required for maintenance of mean arterial pressure, which likely lies in alterations in the response of neurons in the hypothalamus.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2016
Publisher: Wiley
Date: 10-07-2012
DOI: 10.1113/EXPPHYSIOL.2012.064972
Abstract: Methodological improvements in measuring cardiovascular parameters have meant that data can be collected from freely moving animals in their home cage. However, experiments in rabbits still often require them to be restrained in a laboratory setting. The aim of this study was to determine whether measurements collected when rabbits were placed in a holding box in the laboratory are representative of values obtained in freely moving conscious rabbits. Nine New Zealand White rabbits received two radiotelemetry implants to monitor mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). The MAP measured in the laboratory (71 ± 1 mmHg) was similar to that in the home cage (69 ± 1 mmHg), but there was less MAP variability. The RSNA was also similar in both environments. In contrast, laboratory heart rate (HR) was 7% lower than home cage HR (181 ± 4 beats min(-1), P < 0.001), but HR variability was similar. Baroreflex gain, assessed by spectral analysis, was 19% higher in the laboratory than in the home cage due to lower MAP mid-frequency variability in the laboratory. Home cage circadian patterns of MAP and HR were strongly influenced by feeding and activity. Nevertheless, MAP and RSNA laboratory measurements were the same as average 24 h values and remained similar over several weeks. We conclude that while HR is generally lower in the laboratory, a valid representation of MAP and RSNA can be given by laboratory measurements.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2021
DOI: 10.1161/HYPERTENSIONAHA.121.17037
Abstract: There is increasing evidence that renal denervation is effective in alleviating hypertension associated with elevation of renal sympathetic nerve activity (RSNA) in chronic kidney disease (CKD), but whether this is due to reduction in renal afferent signaling is unclear. We determined the cardiovascular and sympathetic effects of total renal denervation or afferent renal denervation (topical capsaicin) on CKD induced by glomerular layer lesioning of the left kidney and right nephrectomy in conscious rabbits. CKD increased blood pressure by 18±2 mmHg and plasma creatinine by 40% over 2 to 4 weeks (both P .001), while RSNA (43%) and total norepinephrine spillover (28%) were elevated in CKD compared with sham (both P =0.04). After total or afferent renal denervation blood pressure, RSNA and norepinephrine spillover were similar or lower than non-CKD (sham) rabbits. While plasma creatinine in CKD rabbits was not affected by total renal denervation, deafferented rabbits had lower levels ( P =0.017). The greater hypotensive response to pentolinium in CKD was also normalized after total or afferent denervation. Heart rate and RSNA baroreflex gain were similar in all groups. The RSNA response to airjet stress was greater in CKD compared with sham but not after total or afferent renal denervation. By contrast, the sympathetic response to hypoxia was similar in sham and CKD intact or deafferented groups but elevated in total denervated CKD animals. We conclude that the elevated sympathetic activity and blood pressure in this model of CKD is predominantly driven by renal afferents.
Publisher: AMPCo
Date: 2013
DOI: 10.5694/MJA12.11516
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2003
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2019
DOI: 10.1161/HYPERTENSIONAHA.118.12250
Abstract: We examined whether renal denervation (RDN) reduced blood pressure (BP), improved glomerular filtration rate, albuminuria, and left ventricular mass in sheep with hypertensive chronic kidney disease (CKD). To examine whether renal nerve function returned in the long term, we examined vascular contraction to nerve stimulation in renal arteries and determined nerve regrowth by assessing renal TH (tyrosine hydroxylase), CGRP (calcitonin gene-related peptide), and norepinephrine levels in kidneys at 30 months after RDN. RDN normalized BP in hypertensive CKD sheep such that BP was similar to that of the normotensive sheep with intact nerves. Glomerular filtration rate decreased by ≈22% in CKD sheep with intact nerves but increased ≈26% in hypertensive CKD-RDN sheep by 30 months. At 30 months, urinary albumin was ≈127% and left ventricular mass was ≈41% greater in CKD sheep with intact nerves than control. However, urinary albumin was ≈60% less and left ventricular mass was ≈40% less in the CKD sheep that underwent RDN compared with intact counterpart. At 30 months in CKD-RDN sheep, neurovascular contraction (≈56%), renal proportion of TH (≈50%), CGRP (≈67%), and norepinephrine content (≈49%) were all less than CKD-intact all these variables were similar between normotensive-intact and normotensive-RDN groups. RDN caused a sustained reduction in BP and improvements in renal function. Regrowth of renal nerves and return of function were observed in hypertensive CKD-RDN sheep, but levels were only partially restored to levels of intact. These suggest that RDN lowers BP in the long term and is renoprotective and cardioprotective as a result of lesser nerve regrowth in CKD.
Publisher: Wiley
Date: 25-11-2020
DOI: 10.1111/JCH.13740
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.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2014
DOI: 10.1007/S11906-014-0466-4
Abstract: The activation of the sympathetic nervous system is a major mechanism underlying both human and experimental models of obesity-related hypertension. While insulin and the adipokine leptin have long been thought to contribute to obesity-related neurogenic mechanisms, the evidence is now very strong that they play a major role, shown particularly in animal studies using selective receptor antagonists. There is not just maintenance of leptin's sympatho-excitatory actions as previously suggested but considerable lification particularly in renal sympathetic nervous activity. Importantly, these changes are not dependent on short-term elevation or reduction in plasma leptin or insulin, but require some weeks to develop indicating a slow "neural adaptivity" within hypothalamic signalling. These effects can be carried across generations even when offspring are raised on a normal diet. A better understanding of the underlying mechanism should be a high research priority given the prevalence of obesity not just in the current population but also for future generations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2007
DOI: 10.1161/HYPERTENSIONAHA.106.086322
Abstract: Several brain regions are proposed as contributing to chronic sympatho-excitatory effects of elevated circulating angiotensin II. However, earlier c-Fos studies have been limited to acute angiotensin II exposure. This study aims to determine brain regions responding with chronic elevated angiotensin II. Rabbits were administered angiotensin II (50 ng/kg per minute) or saline for 3 hours, 3 days, or 14 days. Basal mean arterial pressure was 71±2 mm Hg and increased 23±2 mm Hg, 32±4 mm Hg, and 22±2 mm Hg for 3 hours, 3 days, and 14 days, respectively, with angiotensin II infusion. Neuronal activation was detected using Fos-related antigens, which recognizes all of the known members of the Fos family. Neurons located in the amygdala and area postrema were activated transiently after acute infusion of angiotensin II but were not responsive by days 3 or 14. Neurons located in the nucleus of the solitary tract, caudal ventrolateral medulla, and lateral parabrachial nucleus were activated for ≤3 days after infusion of angiotensin II but were not responsive by day 14, which is consistent with their role in response to baroreceptor pathways that reset with sustained hypertension. The vascular organ of the lamina terminalis and subfornical organ showed sustained but diminishing activation over the 14-day period. However, the downstream hypothalamic nuclei that receive inputs from these nuclei, the paraventricular, supraoptic, and arcuate nuclei, showed marked sustained activation. These findings suggest that there is desensitization of circumventricular organs but sensitization of neurons in hypothalamic regions to long-term angiotensin II infusion.
Publisher: Frontiers Media SA
Date: 23-02-2017
Publisher: Springer Science and Business Media LLC
Date: 16-09-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/HYPERTENSIONAHA.114.03756
Abstract: The lineage of the Y chromosome accounts for up to 15 to 20 mm Hg in arterial pressure. Genes located on the Y chromosome from the spontaneously hypertensive rat (SHR) are associated with the renin–angiotensin system. Given the important role of the renin–angiotensin system in the renal regulation of fluid homeostasis and arterial pressure, we hypothesized that the origin of the Y chromosome influences arterial pressure via interaction between the intrarenal vasculature and the renin–angiotensin system. Sixteen-week-old normotensive rats (Wistar Kyoto [WKY]), spontaneously hypertensive stroke-prone rat (SHRSP), and 2 reciprocal Y consomic rat strains, 1 comprising the WKY autosomes and X chromosome with the Y chromosome from the hypertensive rat strain (WKY.SP Gla Y) and vice versa (SP.WKY Gla Y), were examined. SP.WKY Gla Y had lower systolic blood pressure than SHRSP (195±5 versus 227±8 mm Hg P .03), whereas WKY.SP Gla Y had higher systolic blood pressure compared with WKY (157±3 versus 148±3 mm Hg P .05), measured by radiotelemetry. Compared with WKY rats, SHRSP had higher plasma angiotensin(1-7) (Ang (1-7)):Ang II ratio (WKY: 0.13±0.01 versus SHRSP: 1.33±0.4 P .005), greater angiotensin II receptor type 2 and Mas receptor mRNA expression, and a blunted renal constrictor response to intrarenal Ang I and Ang(1-7) infusions. Introgression of the normotensive Y chromosome into the SHRSP background (SP.WKY Gla Y) restored responses in the SHRSP to WKY levels, evidenced by a reduction in plasma Ang(1-7):Ang II ratio (SP.WKY Gla Y: 0.24±0.02 P .01), angiotensin II receptor type 2, and Mas receptor mRNA expression and an increased vasoconstrictor response to intrarenal Ang I and Ang(1-7) infusion. This study demonstrates that the origin of the Y chromosome significantly impacts the renal vascular responsiveness and therefore may influence the long-term renal regulation of blood pressure.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.IJCARD.2017.05.075
Abstract: There is a high prevalence of late hypertension after coarctation repair. The relative contribution of elevated sympathetic tone and endothelial dysfunction to its development is unknown. This study aims to investigate the neural profile of coarctation patients including muscle sympathetic nerve activity testing to directly measure sympathetic nervous activity. Twenty-three patients aged ≥18years with a coarctation repair underwent measurements of clinic and 24-h blood pressures, muscle sympathetic nerve activity, sympathetic and cardiac baroreflex functions, digital endothelial function, and ambulatory arterial stiffness index. Median age at repair was 1.2months (interquartile range: 0-9months). Patients were compared to 17 healthy matched controls. After 26±5years, 6% (1/18) and 44% (8/18) suffered clinic hypertension and prehypertension, respectively. On 24-h blood pressure monitoring, 15% (3/20) and 20% (4/20) had hypertension and prehypertension, respectively. Coarctation patients had elevated muscle sympathetic nerve activity compared with controls (49.6±24.9 vs. 29.9±14.0 bursts/100 heartbeats, p=0.02), d ened sympathetic baroreflex function (-2.2±2.1 vs. -7.0±5.6 bursts/100heartbeats·mm·Hg After coarctation repair patients have increased muscle sympathetic nerve activity, d ened sympathetic baroreflex response, endothelial dysfunction, and increased ambulatory arterial stiffness index, all of which may contribute to the development of late hypertension.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2003
Publisher: Wiley
Date: 09-1996
DOI: 10.1111/J.1440-1681.1996.TB02822.X
Abstract: 1. It was first shown several years ago that the rostral part of the ventrolateral medulla (VLM) contains a high density of receptor binding sites for angiotensin II (AngII). In the present paper we briefly review recent studies aimed at determining the actions of both exogenous and endogenous angiotensin peptides in the rostral VLM, as well as their specific sites of action. 2. The results of these studies have shown that angiotensin peptides can excite pressor and sympathoexcitatory neurons in the rostral VLM, but do not appear to affect non-cardiovascular neurons in this region. 3. It is known that pressor neurons in the rostral VLM include both catecholamine and non-catecholamine neurons. There is evidence that, at least in conscious rabbits, both of these types of neurons are activated by AngII. The specific endogenous angiotensin peptide or peptides that affect pressor neurons in the rostral VLM have not yet been definitively identified. 4. It is also possible that different angiotensin peptides may have different effects on pressor neurons in the rostral VLM, mediated by different receptors. Further studies will be needed to define these different functions as well as the specific receptors and cellular mechanisms that subserve them.
Publisher: Wiley
Date: 21-11-2016
DOI: 10.1113/EP085472
Publisher: SAGE Publications
Date: 07-04-2016
Abstract: Blood pressure variability is associated with macrovascular complications and stroke, but its association with the microcirculation in type II diabetes has not been assessed. This study aimed to determine the relationship between blood pressure variability indices and retinal arteriolar diameter in non-diabetic and type II diabetes participants. Digitized retinal images were analysed to quantify arteriolar diameters in 35 non-diabetic (aged 52 ± 11 years 49% male) and 28 type II diabetes (aged 61 ± 9 years 50% male) participants. Blood pressure variability was derived from 24-h ambulatory blood pressure. Arteriolar diameter was positively associated with daytime rate of systolic blood pressure variation ( p = 0.04) among type II diabetes participants and negatively among non-diabetics ( p = 0.008 interaction p = 0.001). This finding was maintained after adjusting for age, sex, body mass index and mean daytime systolic blood pressure. These findings suggest that the blood pressure variability–related mechanisms underlying retinal vascular disease may differ between people with and without type II diabetes.
Publisher: Wiley
Date: 26-10-2019
DOI: 10.1111/JCH.13710
Publisher: Frontiers Media SA
Date: 18-10-2019
Publisher: Wiley
Date: 16-02-2015
DOI: 10.1111/JCH.12502
Publisher: Springer Science and Business Media LLC
Date: 05-2009
DOI: 10.1038/HR.2009.59
Abstract: Pharmacological evidence suggests that angiotensin II type 1 (AT(1)) receptors are involved in the regulation of cardiovascular response to emotional stress and reinforcing effect of dietary salt on this response. In this study, we examined the effect of genetic deletion of AT(1A) receptors on the cardiovascular effects of stress and salt in mice. AT(1A) receptor knockout (AT(1A)(-/-)) and wild-type (AT(1A)(+/+)) mice were implanted with telemetry devices and placed on a normal (0.4%) or high (3.1%) salt diet (HSD). Resting blood pressure (BP) in AT(1A)(-/-) mice (84+/-3 mm Hg) was lower than in AT(1A)(+/+) mice (107+/-2 mm Hg). Negative emotional (restraint) stress increased BP by 33+/-3 mm Hg in AT(1A)(+/+) mice. This response was attenuated by 40% in AT(1A)(-/-) mice (18+/-3 mm Hg). Conversely, the BP increase caused by food presentation and feeding was similar in AT(1A)(-/-) (25+/-3 mm Hg) and AT(1A)(+/+) mice (26+/-3 mm Hg). HSD increased resting BP by 14+/-4 mm Hg in AT(1A)(-/-) mice without affecting it significantly in AT(1A)(+/+) mice. Under these conditions, the pressor response to restraint stress in AT(1A)(-/-) mice (30+/-3 mm Hg) was no longer different from that in wild-type animals (28+/-3 mm Hg). The BP response to feeding was not altered by HSD in either AT(1A)(-/-) or AT(1A)(+/+) mice (25+/-2 and 27+/-3 mm Hg, respectively). These results indicate that AT(1A) receptor deficiency leads to a reduction in BP reactivity to negative emotional stress, but not feeding. HSD can selectively reinforce the cardiovascular response to negative stress in AT(1A)(-/-) mice. However, there is little interaction between AT(1A) receptors, excess dietary sodium and feeding-induced cardiovascular arousal.
Publisher: Oxford University Press (OUP)
Date: 24-07-2013
DOI: 10.1093/CVR/CVT183
Abstract: The nucleus of the solitary tract (NTS) is important for cardiovascular regulation and contains angiotensin type 1A (AT1A) receptors. To assess its function, we examined the effect of expressing in AT1A receptors in the NTS of mice lacking these receptors. Bilateral microinjections of lentivirus expressing AT1A receptors (AT1Av mice, n = 6) or green fluorescent protein (GFPv, n = 8, control) under the control of the PRSx8 promotor were made into the NTS of AT1A receptors null mice (AT1A(-/-)). Telemetry devices recorded blood pressure (BP), heart rate (HR), and locomotor activity. Expression of AT1A receptors in the NTS increased BP by 11.2 ± 4 mmHg (P < 0.05) at 2 and 3 weeks, whereas GFPv mice remained at pre-injection BP. Ganglion blockade reduced BP to similar levels pre- and post-transfection in GFPv and AT1Av mice. Greater pressor responses to cage-switch stress were observed following AT1A receptors expression (+18 ± 2 mmHg pre- to +24 ± 2 mmHg post-virus, P < 0.05) with similar stress-induced pressor responses pre- and post-virus in GFPv mice. Pressor responses to restraint stress pre- and post-virus were similar in AT1Av but were 20% less post-GFPv (P < 0.001). The lack of attenuation in BP to restraint was associated with four-fold greater Fos-expression in AT1A receptors mice. AT1A receptors expression in the NTS did not alter baroreflex gain differently between groups. The results suggest that transfection of AT1A receptors on neurons in the NTS elevates BP independent of the SNS and pressor responses to aversive stimuli are associated with greater Fos-expression in forebrain regions. This study suggests a novel mechanism by which the NTS may modulate MAP in the long-term via AT1A receptors.
Publisher: Informa UK Limited
Date: 28-05-2015
DOI: 10.3109/07420528.2015.1032414
Abstract: Meal-fed conscious rabbits normally exhibit postprandial elevation in blood pressure, heart rate (HR) and locomotor activity, which is abolished by consumption of a high-fat diet (HFD). Here, we assessed whether the cardiovascular changes are attributable to the increased caloric intake due to greater fat content or to hyperphagia. Rabbits were meal-fed during the baseline period then maintained on either an ad libitum normal fat diet (NFD) or ad libitum HFD for 2 weeks. Blood pressure, HR and locomotor activity were measured daily by radio-telemetry alongside food intake and body weight. Caloric intake in rabbits given a NFD ad libitum rose 50% from baseline but there were no changes in cardiovascular parameters. By contrast, HR increased by 10% on the first day of the ad libitum HFD (p < 0.001) prior to any change in body weight while blood pressure increased 7% after 4 d (p < 0.01) and remained elevated. Baseline 24-h patterns of blood pressure and HR were closely associated with mealtime, characterised by afternoon peaks and morning troughs. When the NFD was changed from meal-fed to ad libitum, blood pressure and HR did not change but afternoon activity levels decreased (p < 0.05). By contrast, after 13 d ad libitum HFD, morning HR, blood pressure and activity increased by 20%, 8% and 71%, respectively. Increased caloric intake specifically from fat, but not as a result of hyperphagia, appears to directly modulate cardiovascular homeostasis and circadian patterns, independent of white adipose tissue accumulation.
Publisher: Wiley
Date: 15-12-2009
DOI: 10.1113/EXPPHYSIOL.2008.046300
Abstract: Since the first recording of sympathetic nerve activity (SNA) early last century, numerous methods for presentation of the resulting data have developed. In this paper, we discuss the common ways of describing SNA and their application to chronic recordings. Suggestions on assessing the quality of SNA are made, including the use of arterial pressure wave-triggered averages and nasopharyngeal stimuli. Calculation of the zero level of the SNA signal from recordings during ganglionic blockade, the average level between bursts and the minimum of arterial pressure wave-triggered averages are compared and shown to be equivalent. The use of normalization between zero and maximal SNA levels to allow comparison between groups is discussed. We recommend that measured microvolt levels of integrated SNA be presented (with the zero/noise level subtracted), along with burst litude and frequency information whenever possible. We propose that standardization of the quantifying/reporting of SNA will allow better comparison between disease models and between research groups and ultimately allow data to be more reflective of the human situation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2016
DOI: 10.1161/HYPERTENSIONAHA.115.07053
Abstract: BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system. Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (−16.1±1.6 and −11.0±1.1 mm Hg, respectively P .001 compared with vehicle). However, when almorexant (100 mg/kg, IP) was administered during the light-inactive period (5 hours before lights off) no reduction from baseline was observed ( P =0.64). The same dose of almorexant in BPN/3J mice had no effect on blood pressure during the dark ( P =0.79) or light periods ( P =0.24). Almorexant attenuated the depressor response to ganglion blockade ( P =0.018) and reduced the mid frequency mean arterial pressure power in BPH/2J mice ( P .001), but not BPN/3J mice ( P =0.70). Immunohistochemical labeling revealed that BPH/2J mice have 29% more orexin neurons than BPN/3J mice which are preferentially located in the lateral hypothalamus. The results suggest that enhanced orexinergic signaling contributes to sympathetic overactivity and hypertension during the dark period in BPH/2J mice.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2014
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.
Publisher: American Physiological Society
Date: 05-2017
DOI: 10.1152/AJPHEART.00703.2016
Abstract: Over the past several decades, studies of the sympathetic nervous system in humans, sheep, rabbits, rats, and mice have substantially increased mechanistic understanding of cardiovascular function and dysfunction. Recently, interest in sympathetic neural mechanisms contributing to blood pressure control has grown, in part because of the development of devices or surgical procedures that treat hypertension by manipulating sympathetic outflow. Studies in animal models have provided important insights into physiological and pathophysiological mechanisms that are not accessible in human studies. Across species and among laboratories, various approaches have been developed to record, quantify, analyze, and interpret sympathetic nerve activity (SNA). In general, SNA demonstrates “bursting” behavior, where groups of action potentials are synchronized and linked to the cardiac cycle via the arterial baroreflex. In humans, it is common to quantify SNA as bursts per minute or bursts per 100 heart beats. This type of quantification can be done in other species but is only commonly reported in sheep, which have heart rates similar to humans. In rabbits, rats, and mice, SNA is often recorded relative to a maximal level elicited in the laboratory to control for differences in electrode position among animals or on different study days. SNA in humans can also be presented as total activity, where normalization to the largest burst is a common approach. The goal of the present paper is to put together a summary of “best practices” in several of the most common experimental models and to discuss opportunities and challenges relative to the optimal measurement of SNA across species. Listen to this article's corresponding podcast at /guidelines-for-measuring-sympathetic-nerve-activity/
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2009
DOI: 10.1161/HYPERTENSIONAHA.108.121731
Abstract: Arginase upregulation is associated with aging and cardiovascular diseases. In this study we report on the cardiovascular phenotype of the arginase II knockout (KO) mouse. We demonstrate that vascular sensitivity and reactivity altered over time in these animals such that no influence on responses to vasoconstrictor activity was observed in 7-week-old KO mice, but d ened responses to norepinephrine and phenylephrine were observed by 10 and 15 weeks with Rho kinase influencing these effects in the 15-week-old animals. Despite these d ened vasoconstrictory responses, KO mice demonstrated increased mean arterial pressure from 8 weeks old. This hypertensive phenotype was associated with an increase in left ventricular weight, left ventricular systolic pressure, and diminished diastolic function. KO mice also show enhanced plasma norepinephrine turnover, suggesting an increased sympathetic outflow. In conclusion, our data suggest that global loss of arginase II activity results in hypertension. We suggest that this strain of mouse warrants further investigation as a potentially novel model of hypertension.
Publisher: Oxford University Press (OUP)
Date: 13-04-2016
DOI: 10.1093/AJH/HPW037
Abstract: The average of multiple blood pressure (BP) readings (mean BP) independently predicts target organ damage (TOD). Observational studies have also shown an independent relationship between BP variability (BPV) and TOD, but there is limited longitudinal data. This study aimed to determine the effects of changes in mean BP levels compared with BPV on left ventricular mass index (LVMI) and aortic pulse wave velocity (aPWV). Mean BP levels (research-protocol clinic BP (clinic BP), 24-hour ambulatory BP, and 7-day home BP) and BPV were assessed in 286 patients with uncomplicated hypertension (mean age 64±8 SD years, 53% women) over 12 months. Reading-to-reading BPV (from 24-hour ambulatory BP) and day-to-day BPV (from 7-day home BP) were assessed at baseline and 12 months, and visit-to-visit BPV (clinic BP) was assessed from 5 visits over 12 months. LVMI was measured by 3D echocardiography and aPWV with applanation tonometry. The strongest predictors of the changes in LVMI (ΔLVMI) were the changes in mean 24-hour systolic BPs (SBPs) (P < 0.02). Similarly, the strongest predictors of the changes in aPWV (ΔaPWV) were the changes in mean 24-hour ambulatory SBPs (P < 0.01) and the changes in mean clinic SBP (P 0.05 for all). Changes in mean BP levels, but not BPV, were most relevant to changes in TOD in patients with uncomplicated hypertension. Thus, from this point of view, BPV appears to have limited clinical utility in this patient population.
Publisher: Wiley
Date: 04-01-2018
Publisher: Elsevier BV
Date: 06-2002
DOI: 10.1016/S1566-0702(02)00024-3
Abstract: In conscious, chronically instrumented rabbits (n = 7), airjet stress evoked increases in arterial pressure (AP) and renal sympathetic nerve activity (RSNA), which were greatest in the first 2 min (+ 10 mm Hg and + 127%, respectively), but then rapidly reached a stable level (+ 7 mm Hg and + 37%, respectively). Bilateral microinjection into the rostral ventrolateral medulla (RVLM) of an ionotropic excitatory amino acid (EAA) receptor antagonist kynurenate (10 nmol/200 nl) did not affect resting AP and RSNA, but reduced their initial peak responses to airjet by 80% and 52%, respectively, without altering the stable levels of these responses. By contrast, bilateral microinfusion of glutamate (2 nmol/20 nl/min) into the RVLM increased resting AP by 13 mm Hg, but did not alter the RSNA and AP responses to airjet stress. These results suggest that the RVLM is an essential site for conveying excitatory environmental influences to the sympathetic nervous system in conscious rabbits. The EAA receptors are critically important in initiating the pressor and sympathoexcitatory responses to acute emotional stress, but play relatively little role in the maintenance of these responses.
Publisher: Frontiers Media SA
Date: 10-02-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2004
DOI: 10.1161/01.HYP.0000116301.02975.AA
Abstract: We determined whether the sympathetic excitatory responses to environmental stressors and the sympathoinhibitory responses to rilmenidine are altered by renovascular hypertension. Rabbits were made hypertensive with a clip on the right renal artery, and a left renal nerve recording electrode was implanted. After 3 or 6 weeks, the animals were given air-jet stress and loud noise stress before and after intravenous rilmenidine. Three and 6 weeks after renal clipping, mean arterial pressure was 28% and 36% greater than preclip values. Air-jet stress elicited a marked increase in renal sympathetic nerve activity, mean arterial pressure, and heart rate. Renal sympathetic nerve activity responses were much greater in hypertensive rabbits, but the pressor responses were similar to those observed in normotensive animals. Acute administration of rilmenidine decreased blood pressure more in hypertensive animals but with a much lesser inhibition of sympathetic activity. Rilmenidine markedly reduced increased sympathetic activity during air-jet stress in 3-week clipped rabbits but to a lesser extent in the other groups. These studies show that while sympathetic responses to stress were markedly enhanced in renal clip hypertensive rabbits, they did not result in greater pressor responses, thus suggesting that vascular neuroeffector mechanisms were not altered. By contrast, the increased effects of rilmenidine suggest a much greater contribution to the hypertension by the sympathetic nervous system, but one that is caused by an enhanced “nonvascular” neuroeffector mechanism. As such, sympathoinhibitory agents such as rilmenidine are very suitable and very effective agents for the treatment of renovascular hypertension.
Publisher: Springer Science and Business Media LLC
Date: 05-12-2013
DOI: 10.1038/HR.2013.156
Abstract: Recent evidence indicates that genetic hypertension in BPH/2J mice is sympathetically mediated, but these mice also have lower body weight (BW) and elevated locomotor activity compared with BPN/3J normotensive mice, suggestive of metabolic abnormalities. The aim of the present study was to determine whether hypertension in BPH/2J mice is associated with metabolic differences. Whole-body metabolic and cardiovascular parameters were measured over 24 h by indirect calorimetry and radiotelemetry respectively, in conscious young (10-13 weeks) and older (22-23 weeks) BPH/2J, normotensive BPN/3J and C57Bl6 mice. Blood pressure (BP) was greater in BPH/2J compared with both normotensive strains at both ages (P<0.01). Metabolic rate was greater in young BPH/2J compared with BPN/3J mice (P 0.1) suggesting differences in this relationship are not responsible for hypertension. EchoMRI revealed that percentage body composition was comparable in BPN/3J and BPH/2J mice (P>0.1) and both strains gained weight similarly with age (P=0.3). Taken together, the present findings indicate that hypertension in BPH/2J mice does not appear to be related to altered energy metabolism.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2011
Publisher: Cambridge University Press (CUP)
Date: 19-09-2014
DOI: 10.1017/S0007114514002542
Abstract: High blood pressure (BP) variability, which may be an important determinant of hypertensive end-organ damage, is emerging as an important predictor of cardiovascular health. Dietary antioxidants can influence BP, but their effects on variability are yet to be investigated. The aim of the present study was to assess the effects of vitamin E, vitamin C and polyphenols on the rate of daytime and night-time ambulatory BP variation. To assess these effects, two randomised, double-blind, placebo-controlled trials were performed. In the first trial (vitamin E), fifty-eight in iduals with type 2 diabetes were given 500 mg/d of RRR -α-tocopherol, 500 mg/d of mixed tocopherols or placebo for 6 weeks. In the second trial (vitamin C–polyphenols), sixty-nine treated hypertensive in iduals were given 500 mg/d of vitamin C, 1000 mg/d of grape-seed polyphenols, both vitamin C and polyphenols, or neither (placebo) for 6 weeks. At baseline and at the end of the 6-week intervention, 24 h ambulatory BP and rate of measurement-to-measurement BP variation were assessed. Compared with placebo, treatment with α-tocopherol, mixed tocopherols, vitamin C and polyphenols did not significantly alter the rate of daytime or night-time systolic BP, diastolic BP or pulse pressure variation ( P ·05). Treatment with the vitamin C and polyphenol combination resulted in higher BP variation: the rate of night-time systolic BP variation ( P = 0·022) and pulse pressure variation ( P = 0·0036) were higher and the rate of daytime systolic BP variation was higher ( P = 0·056). Vitamin E, vitamin C or grape-seed polyphenols did not significantly alter the rate of BP variation. However, the increase in the rate of BP variation suggests that the combination of high doses of vitamin C and polyphenols could be detrimental to treated hypertensive in iduals.
Publisher: Springer Science and Business Media LLC
Date: 22-11-2013
DOI: 10.1038/JHH.2012.44
Abstract: A morning blood pressure surge (MBPS) may be either a mechanism for, or a marker of, increased cardiovascular events. This study has examined factors which may influence the morning surge: age, gender, metabolic factors, sympathetic function, blood pressure and arterial stiffness. Four measures of the MBPS were examined--sleep-trough surge, pre-awake surge, rate of blood pressure rise and a Power function. Subjects underwent ambulatory blood pressure monitoring, glucose tolerance test, central pulse wave velocity, sympathetic autonomic function tests (mental stress and sustained handgrip). MBPS was associated with age, hypertension, blood pressure variability and serum lipids. After adjustment for age and waist circumference, all four measures of MBPS remained positively associated with low-density lipoprotein (LDL) cholesterol. The novel finding of a significant relationship between measures of MBPS and LDL-cholesterol is an intriguing link between two major cardiovascular risk factors.
Publisher: Frontiers Media SA
Date: 29-05-2019
Publisher: Informa UK Limited
Date: 20-05-2013
DOI: 10.3109/07420528.2013.784771
Abstract: Consumption of a high-fat diet (HFD) by rabbits results in increased blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) within 1 wk. Here, we determined how early this activation occurred and whether it was related to changes in cardiovascular and neural 24-h rhythms. Rabbits were meal-fed a HFD for 3 wks, then a normal-fat diet (NFD) for 1 wk. BP, HR, and RSNA were measured daily in the home cage via implanted telemeters. Baseline BP, HR, and RSNA over 24 h were 71 ± 1 mm Hg, 205 ± 4 beats/min and 7 ± 1 normalized units (nu). The 24-h pattern was entrained to the feeding cycle and values increased from preprandial minimum to postprandial maximum by 4 ± 1 mm Hg, 51 ± 6 beats/min, and 1.6 ± .6 nu each day. Feeding of a HFD markedly diminished the preprandial dip after 2 d (79-125% of control p < 0.05) and this reduction lasted for 3 wks of HFD. Twenty-four-hour BP, HR, and RSNA concurrently increased by 2%, 18%, and 22%, respectively. Loss of preprandial dipping accounted for all of the BP increase and 50% of the RSNA increase over 3 wks and the 24-h rhythm became entrained to the light-dark cycle. Resumption of a NFD did not alter the BP preprandial dip. Thus, elevated BP induced by a HFD and mediated by increased sympathetic nerve activity results from a reduction in preprandial dipping, from the first day. Increased calories, glucose, insulin, and leptin may account for early changes, whereas long-term loss of dipping may be related to increased sensitivity of sympathetic pathways.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2017
Publisher: Portland Press Ltd.
Date: 10-2019
DOI: 10.1042/CS20190851
Abstract: The precise mechanisms underlying resistant hypertension remain elusive. Reduced nitric oxide (NO) bioavailability is frequently documented in chronic kidney disease, obesity, diabetes and advanced age, all of which are risk factors for resistant hypertension. Sympathetic overactivity and chronic activation of the renin–angiotensin system are salient features of resistant hypertension. Interestingly, recent data indicate that renal sympathetic overactivity can reduce the expression of neuronal nitric oxide synthase in the paraventricular nucleus. Reduced NO levels in the paraventricular nucleus can increase sympathetic outflow and this can create a vicious cycle contributing to resistant hypertension. Angiotensin II can reduce l-arginine transport and hence NO production. Reduced NO levels may reduce the formation of angiotensin 1-7 d ening the cardio-protective effects of the renin–angiotensin system contributing to resistant hypertension. In addition, interleukin-6 (IL-6) is demonstrated to be independently associated with resistant hypertension, and IL-6 can reduce NO synthesis. Despite this, NO levels have not been quantified in resistant hypertension. Findings from a small proof of concept study indicate that NO donors can reduce blood pressure in patients with resistant hypertension but more studies are required to validate these preliminary findings. In the present paper, we put forward the hypothesis that reduced NO bioavailability contributes substantially to the development of resistant hypertension.
Publisher: Elsevier BV
Date: 08-2000
Publisher: Wiley
Date: 10-2015
DOI: 10.1113/EP085312
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2009
DOI: 10.1097/HJH.0B013E328317A7A7
Abstract: We examined whether renal sympathetic nerve activity (RSNA) and heart rate (HR) baroreflexes in conscious rabbits were altered by exposure to a combination of stress and hypertension and determined how this was modified by acute and chronic treatment with the sympathoinhibitory agent rilmenidine. Rabbits were made hypertensive with a renal-artery clip and a renal nerve recording electrode was implanted 4-5 weeks later. After recovery, baroreflexes were measured before and during airjet stress and again after receiving rilmenidine (either acutely or by infusion for 3 weeks). Renal clipping increased mean arterial pressure (MAP) and shifted baroreflex RSNA and HR curves rightward. The HR and RSNA upper plateaus were similar to those of normotensive animals but HR baroreflex sensitivity was reduced in the hypertensive group. Airjet stress lowered HR baroreflex sensitivity in sham but not in hypertensive rabbits. By contrast, stress increased the baroreflex-induced maximum RSNA in hypertensive animals but not in normotensive rabbits. MAP variability was greater in the hypertensive group but was unaffected by airjet stress. Acute and chronic rilmenidine lowered MAP to close to normotensive levels, markedly reduced MAP variability and RSNA but did not prevent the RSNA baroreflex facilitation produced by airjet stress. Baroreflex control of HR was diminished by either hypertension or acute airjet stress but the effects were not additive. Although the baroreflex-induced RSNA maximum was increased by stress only in hypertensive animals, rilmenidine was effective in minimizing the reflex autonomic disturbances produced by hypertension and stress.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2014
Publisher: Portland Press Ltd.
Date: 03-07-2012
DOI: 10.1042/CS20110668
Abstract: Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting enzyme 2), which is reduced in diabetic tissues. In the present study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS (renin–angiotensin system) activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male ApoE (apolipoprotein E)-KO mice and ApoE/Ace2-double-KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks. The induction of diabetes in wild-type mice led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and reduced cardiac Ang-(1–7) [angiotensin-(1–7)] levels. This was associated structurally with thinning of the LV (left ventricular) wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2-KO mice failed to increase circulating AngII concentration, experienced a paradoxical fall in cardiac AngII levels and no change in Ang-(1–7) following the onset of diabetes. At the same time the major phenotypic differences between Ace2-deficient and Ace2-replete mice with respect to BP (blood pressure) and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic ApoE-KO mice was not seen in diabetic ApoE/Ace2-KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in ApoE/Ace2-KO mice. These results point to the potential role of ACE2 deficiency in regulating the tissue and circulating levels of AngII and their sequelae in the context of diabetes, as well as the preservation or augmentation of ACE2 expression or activity as a potential therapeutic target for the prevention of CVD (cardiovascular disease) in diabetes.
Publisher: Bentham Science Publishers Ltd.
Date: 2006
DOI: 10.2174/187152506775268758
Abstract: The initial realization that agents containing an imidazoline structure may interact with a distinct class of receptors, has led to a major class of cardiovascular agents, which now has the potential to enter a third generation. There is now general acceptance that there are three main imidazoline receptor classes, the I(1) imidazoline receptor which mediates the sympatho-inhibitory actions to lower blood pressure, the I(2) receptor which is an important allosteric binding site of monoamine oxidase and the I(3) receptor which regulates insulin secretion from pancreatic beta cells. Thus all three represent important targets for cardiovascular research. Interestingly, an I(1)- receptor candidate has been cloned (IRAS, imidazoline receptor antisera selected) which is a homologue of the mouse cell adhesion integrin binding protein Nischarin. There has been range of new agonists and antagonists with very high selectivity for I(1), I(2) and I(3) receptors developed. Three different endogenous ligands have been characterized including agmatine (decarboxylated arginine), a range of beta-carbolines including harman and harmane, and more recently imidazoleacetic acid-ribotide. The imidazoline field has recently seen an enormous ersification with discoveries that I(1) and I(2) receptors also play a role in cell proliferation, regulation of body fat, neuroprotection, inflammation and some psychiatric disorders such as depression. This ersification has continued with the addition of effective agents with imidazoline affinity in the fields of cancer, pain and opioid addiction, stress, cell adhesion, epilepsy and appetite. The imidazoline field has maturated considerably with a range of highly selective leader molecules, candidate receptors and endogenous ligands. We are therefore only at the threshold of an exciting new era as we begin to understand the erse and complex nature of their function.
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.
Publisher: Wiley
Date: 27-02-2008
DOI: 10.1111/J.1440-1681.2008.04908.X
Abstract: 1. The morning period has been recognized as the highest risk period of the day for cardiovascular events, particularly stroke and is also associated with a rapid surge in blood pressure. 2. Evidence now exists to show that the morning surge in blood pressure is an independent risk factor in some elderly hypertensive subjects. 3. However, methods to assess the contribution of the morning blood pressure surge from ambulatory recordings or home recordings, using clock times or times of waking, do not take into consideration the in idual patterns of blood pressure change which can range from a rapid rise prior to or following waking to a slow increase over several hours. 4. In the present review we describe a novel method for determining the in idual changes using a double logistic equation fitted to the in idual pattern of blood pressure change. 5. Methods are presented to determine the rate of rise function over the morning period as well as predicting the change over a fixed time window which may be useful in refining the contribution of the blood pressure surge to cardiovascular risk. 6. Hypertensive people have an exaggerated rise in morning blood pressure as well as a greater rate of rise. 7. Antihypertensive drugs and dosing regimes are being developed which may be useful adjuncts to standard therapy for preventing morning hypertension and hopefully also reducing cardiovascular damage or events.
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.NEUROSCIENCE.2010.07.040
Abstract: Schlager inbred hypertensive mice (BPH/2J) have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS). The brain nuclei associated with the hypertension are also those involved in the integration of the cardiovascular responses to stress. Therefore, in the present study, we hypothesize that BPH/2J mice likely have a greater response to stress that is associated with greater neuronal activation in the limbic system, hypothalamus and medulla in regions known to regulate sympathetic activity. Male hypertensive BPH/2J and normotensive BPN/3J mice were implanted with telemetry devices and exposed to dirty cage-switch, an acute model of aversive stress. Stress exposure caused a 60% greater pressor response in BPH/2J compared with BPN/3J mice and an increase in activity, by contrast the level of tachycardia was less in BPH/2J mice. Stress-induced cardiovascular responses were also associated with greater neuronal activation, as detected by c-Fos expression, in BPH/2J compared with BPN/3J mice in the medial nucleus of the amygdala (MeAm), dorsomedial hypothalamus (DMH) (P<0.001) and marginally in the rostral ventrolateral medulla (RVLM P=0.7). These findings suggest that hypertension in the BPH/2J mice is associated with greater sympathetic vasomotor responses to central pathways mediating the arousal responses to acute aversive stress in particular the amygdala, hypothalamus and rostral ventrolateral medulla.
Publisher: American Physiological Society
Date: 12-2010
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2002
Publisher: Society for Neuroscience
Date: 08-02-2012
DOI: 10.1523/JNEUROSCI.5360-11.2012
Abstract: The rise in blood pressure during an acute aversive stress has been suggested to involve activation of angiotensin type 1A receptors (AT 1A Rs) at various sites within the brain, including the rostral ventrolateral medulla. In this study we examine the involvement of AT 1A Rs associated with a subclass of sympathetic premotor neurons of the rostral ventrolateral medulla, the C1 neurons. The distribution of putative AT 1A R-expressing cells was mapped throughout the brains of three transgenic mice with a bacterial artificial chromosome-expressing green fluorescent protein under the control of the AT 1A R promoter. The overall distribution correlated with that of the AT 1A Rs mapped by other methods and demonstrated that the majority of C1 neurons express the AT 1A R. Cre-recombinase expression in C1 neurons of AT 1A R-floxed mice enabled demonstration that the pressor response to microinjection of angiotensin II into the rostral ventrolateral medulla is dependent upon expression of the AT 1A R in these neurons. Lentiviral-induced expression of wild-type AT 1A Rs in C1 neurons of global AT 1A R knock-out mice, implanted with radiotelemeter devices for recording blood pressure, modulated the pressor response to aversive stress. During prolonged cage-switch stress, expression of AT 1A Rs in C1 neurons induced a greater sustained pressor response when compared to the control viral-injected group (22 ± 4 mmHg for AT 1A R vs 10 ± 1 mmHg for GFP p 0.001), which was restored toward that of the wild-type group (28 ± 2 mmHg). This study demonstrates that AT 1A R expression by C1 neurons is essential for the pressor response to angiotensin II and that this pathway plays an important role in the pressor response to aversive stress.
Publisher: Springer International Publishing
Date: 2016
Publisher: Elsevier BV
Date: 09-2013
Publisher: Wiley
Date: 05-10-2016
DOI: 10.1111/JCH.12706
Publisher: American Physiological Society
Date: 2006
DOI: 10.1152/AJPREGU.00372.2005
Abstract: The dorsomedial hypothalamus (DMH) is critically implicated in the cardiovascular response to emotional stress. This study aimed to determine whether the DMH is also important in cardiovascular arousal associated with appetitive feeding behavior and, if so, whether locally released angiotensin II and glutamate are important in this arousal. Emotional (air-jet) stress and feeding elicited similar tachycardic (+51 and +45 beats/min, respectively) and pressor (+16 and +9 mmHg, respectively) responses in conscious rabbits. Bilateral microinjection of GABA A agonist muscimol (500 pmol) into the DMH, but not nearby hypothalamic regions, attenuated pressor and tachycardic responses to air-jet by 56–63% and evoked anorexia. Conversely, stimulation of the DMH with the glutamate analog kainic acid (250 pmol) elicited hypertension (+25 mmHg) and tachycardia (+114 beats/min) and activated feeding behavior. Local microinjection of a glutamate receptor antagonist, kynurenic acid (10 nmol), decreased pressor responses to stress and eating by 46 and 72%, respectively, without affecting feeding behavior. Bilateral microinjection of a selective AT 1 -receptor antagonist, candesartan (500 pmol), into the DMH, but not nearby sites, attenuated pressor and tachycardic stress responses by 31 and 33%, respectively. Candesartan did not alter feeding behavior or circulatory response to feeding. These results indicate that, in addition to its role in mediating stress responses, the DMH may be important in regulating cardiovascular arousal associated with feeding. Local glutamatergic inputs appear to regulate cardiovascular response to both stress and feeding. Conversely, angiotensin II, acting via AT 1 receptors, may selectively modulate, in the DMH, cardiovascular response to stress, but not feeding.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2016
DOI: 10.1161/HYPERTENSIONAHA.116.07461
Abstract: High fat diet (HFD)–induced hypertension in rabbits is neurogenic and caused by the central action of leptin, which is thought to be dependent on activation of α-melanocortin–stimulating hormone (α-MSH) and neuropeptide Y–positive neurons projecting to the dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). However, leptin may act directly in these nuclei. Here, we assessed the contribution of leptin, α-MSH, and neuropeptide Y signaling in the DMH and VMH to diet-induced hypertension. Male New Zealand white rabbits were instrumented with a cannula for drug injections into the DMH or VMH and a renal sympathetic nerve activity (RSNA) electrode. After 3 weeks of an HFD (13.3% fat n=19), rabbits exhibited higher RSNA, mean arterial pressure (MAP), and heart rate compared with control diet–fed animals (4.2% fat n=15). Intra-VMH injections of a leptin receptor antagonist or SHU9119, a melanocortin 3/4 receptor antagonist, decreased MAP, heart rate, and RSNA compared with vehicle in HFD rabbits ( P .05) but not in control diet–fed animals. By contrast, α-MSH or neuropeptide Y injected into the VMH had no effect on MAP but produced sympathoexcitation in HFD rabbits ( P .05) but not in control diet–fed rabbits. The effects of the leptin antagonist, α-MSH, or neuropeptide Y injections into the DMH on MAP or RSNA of HFD rabbits were not different from those after vehicle injection. α-MSH into the DMH of control diet–fed animals did increase MAP, heart rate, and RSNA. We conclude that the VMH is the likely origin of leptin-mediated sympathoexcitation and α-MSH hypersensitivity that contribute to obesity-related hypertension.
Publisher: Frontiers Media SA
Date: 09-11-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2012
Publisher: Public Library of Science (PLoS)
Date: 21-12-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2009
Publisher: American Physiological Society
Date: 04-2014
DOI: 10.1152/AJPRENAL.00264.2013
Abstract: The degradation of ANG II by angiotensin-converting enzyme 2 (ACE2), leading to the formation of ANG(1–7), is an important step in the regulation of the renin-angiotensin-aldosterone system (RAAS), and one that is significantly altered in the diabetic kidney. This study examined the role of ACE2 in the hyperfiltration associated with diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and ACE2 knockout (KO) mice. C57BL6 mice were further randomized to receive the selective ACE2 inhibitor MLN-4760. After 2 wk of study, animals were subjected to micropuncture experiments. The renal reserve was further assessed in C57BL6 mice and ACE2 KO mice after exposure to a high-protein diet. The induction of diabetes in wild-type mice was associated with increased renal ACE2 activity, hyperfiltration, and renal hypertrophy. On micropuncture, diabetes was associated with increased tubular free flow and stop-flow pressure, enhanced tubuloglomerular feedback reactivity, and an increased maximal response indicative of increased glomerular hydrostatic capillary pressure. Each of these increases were prevented in diabetic ACE2 KO mice and diabetic mice treated with a selective ACE2 inhibitor for 2 wk. However, unlike chronically treated animals, ACE2 inhibition with MLN-4760 had no acute effect on stop-flow pressure or tubuloglomerular feedback reactivity. ACE2 KO mice also failed to increase their creatinine clearance in response to a high-protein diet. The results of our study suggest that ACE2 plays a key role in the recruitment of the renal reserve and hyperfiltration associated with diabetes.
Publisher: Elsevier BV
Date: 08-08-2006
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.TOXICON.2010.12.001
Abstract: Natriuretic peptides are body fluid volume modulators, termed natriuretic peptides due to a role in natriuresis and diuresis. The three mammalian NPs, atrial natriuretic peptide (ANP), brain or b-type natriuretic peptide (BNP) and c-type natriuretic peptide (CNP), have been extensively investigated for their use as therapeutic agents for the treatment of cardiovascular diseases. Although effective, short half-lives and renal side effects limit their use. In approximately 30 years of research, NPs have been discovered in many vertebrates including mammals, hibians, reptiles and fish, with plants and, more recently, bacteria also being found to possess NPs. Reptiles have produced some of the more interesting NPs, with dendroaspis natriuretic peptide (DNP), which was isolated from the venom of the green mamba (Dendroaspis angusticeps), having greater potency and increased stability as compared to the mammalian family members, and taipan natriuretic peptide c (TNPc), which was isolated from the venom of the inland taipan (Oxyuranus microlepidotus) displaying similar activity to ANP and DNP at rat natriuretic peptide receptor A. Although promising, more research is required in this field to develop therapeutics that overcome receptor-mediated clearance, and potential toxicity issues. This review investigates the use of snake venom NPs as therapeutic drug leads.
Publisher: Elsevier BV
Date: 02-2022
Publisher: Oxford University Press (OUP)
Date: 09-04-2014
DOI: 10.1093/AJH/HPU050
Abstract: Obesity is associated with elevated cardiovascular mortality, which may be attributed, in part, to sympathetic nervous system (SNS) activation and an associated poor metabolic profile. We examined the effects of laparoscopic adjustable gastric band (LAGB) on SNS activity and cardiovascular profile when the initial weight loss of 10%, corresponding to the recommendation of clinical guidelines, was reached. Direct muscle sympathetic nerve activity (MSNA, microneurography), baroreflex function, and cardiovascular profile were examined before and after a predetermined weight loss of 10% in 23 severely obese nondiabetic in iduals. The 10% weight loss was achieved at an average of 7.3 ± 1.4 months (range = 1.3-23.3 months). This was associated with significant improvement in office systolic and diastolic blood pressure (BP) (-12 mm Hg and -5 mm Hg, respectively), a decrease in MSNA (33 ± 3 to 22 ± 3 bursts per minute), improvement in cardiac (16 ± 3 to 31 ± 4 ms/mm Hg) and sympathetic (-2.23 ± 0.39 to -4.30 ± 0.96 bursts/100 heartbeats/mm Hg) baroreflex function, total cholesterol (5.33 ± 0.13 to 4.97 ± 0.16 mmol/L), fasting insulin (29.3 ± 2.4 to 19.6 ± 1.1 mmol/L), and creatinine clearance (172 ± 11 to 142 ± 8 ml/min). None of the cardiovascular risk improvement related to the rate of weight loss. The change in systolic and diastolic BP correlated with change in waist circumference (r = 0.46, P = 0.04 r = 0.50, P = 0.02, respectively). The initial 10% weight loss induced by LAGB was associated with substantial hemodynamic, metabolic, SNS, and renal function improvements. Changes in waist circumference appear to be an important factor contributing to BP adaptation after LAGB surgery.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2010
DOI: 10.1161/HYPERTENSIONAHA.110.155663
Abstract: Excess weight is established as a major risk factor for cardiovascular diseases, particularly in young in iduals. To get a better understanding of the pathophysiology underlying increased cardiovascular disease risk, we evaluated early signs of organ damage and their possible relationship to sympathetic nervous activity. Eighteen lean (body mass index kg/m 2 ) and 25 overweight or obese (body mass index kg/m 2 ) healthy university students were included in the study. We comprehensively assessed subclinical target organ damage, including the following: (1) assessment of renal function (2) left ventricular structure and systolic and diastolic function and (3) endothelial function. Muscle sympathetic nervous activity was assessed by microneurography. Participants with excess weight had decreased endothelial function ( P .01), elevated creatinine clearance ( P .05), increased left ventricular mass index ( P .05), increased left ventricular wall thickness ( P .01), lower systolic and diastolic function ( P .01), and elevated muscle sympathetic nervous activity ( P .001) compared with lean in iduals. In multiple regression analysis, endothelial function was inversely related to muscle sympathetic nervous activity ( R 2 =0.244 P .05), whereas creatinine clearance and left ventricular mass index were positively related to muscle sympathetic nervous activity, after adjustment for body mass index, sex, and blood pressure ( R 2 =0.318, P .01 and R 2 =0.312, P .05, respectively). Excess weight in young in iduals is associated with subclinical alterations in renal and endothelial function, as well as in the structure of the heart, even in the absence of hypertension. Sympathetic activity is closely associated with cardiovascular and renal alterations observed in these subjects.
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.
Publisher: Wiley
Date: 12-2014
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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2009
DOI: 10.1161/HYPERTENSIONAHA.109.139741
Abstract: We determined whether genetic deficiency of angiotensin II Type 1A (AT 1A ) receptors in mice results in altered neuronal responsiveness and reduced cardiovascular reactivity to stress. Telemetry devices were used to measure mean arterial pressure, heart rate, and activity. Before stress, lower resting mean arterial pressure was recorded in AT 1A −/− (85±2 mm Hg) than in AT 1A +/+ (112±2 mm Hg) mice heart rate was not different between groups. Cage-switch stress for 90 minutes elevated blood pressure by +24±2 mm Hg in AT 1A +/+ and +17±2 mm Hg in AT 1A −/− mice ( P .01), and heart rate increased by +203±9 bpm in AT 1A +/+ and +121±9 bpm in AT 1A −/− mice ( P .001). Locomotor activation was less in AT 1A −/− (3.0±0.4 U) than in AT 1A +/+ animals (6.0±0.4 U), but differences in blood pressure and heart rate persisted during nonactive periods. In contrast to wild-type mice, spontaneous baroreflex sensitivity was not inhibited by stress in AT 1A −/− mice. After cage-switch stress, c-Fos immunoreactivity was less in the paraventricular ( P .001) and dorsomedial ( P =0.001) nuclei of the hypothalamus and rostral ventrolateral medulla ( P .001) in AT 1A −/− compared with AT 1A +/+ mice. Conversely, greater c-Fos immunoreactivity was observed in the medial nucleus of the amygdala, caudal ventrolateral medulla, and nucleus of the solitary tract ( P .001) of AT 1A −/− compared with AT 1A +/+ mice. Greater activation of the amygdala suggests that AT 1A receptors normally inhibit the degree of stress-induced anxiety, whereas the lesser activation of the hypothalamus and rostral ventrolateral medulla suggests that AT 1A receptors play a key role in autonomic cardiovascular reactions to acute aversive stress, as well as for stress-induced inhibition of the baroreflex.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2022
DOI: 10.1161/HYPERTENSIONAHA.122.19350
Abstract: Blood pressure (BP) variability is an independent risk factor for cardiovascular events. Recent evidence supports a role for the gut microbiota in BP regulation. However, whether the gut microbiome is associated with BP variability is yet to be determined. Here, we aimed to investigate the interplay between the gut microbiome and their metabolites in relation to BP variability. Ambulatory BP monitoring was performed in 69 participants from Australia (55.1% women mean±SD, 59.8±7.26 years body mass index, 25.2±2.83 kg/m 2 ). These data were used to determine nighttime dipping, morning BP surge (MBPS) and BP variability as SD. The gut microbiome was determined by 16S ribosomal RNA (rRNA) sequencing and metabolite levels by gas chromatography. We identified specific taxa associated with systolic BP variability, nighttime dipping, and MBPS. Notably, Alistipesfinegoldii and Lactobacillus spp. were only present in participants within the normal ranges of BP variability, MBPS and dipping, while Prevotella spp. and Clostridium spp., were found to be present in extreme dippers and the highest quartiles of BP SD and MBPS. There was a negative association between MBPS and microbial α- ersity (r=−0.244, P =0.046). MBPS was also negatively associated with plasma levels of microbial metabolites called short-chain fatty acids (r=−0.305, P =0.020), particularly acetate (r=−0.311, P =0.017). Gut microbiome ersity, levels of microbial metabolites, and the bacteria Alistipesfinegoldii and Lactobacillus were associated with lower BP variability and Clostridium and Prevotella with higher BP variability. Thus, our findings suggest the gut microbiome and metabolites may be involved in the regulation of BP variability.
Publisher: Frontiers Media SA
Date: 12-12-2019
Publisher: Oxford University Press (OUP)
Date: 10-2010
DOI: 10.1038/AJH.2010.126
Abstract: We defined a new measure of the morning blood pressure (BP) surge (MBPS) that is derived by the product of the rate of morning rise (RoR) and the litude (day-night difference) giving an effective "Power" of the BP rise (BP(Power)). We applied this method to determine whether morning BP(Power) is different in hypertensives compared to normotensives, males compared to females or altered by antihypertensive treatment. BP(Power), RoR, and day-night litude were calculated using a double logistic fit of 691 ambulatory recordings. Ambulatory recordings from untreated male and female subjects showed that upper quartile (distributed by day BP, n = 100) had a 92% greater BP(Power) (P < 0.001) than the lower quartile subjects (n = 100) due to both a faster RoR and greater litude. Males had a 29% greater BP(Power) than females (P = 0.003). Untreated hypertensives and white coat hypertensives showed a greater morning BP(Power) (+158% and +86%, respectively) compared to matched normotensives. Subjects taking calcium channel blockers and diuretics alone or in combination with angiotensin receptor blockers had lower morning BP(Power) than those on angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor antagonists alone. A new measure of the MBPS, BP(Power) which is based on a mathematical estimate of the rate and litude of the rise, is higher in hypertensives, white coat hypertensives, and is modifiable by some specific antihypertensive therapies suggests that it may be theoretically useful to highlight those subjects at greatest risk of cardiovascular events and for determining the most benefit of antihypertensive therapy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2004
DOI: 10.1161/01.HYP.0000131290.12255.04
Abstract: Superoxide has been shown to be an important intracellular mediator of actions of angiotensin II. Recently, we found that blockade of angiotensin II type-1 receptors in the rostral ventrolateral medulla (RVLM) abrogated the pressor effect of emotional stress in rabbits. In the present study, we examined the influence of superoxide dismutase mimetics, tempol and tiron, in RVLM on cardiovascular stress response in conscious rabbits. Air-jet stress evoked a sustained increase in blood pressure (+14±2 mm Hg), tachycardia (+52±7 bpm), and renal sympathoactivation (+58±8%). Bilateral microinjections of tempol or tiron (20 nmol) into RVLM did not alter resting cardiovascular parameters, but attenuated the pressor, sympathetic, and tachycardiac response to stress by 40% to 55%. By contrast, 3-carbamoylproxyl, which is structurally close to tempol but has a lower superoxide scavenging activity, did not alter the stress response. Neither tempol nor tiron altered the sympathoexcitatory response to glutamate microinjections into RVLM or to baroreceptor unloading. Microinjections of nitric oxide synthase inhibitor N G -nitro- l -arginine methyl ester ( l -NAME 10 nmol) into RVLM did not affect the stress response. Coinjections of tempol and l -NAME decreased the pressor response to stress by 35±3%. Tempol attenuated the pressor response to microinjection of angiotensin II into RVLM by 59±15%, whereas l -NAME did not alter this response. These results suggest that superoxide dismutase mimetics in RVLM attenuate, partially via a nitric oxide-independent mechanism, the pressor effect of emotional stress in rabbits. Together with our previous studies, these results also indicate that superoxide is a key mediator of excitatory actions of angiotensin II in RVLM during acute stress.
Publisher: American Physiological Society
Date: 06-2011
DOI: 10.1152/PHYSIOLGENOMICS.00009.2011
Abstract: The hypothalamus has an important etiological role in the onset and maintenance of hypertension and stress responses in the Schlager high blood pressure (BP) (BPH/2J) mouse, a genetic model of neurogenic hypertension. Using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays we identified 1,019 hypothalamic genes whose expression differed between 6 wk old BPH/2J and normal BP (BPN/3J) strains, and 466 for 26 wk old mice. Of these, 459 were in 21 mouse BP quantitative trait loci. We validated 46 genes by qPCR. Gene changes that would increase sympathetic outflow at both ages were: Dynll1 encoding dynein light chain LC8-type 1, which physically destabilizes neuronal nitric oxide synthase, decreasing neuronal nitric oxide, and Hcrt encoding hypocretin and Npsr1 encoding neuropeptide S receptor 1, each involved in sympathetic response to stress. At both ages we identified genes for inflammation, such as CC-chemokine ligand 19 ( Ccl19), and oxidative stress. Via reactive oxygen species generation, these could contribute to oxidative damage. Other genes identified could be responding to such perturbations. Atp2b1, the major gene from genome-wide association studies of BP variation, was underexpressed in the early phase. Comparison of profiles of young and adult BPH/2J mice, after adjusting for maturation genes, pointed to the proopiomelanocortin-α gene ( Pomc) and neuropeptide Y gene ( Npy), among others, as potentially causative. The present study has identified a ersity of genes and possible mechanisms involved in hypertension etiology and maintenance in the hypothalamus of BPH/2J mice, highlighting both common and ergent processes in each phase of the condition.
Publisher: Oxford University Press (OUP)
Date: 08-2010
DOI: 10.1038/AJH.2010.69
Abstract: Schlager inbred hypertensive mice (BPH/2J) have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS). The brain nuclei associated with the hypertension are also those involved in the integration of the cardiovascular responses to stress. Therefore, in the present study, we hypothesize that an increased contribution of the SNS in BPH/2J mice may culminate in a greater pressor response to stressful stimuli in these hypertensive mice than normotensive (BPN/3J) mice. Male hypertensive BPH/2J and normotensive BPN/3J mice were implanted with telemetry devices and exposed to a series of behavioral "stress" tests including aversive stress (shaker, clean cage switch, and restraint) and nonaversive stress (feeding). Aversive stress caused a 67-88% greater pressor response in BPH/2J compared with BPN/3J mice. By contrast, the feeding-induced pressor response was not different between groups. All stressors induced tachycardia that was less in BPH/2J mice (feeding and restraint) and others were not different between groups (clean cage switch and shaker). These findings indicate that hypertension in BPH/2J mice is associated with greater pressor responsiveness to aversive stress but not to appetitive arousal. Thus, BPH/2J hypertensive mice may be a particularly relevant model for human hypertensive patients that overrespond to daily stressors.
Publisher: Oxford University Press (OUP)
Date: 08-2007
DOI: 10.1016/J.AMJHYPER.2007.02.010
Abstract: We have recently shown that the renin enhancer, a regulatory element of renin gene transcription, is important in the long-term control of basal blood pressure (BP). In this study, we examined whether the renin enhancer deficit alters the acute pressor response to emotional stress in mice. Under fluothane anesthesia, wild-type (C57BL6, n=7) and the Ren-1c enhancer knockout (REKO, n=8) mice were implanted with telemetry devices to measure BP and locomotor activity. Resting BP in REKO mice (94+/-3 mm Hg) was lower than in wild-type mice (102+/-2 mm Hg). Shaker stress elicited prompt pressor (+25+/-2 mm Hg), tachycardic (+145+/-25 beats/min), and locomotor responses in wild-type mice. The BP and locomotor responses were decreased in REKO mice by 39%+/-12% (P=.03) and 64%+/-11% (P=.02), respectively, whereas the tachycardic response remained unchanged. Restraint stress increased BP by 27+/-1 mm Hg in wild-type mice. The BP response was attenuated in REKO mice by 21%+/-8% (P=.05), and this attenuation could not be ascribed to reduced locomotor activity during stress. Cardiovascular arousal associated with presentation and eating palatable food was similar in wild-type (+19+/-2 mm Hg and +174+/-21 beats/min) and REKO (+19+/-2 mm Hg and +147+/-17 beats/min) mice. The contractile response to the alpha-adrenoceptor agonist phenylephrine was reduced in aortas from REKO mice, whereas that to angiotensin II was not different between strains. The disrupted regulation of renin synthesis caused by the renin enhancer deficit in mice is associated with a selective reduction in BP reactivity to aversive stress, which may be mediated by multiple central and peripheral mechanisms.
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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2016
Publisher: Elsevier BV
Date: 09-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2010
DOI: 10.1161/HYPERTENSIONAHA.109.141119
Abstract: The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively ( P .05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher ( P .05) in HFD compared with control diet rabbits and was correlated to plasma leptin ( r =0.87 P .01). Intracerebroventricular leptin administration (5 to 100 μg) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: −54%, paraventricular: −69%, and dorsomedial hypothalamus: −65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked “selective leptin resistance” in these animals.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2013
DOI: 10.1161/HYPERTENSIONAHA.111.00705
Abstract: Feeding a high-fat diet (HFD) to rabbits results in increased blood pressure and renal sympathetic nerve activity (RSNA) and marked increases in plasma leptin and insulin. We determined the contribution of insulin and leptin signaling in the central nervous system to the increased blood pressure and RSNA during a HFD using specific antagonists. New Zealand White rabbits were implanted with an intracerebroventricular (ICV) catheter and RSNA electrode and placed on a normal or 13.5% HFD for 1 or 3 weeks. Blood pressure, heart rate, and RSNA were recorded before and for 90 minutes after ICV administration of a leptin antagonist (100 µg), insulin antagonist (0.5 U), or vehicle (50 µL) on separate days. Rabbits had higher blood pressure (+8%, +17%) and RSNA (+55%, +71%), at 1 and 3 weeks, respectively, of HFD compared with controls (n=7–11). ICV leptin antagonist reduced blood pressure by 9% and RSNA by 17% ( P .001) after 3 weeks of HFD but had no effect at week 1. ICV administration of the insulin antagonist reduced blood pressure by ≈5% at both times ( P .05) but there was no effect on RSNA. Leptin and insulin antagonist doses were confirmed to effectively block the pressor responses to ICV leptin and insulin, respectively. The elevation of blood pressure and RSNA induced by a HFD is predominantly mediated by central actions of leptin. Central actions of insulin contribute a smaller proportion of the hypertension but independently of RSNA.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2016
DOI: 10.1038/SREP26777
Abstract: Previously, we demonstrated that renal hemodynamic responses to nitric oxide (NO) inhibition were attenuated in aged, hypertensive sheep born with a solitary functioning kidney (SFK). NO is an important regulator of renal function, particularly, in the postnatal period. We hypothesized that the onset of renal dysfunction and hypertension in in iduals with a SFK is associated with NO deficiency early in life. In this study, renal and cardiovascular responses to L-NAME infusion (N w -nitro-L-arginine methyl ester) were examined in 6-month old lambs born with a SFK, induced by fetal unilateral nephrectomy (uni-x). Renal responses to L-NAME were attenuated in uni-x sheep with the fall in glomerular filtration rate (GFR) and urinary sodium excretion (U Na V) being less in the uni-x compared to sham lambs (%ΔGFR −41 ± 3 vs −54 ± 4: P = 0.03, %ΔU Na V −48 ± 5 vs −76 ± 3, P = 0.0008). 24 hour-basal urinary nitrate and nitrite (NOx) excretion was less in the uni-x animals compared to the sham (NOx excretion μM/min/kg sham: 57 ± 7 uni-x: 38 ± 4, P = 0.02). L-NAME treatment reduced urinary NOx to undetectable levels in both groups. A reduction in NO bioavailability in early life may contribute to the initiation of glomerular and tubular dysfunction that promotes development and progression of hypertension in offspring with a congenital nephron deficit, including those with a SFK.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2001
DOI: 10.1097/00004872-200109000-00014
Abstract: It has been suggested that imidazoline receptors rather than alpha2-adrenoceptors are involved in the sympathoinhibitory action of centrally acting antihypertensive drugs such as rilmenidine. In the present study, we examined the relative importance of alpha2-adrenoceptors and imidazoline receptors in modulating the renal sympathetic and heart rate (HR) baroreflex in response to central administration of rilmenidine in conscious normotensive rabbits. In seven conscious rabbits, chronically instrumented with a fourth ventricular (4V) catheter, aortic and vena caval cuff occluders and a renal nerve electrode, we continuously recorded renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and HR and assessed baroreflex MAP-RSNA and MAP-HR relationships with balloon-induced r rises and falls in MAP. Rabbits were treated with 4V rilmenidine (22 microg/kg) followed by 4V idazoxan (30 microg/kg a mixed alpha2-adrenoceptor and imidazoline receptor antagonist) or 4V 2-methoxy-idazoxan (1 microg/kg an alpha2-adrenoceptor antagonist with little affinity for imidazoline receptors). Rilmenidine lowered blood pressure by 24% and reduced both upper and lower plateaus of the renal sympathetic baroreflex curve, such that the RSNA range (difference between plateaus) was reduced by 40% (-32 +/- 10 normalized units). Curves were shifted to the left with the fall in MAP. Idazoxan restored MAP, maximum RSNA and the RSNA baroreflex range. By contrast the alpha2-adrenoceptor antagonist 2-methoxy-idazoxan caused only a partial recovery of MAP and RSNA baroreflex upper plateau and range (-9 +/- 2 mmHg, 29 and 33% lower than control). Both antagonists partially restored the HR baroreflex. These findings suggest that in conscious rabbits, both imidazoline receptors and alpha2-adrenoceptors are involved in the central antihypertensive and baroreflex actions of rilmenidine, but that activation of imidazoline receptors is more important for its renal sympathoinhibitory action.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2014
Publisher: Springer Science and Business Media LLC
Date: 05-04-2016
DOI: 10.1038/MP.2016.40
Abstract: Norepinephrine released from sympathetic nerves is removed from the neuroeffector junction via the action of the norepinephrine transporter (NET). NET impairment is evident in several clinically important conditions including major depressive disorder (MDD), panic disorder (PD), essential hypertension and the postural orthostatic tachycardia syndrome (POTS). We aimed to determine whether a single nucleotide polymorphism (SNP) in the 3' untranslated region (UTR) of the NET gene is associated with NET impairment and to elucidate the mechanisms involved. The analyses were carried out in two cohorts of European ancestry, which included healthy controls and MDD, PD, hypertensive and POTS patients. Compared with controls, cases had significantly higher prevalence of the T allele of rs7194256 (C/T), arterial norepinephrine, depression and anxiety scores, larger left ventricular mass index, higher systolic and diastolic blood pressures, and heart rate. Bioinformatic analysis identified that the microRNA miR-19a-3p could bind preferentially to the sequence created by the presence of the T allele. This was supported by results of luciferase assays. Compared with controls, cases had significantly lower circulating miR-19a-3p, which was associated with pathways related to blood pressure and regulation of neurotransmission. In vitro norepinephrine downregulated miR-19a-3p. In conclusion, the T allele of the rs7194256 SNP in the 3'UTR of the NET gene is more prevalent in diseases where NET impairment is evident. This might be explained by the creation of a binding site for the microRNA miR-19a-3p. A defect in NET function may potentiate the sympathetic neurochemical signal, predisposing in iduals with affective diseases to increased risk of cardiovascular disease development.
Publisher: Wiley
Date: 12-2003
Abstract: An increased role of the sympathetic nervous system has been suggested to be a major contributor to the chronic elevation of BP in renovascular hypertension. We assessed the effects of rilmenidine, a centrally acting antihypertensive imidazoline agent, on BP and renal sympathetic nerve activity (RSNA) in 2K1C renovascular hypertensive conscious rabbits. Rabbits were made hypertensive with a renal clip or were sham-operated and were studied 3 and 6 weeks later. Acute treatment with rilmenidine reduced BP to a greater extent in the hypertensive rabbits. Although rilmenidine reduced the heart rate by the same extent in all groups, rilmenidine produced much less inhibition of RSNA in the hypertensive animals. These studies suggest that the contribution of the sympathetic nervous system is greater in 2K1C hypertension and that imidazoline agents may be beneficial in treating renovascular hypertension.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2018
Publisher: Wiley
Date: 26-02-2013
Publisher: Frontiers Media SA
Date: 2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2012
DOI: 10.1161/HYPERTENSIONAHA.111.178715
Abstract: Awareness of sex differences in the pathology of cardiovascular disease is increasing. Previously, we have shown a role for the angiotensin type 2 receptor (AT 2 R) in the sex differences in the arterial pressure response to Ang II. Tubuloglomerular feedback (TGF) contributes in setting pressure-natriuresis properties, and its responsiveness is closely coupled to renal Ang II levels. We hypothesize that, in females, the attenuated pressor response to Ang II is mediated via an enhanced AT 2 R mechanism that, in part, offsets Ang II–induced sensitization of the TGF mechanism. Mean arterial pressure was measured via telemetry in male and female wild-type (WT) and AT 2 R knockout (AT 2 R-KO) mice receiving Ang II (600 ng/kg per minute SC). Basal 24-hour mean arterial pressure did not differ among the 4 groups. After 10 days of Ang II infusion, mean arterial pressure increased in the male WT (28±6 mm Hg), male AT 2 R-KO (26±2 mm Hg), and female AT 2 R-KO (26±4 mm Hg) mice, however, the response was attenuated in female WT mice (12±4 mm Hg P between sex and genotype=0.016). TGF characteristics were determined before and during acute subpressor Ang II infusion (100 ng/kg per minute IV). Basal TGF responses did not differ between groups. The expected increase in maximal change in stop-flow pressure and enhancement of TGF sensitivity in response to Ang II was observed in the male WT, male AT 2 R-KO, and female AT 2 R-KO but not in the female WT mice ( P between sex and genotype .05 both). In conclusion, these data indicate that an enhanced AT 2 R-mediated pathway counterbalances the hypertensive effects of Ang II and attenuates the Ang II–dependent resetting of TGF activity in females. Thus, the enhancement of the AT 2 R may, in part, underlie the protection that premenopausal women demonstrate against cardiovascular disease.
Publisher: Georg Thieme Verlag KG
Date: 2011
DOI: 10.1160/TH10-07-0449
Abstract: Left ventricular thrombus (LVT) and rupture are important mechanical complications following myocardial infarction (MI) and are believed to be due to unrelated mechanisms. We studied whether, in fact, wall rupture and LVT are closely related in their pathogenesis with intramural platelet thrombus (IMT) playing a pivotal role. Male 129sv and C57Bl/6 mice underwent operation to induce MI, and autopsy was performed to confirm rupture deaths. Haemodynamic features of rupture events were monitored by telemetry in conscious mice. Detailed histological examination was conducted with special attention to the presence of IMT in relation to rupture location and LVT formation. IMT was detected in infarcted hearts of 129sv (82%) and C57Bl/6 (39%) mice with rupture in the form of a narrow streak spanning the wall or an occupying mass dissecting the infarcted myofibers apart. IMT often contained dense inflammatory cells and blood clot, indicating a dynamic process of thrombus formation and destruction. Notably, IMT was found extending into the cavity to form LVT. Haemodynamic monitoring by telemetry revealed that rupture occurred either as a single event or recurrent episodes. Importantly, the anti-platelet drug clopidogrel, but not aspirin, reduced the prevalence of rupture (10% vs. 45%) and IMT, and suppressed the degree of inflammation. Thus, IMT is a key pathological element in the infarcted heart closely associated with the complications of rupture and LVT. IMT could be either triggered by a wall tear or act as initiator of rupture. IMT may propagate towards the ventricular chamber to trigger LVT.
Publisher: Frontiers Media SA
Date: 15-11-2016
Publisher: Springer Science and Business Media LLC
Date: 27-05-2017
DOI: 10.1007/S11906-017-0750-1
Abstract: The major health issue of being overweight or obese relates to the development of hypertension, insulin resistance and diabetic complications. One of the major underlying factors influencing the elevated blood pressure in obesity is increased activity of the sympathetic nerves to particular organs such as the kidney. There is now convincing evidence from animal studies that major signals such as leptin and insulin have a sympathoexcitatory action in the hypothalamus to cause hypertension. Recent studies suggest that this may involve 'neural plasticity' within hypothalamic signalling driven by central actions of leptin mediated via activation of melanocortin receptor signalling and activation of brain neurotrophic factors. This review describes the evidence to support the contribution of the SNS to obesity related hypertension and the major metabolic and adipokine signals.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JACC.2016.12.014
Abstract: Clinical trials applying catheter-based radiofrequency renal denervation (RDN) demonstrated a favorable safety profile with minimal acute or procedural adverse events. Whether ablation of renal nerves adversely affects compensatory responses to hemodynamic challenge has not been extensively investigated. The aim of this study was to examine the effect of RDN on mean arterial pressure, renal function, and the reflex response to hemorrhage in sheep with normotension (control) or with hypertensive chronic kidney disease (CKD). Sheep underwent RDN (control-RDN, n = 8 CKD-RDN, n = 7) or sham procedures (control-intact, n = 6 CKD-intact, n = 7). Response to hemorrhage (20% loss of blood volume), including plasma renin activity, was assessed at 2 and 5 months post-procedure. RDN caused a complete reversal of hypertension and improved renal function in CKD-RDN sheep (p < 0.0001 for 2 and 5 months vs. pre-RDN). In response to hemorrhage, mean arterial pressure fell in all groups, with the fall being greater in the RDN than the intact group (2-month fall in mean arterial pressure: control-intact, -10 ± 1 mm Hg control-RDN, -15 ± 1 mm Hg p < 0.05 CKD-intact, -11 ± 3 mm Hg CKD-RDN, -19 ± 9 mm Hg p < 0.001). Hemorrhage increased heart rate and plasma renin activity in intact sheep, but these responses were significantly attenuated in control-RDN and CKD-RDN animals. Responses to hemorrhage were remarkably similar at 2 and 5 months post-RDN, which suggests that nerve function had not returned within this time frame. In hypertensive CKD sheep, RDN reduced blood pressure and improved basal renal function but markedly compromised compensatory hemodynamic responses to hemorrhage. Therefore, the capacity to respond to a physiological challenge to body fluid homeostasis may be compromised following RDN.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2017
Publisher: Wiley
Date: 27-01-2011
DOI: 10.1111/J.1440-1681.2010.05413.X
Abstract: 1. The amygdala is a part of the limbic system that is associated with mediating the emotional and hormonal response to stress and although studies have focused on the central amygdala, there is increasing evidence that the medial amygdala is a major region activated by stressful stimuli. 2. Neuroanatomical studies in rats have shown greater activation in the medial amygdala following aversive stresses compared with other brain regions, including the central amygdala. Inhibition of the medial, but not the central, amygdala attenuates the development of hypertension in spontaneously hypertensive rats. 3. Schlager (BPH/2J) mice have a neurogenic form of hypertension that is most evident during the night when the mice are most active and is closely correlated with the level of activation of neurons in the medial, but not the central, amygdala. Pressor responses to aversive stimuli, such as restraint and cage-switch stress, are much greater in BPH/2J hypertensive than BPN/3J normotensive mice, but appetitive arousal produces normal increases in blood pressure. The degree of activation in the medial amygdala in BPH/2J hypertensive mice during aversive stress closely correlates with the increased blood pressure. 4. Thus, the inappropriate activation of the medial amygdala evoked by specific fear or aversive stimuli may be key to the neurogenic hypertension.
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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2016
Publisher: Oxford University Press (OUP)
Date: 16-01-2014
DOI: 10.1093/AJH/HPT273
Abstract: An exaggerated morning surge in blood pressure (BP) closely relates to target organ damage and cardiovascular risk, but whether the causative mechanism involves greater reactivity of the sympathetic nervous system (SNS) is unknown. We determined whether the response of the SNS to a cold pressor test predicted the BP morning surge. Ambulatory BP recordings were obtained from 14 men and 19 women (age = 41±4 years), and the litude (day-night difference), rate of rise (RoR), rate by litude product (BPPower), and morning BP surge (MBPS post-awake minus pre-awake) of morning mean arterial pressure (MAP) were determined. The reactivity of the SNS to CPT was assessed by recording of muscle sympathetic nerve activity (MSNA). CPT induced a marked increase in MAP and all parameters of MSNA, including burst litude. Log-normalized BPPower positively correlated with the overall average CPT-induced increases in total MSNA (r = 0.38 P = 0.04) and burst litude (r = 0.43 P = 0.02) but was not related to the increase in MSNA frequency. Furthermore, a strong positive linear trend in the CPT-induced changes in burst litude across tertiles of BPPower and RoR was observed. BPPower and RoR were not related to CPT-induced hemodynamic changes. The MBPS did not correlate with any of the CPT-induced changes in vascular or MSNA variables. These results suggest that the central nervous system mechanisms influencing the increase in MSNA burst litude during arousal may also be fundamental in determining the rate and power of BP rise during the morning period.
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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2002
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2013
Publisher: Elsevier BV
Date: 05-2013
Abstract: Measures of blood pressure variation have been associated with cardiovascular disease and related outcomes. The regular consumption of black tea can lower blood pressure, but its effects on blood pressure variation have yet to be investigated. We aimed to assess the effects of black tea consumption on the rate of ambulatory blood pressure variation. Men and women (n = 111) with systolic blood pressure between 115 and 150 mm Hg at screening were recruited in a randomized, controlled, double-blind, 6-mo parallel-designed trial designed primarily to assess effects on blood pressure. Participants consumed 3 cups/d of either powdered black tea solids (tea) or a flavonoid-free caffeine-matched beverage (control). The 24-h ambulatory blood pressure level and rate of measurement-to-measurement blood pressure variation were assessed at baseline, day 1, and 3 and 6 mo. Across the 3 time points, tea, compared with the control, resulted in lower rates of systolic (P = 0.0045) and diastolic (P = 0.016) blood pressure variation by ~10% during nighttime (2200-0600). These effects, which were immediate at day 1 and sustained over 6 mo, were independent of the level of blood pressure and heart rate. The rate of blood pressure variation was not significantly altered during daytime (0800-2000). These findings indicate that a component of black tea solids, other than caffeine, can influence the rate of blood pressure variation during nighttime. Thus, small dietary changes have the potential to significantly influence the rate of blood pressure variation. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTR12607000543482.
Publisher: Oxford University Press (OUP)
Date: 04-2006
DOI: 10.1016/J.AMJHYPER.2005.09.024
Abstract: We have recently shown that microinjection of the superoxide dismutase mimetic tempol into the pressor region of the rostral ventrolateral medulla attenuates the cardiovascular response to mental (air-jet) stress in rabbits. In the present study, we examined the influence of tempol on the blood pressure (BP) and heart rate (HR) responses to stress in the key region of the hypothalamic defense area, the dorsomedial hypothalamus (DMH). New Zealand White rabbits were implanted with guide cannulae for microinjection into the DMH. After 2 weeks of recovery, the cardiovascular response to air-jet stress was evaluated before and after bilateral injections of equimolar doses (20 nmol) of the superoxide scavengers tempol, tiron, or 3-carbamoyl proxyl (3-CP). Microinjection of superoxide scavengers into the DMH did not alter resting BP or HR. Air-jet stress evoked a sustained increase in BP (+16 +/- 2 mm Hg) and HR (+48 +/- 5 beats/min). Tempol attenuated the pressor and tachycardic responses to air-jet stress by 39% +/- 10% and 37% +/- 8%, respectively (P < .05), without altering stress-induced tachypnea. Similarly, tiron selectively decreased the BP and HR responses to stress by 33% +/- 8% and 53% +/- 13%, respectively (P < .05). Conversely, 3-CP, which is structurally close to tempol but has a lower superoxide scavenging activity, did not alter the cardiovascular stress response, and neither did vehicle. Microinjection of tempol or tiron just outside the DMH had little effect on stress responses. This study provides first published evidence that superoxide in the DMH is important in the regulation of acute hypertensive and tachycardic responses to mental stress.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2014
DOI: 10.1161/HYPERTENSIONAHA.113.02020
Abstract: BPH/2J mice are recognized as a neurogenic model of hypertension primarily based on overactivity of the sympathetic nervous system and greater neuronal activity in key autonomic cardiovascular regulatory brain regions. The medial amygdala (MeAm) is a forebrain region that integrates the autonomic response to stress and is the only region found to have greater Fos during the night and daytime in BPH/2J compared with BPN/3J mice. To determine the contribution of the MeAm to hypertension, the effect of neuronal ablation on blood pressure (BP) was assessed in BPH/2J (n=7) and normotensive BPN/3J mice (n=7). Mice were preimplanted with radiotelemetry devices to measure 24-hour BP and cardiovascular responses to stress, before and 1 to 3 weeks after bilateral lesions of the MeAm. Baseline BP was 121±4 mm Hg in BPH/2J and 101±2 mm Hg in BPN/3J mice ( P strain .001). MeAm lesions reduced BP by 11±2 mm Hg in BPH/2J mice ( P lesion .001) but had no effect in BPN/3J mice. The hypotensive effect of lesions in BPH/2J mice was similar during both day and night, suggesting that the MeAm has tonic effects on BP, but the pressor response to stress was maintained in both strains. Midfrequency BP power was attenuated in both strains ( P lesion .05) and the depressor responses to pentolinium after enalaprilat pretreatment was attenuated after lesions in BPH/2J mice ( P lesion .001 n=3). These findings indicate that the MeAm provides a tonic contribution to hypertension in BPH/2J mice, which is independent of its role in stress reactivity or circadian BP influences.
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 03-2010
Abstract: Delayed vasospasm is a significant cause of morbidity and mortality after subarachnoid hemorrhage (SAH). Proteomic therapeutics offers a new modality in which biologically active proteins or peptides are transduced into cells via covalent linkage to cell permeant peptides (CPPs). The hypothesis of this study was that either intrathecal or intravenous delivery of a phosphopeptide mimetic of the small heat shock–related protein, HSP20, linked to a CPP, would inhibit delayed decreases in cerebral perfusion after experimental SAH in a rat model. This study was conducted in 3 parts: 1) prevention and 2) reversal of delayed decreases in cerebral perfusion via either intrathecal or intravenous administration of a CPP linked to phosphopeptide mimetics of HSP20 (AZX100) and 3) determining the effect of intravenous administration of AZX100 on blood pressure and heart rate. Subarachnoid hemorrhage was induced in rats by endovascular perforation. Subsequently, AZX100 was administered intrathecally via a cisternal catheter or intravenously. Cerebral perfusion was determined by laser Doppler monitoring. Blood pressure was monitored by telemetry in a separate group of naïve animals treated with AZX100 for 24 hours. The maximal decrease in cerebral perfusion occurred 3 days after SAH. Cisternal administration of AZX100 (0.14–0.57 mg/kg) 24 hours after hemorrhage prevented decreases in cerebral perfusion after SAH. Animals receiving lower doses of AZX100 (0.068 mg/kg) or a scrambled sequence of the active HSP20 peptide linked to CPP developed decreases in cerebral perfusion similar to those seen in control animals. Intravenous administration of AZX100 (1.22 mg/kg) 24 hours after hemorrhage prevented the decreases in cerebral perfusion seen in the controls. Intravenous administration (0.175 mg/kg and 1.22 mg/kg) of AZX100 on Days 2 and 3 after SAH reversed decreases in cerebral perfusion as early as Day 3. There was no impact of AZX100 on blood pressure or heart rate at doses up to 2.73 mg/kg. Cisternal administration of AZX100 24 hours after hemorrhage prevented decreases in cerebral perfusion. Intravenous administration of AZX100 also prevented and reversed decreases in cerebral perfusion at doses that did not induce hypotension. Transduction of biologically active motifs of downstream regulators like HSP20 represents a potential novel treatment for SAH.
Publisher: Oxford University Press (OUP)
Date: 06-08-2012
DOI: 10.1093/CVR/CVS252
Abstract: The caudal ventrolateral medulla (CVLM) is important for autonomic regulation and is rich in angiotensin II type 1A receptors (AT(1A)R). To determine their function, we examined whether the expression of AT(1A)R in the CVLM of mice lacking AT(1A)R (AT(1A)(-/-)) alters baroreflex sensitivity and cardiovascular responses to stress. Bilateral microinjections into the CVLM of AT(1A)(-/-) mice of lentivirus with the phox-2 selective promoter (PRSx8) were made to express either AT(1A)R (Lv-PRSx8-AT(1A)) or green fluorescent protein (Lv-PRSx8-GFP) as a control. Radiotelemetry was used to record mean arterial pressure (MAP), heart rate (HR), and locomotor activity. Following injection of Lv-PRSx8-GFP, robust neuronal expression of GFP was observed with ∼60% of the GFP-positive cells also expressing the catecholamine-synthetic enzyme tyrosine hydroxylase. After 5 weeks, there were no differences in MAP or HR between groups, but the Lv-PRSx8-AT(1A)- injected mice showed reduced baroreflex sensitivity (-25%, P = 0.003) and attenuated pressor responses to cage-switch and restraint stress compared with the Lv-PRSx8-GFP-injected mice. Reduced MAP mid-frequency power during cage-switch stress reflected attenuated sympathetic activation (Pgroup × stress = 0.04). Fos-immunohistochemistry indicated greater activation of forebrain and hypothalamic neurons in the Lv-PRSx8-AT(1A) mice compared with the control. The expression of AT(1A)R in CVLM neurons, including A1 neurons, while having little influence on the basal blood pressure or HR, may play a tonic role in inhibiting cardiac vagal baroreflex sensitivity. However, they strongly facilitate the forebrain response to aversive stress, yet reduce the pressor response presumably through greater sympatho-inhibition. These findings outline novel and specific roles for angiotensin II in the CVLM in autonomic regulation.
Publisher: Public Library of Science (PLoS)
Date: 26-04-2011
Publisher: BMJ
Date: 14-04-2010
DOI: 10.1136/BMJ.C1104
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
DOI: 10.1161/CIRCRESAHA.110.219279
Abstract: Angiotensin-converting enzyme (ACE)2 opposes the actions of angiotensin (Ang) II by degrading it to Ang 1-7. Given the important role of Ang II/Ang 1-7 in atherogenesis, we investigated the impact of ACE2 deficiency on the development of atherosclerosis. C57Bl6 , Ace2 knockout (KO), apolipoprotein E ( ApoE ) KO and ApoE/Ace2 double KO mice were followed until 30 weeks of age. Plaque accumulation was increased in ApoE/Ace2 double KO mice when compared to ApoE KO mice. This was associated with increased expression of adhesion molecules and inflammatory cytokines, including interleukin-6, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1, and an early increase in white cell adhesion across the whole aortae on dynamic flow assay. In the absence of a proatherosclerotic ( ApoE KO ) genotype, ACE2 deficiency was also associated with increased expression of these markers, suggesting that these differences were not an epiphenomenon. ACE inhibition prevented increases of these markers and atherogenesis in ApoE/ACE2 double KO mice. Bone marrow macrophages isolated from Ace2 KO mice showed increased proinflammatory responsiveness to lipopolysaccharide and Ang II when compared to macrophages isolated from C57Bl6 mice. Endothelial cells isolated from Ace2 KO mice also showed increased basal activation and elevated inflammatory responsiveness to TNF-α. Similarly, selective inhibition of ACE2 with MLN-4760 also resulted in a proinflammatory phenotype with a physiological response similar to that observed with exogenous Ang II (10 −7 mol/L). Genetic Ace2 deficiency is associated with upregulation of putative mediators of atherogenesis and enhances responsiveness to proinflammatory stimuli. In atherosclerosis-prone ApoE KO mice, these changes potentially contribute to increased plaque accumulation. These findings emphasize the potential utility of ACE2 repletion as a strategy to reduce atherosclerosis.
Publisher: The Endocrine Society
Date: 09-2004
DOI: 10.1210/EN.2004-0421
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2021
DOI: 10.1161/HYPERTENSIONAHA.120.16718
Abstract: Overactivity of renal sympathetic nerves and nitric oxide (NO) deficiency occur in hypertensive chronic kidney disease (CKD). In sheep with hypertensive CKD and NO deficiency, renal denervation (RDN) reduces blood pressure and improves kidney function (glomerular filtration rate). We hypothesized that this improvement in glomerular filtration rate after RDN is associated with increased NO bioavailability. In this study, glomerular filtration rate response to systemic inhibition of NOS (NO synthase) was examined in healthy and CKD sheep at 2 and 30 months after a sham (intact nerves) or RDN procedure. Basal urinary total nitrate (nitrate+nitrite) excretion was examined at 2 and 30 months, and kidney protein expression of endothelial and neuronal NOS was assessed at 30 months. Urinary nitrate+nitrite in CKD-RDN and healthy sheep was ≈50% to 70% greater than in CKD-intact. During NOS inhibition, the fall in glomerular filtration rate in CKD-RDN sheep was ≈20% greater than in CKD-intact. These effects in CKD-RDN sheep were similar to those in healthy sheep. Endothelial NOS protein expression was lower in CKD-intact sheep compared with healthy sheep and compared with CKD-RDN. In summary, RDN normalizes NO bioavailability and restores contribution of NO to renal hemodynamics in CKD. These changes may promote improvements in kidney function and sustained blood pressure lowering after RDN in hypertensive CKD.
Publisher: Frontiers Media SA
Date: 2010
Publisher: AMPCo
Date: 08-2012
DOI: 10.5694/MJA11.11637
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
Publisher: Springer Science and Business Media LLC
Date: 10-12-2018
DOI: 10.1038/S41440-018-0147-9
Abstract: Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J. Mean arterial pressure (MAP) was measured by radiotelemetry before and for 3 weeks after RD in BPH/2J and BPN/3J. The effects of pentolinium and enalaprilat were examined to determine the contribution of the SNS and RAS, respectively. After 3 weeks, MAP was -10.9 ± 2.1 mmHg lower in RD BPH/2J compared to baseline and -2.1 ± 2.2 mmHg in sham BPH/2J (P 0.1). The depressor response to pentolinium was greater in BPH/2J than BPN/3J, but in both cases the response in RD mice was similar to sham. Enalaprilat decreased MAP more in RD BPH/2J compared to sham (-12 vs -3 mmHg, P < 0.001) but had no effect in BPN/3J. RD reduced renal noradrenaline in both strains but more so in BPH/2J. RD reduced renin mRNA and protein, but not plasma renin in BPH/2J to levels comparable with BPN/3J mice. We conclude that renal nerves contribute to hypertension in BPH mice as RD induced a sustained fall in MAP, which was associated with a reduction of intrarenal renin expression. The lack of inhibition of the depressor effects of pentolinium and enalaprilat by RD suggests that vasoconstrictor effects of the SNS or RAS are not involved.
Publisher: Frontiers Media SA
Date: 18-09-2019
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 25-10-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2000
DOI: 10.1097/00004872-200018090-00013
Abstract: To determine the influence of imidazoline receptors and alpha2-adrenoceptors in the rostral ventrolateral medulla (RVLM) on the renal sympathetic baroreflex. The effects of rilmenidine (4 nmol) and alpha-methylnoradrenaline (alpha-MNA, 80 nmol) micro-injected into the RVLM of urethane-anaesthetized rabbits previously implanted with renal nerve recording electrodes were examined before and after micro-injection of the imidazoline receptor/alpha2-adrenoceptor antagonist idazoxan and the alpha2-adrenoceptor antagonist 2-methoxyidazoxan (2-MI). Rilmenidine and alpha-MNA both lowered mean arterial pressure (MAP) by 28% and renal sympathetic nerve activity (RSNA) by 35%, and reduced RSNA upper plateaus and ranges by 30-70%. Rilmenidine decreased both sympathetic burst frequency and litude while alpha-MNA reduced litude only. Rilmenidine shifted the RSNA baroreflex curve to the left while alpha-MNA shifted the curve to the right Idazoxan (13 nmol) reversed the hypotension and all RSNA effects of rilmenidine, while 2-MI (4 nmol) increased MAP 18% above the control and also reversed all RSNA parameters. By contrast, 2-MI reversed the alpha-MNA-induced hypotension and partially restored RSNA and the upper plateau of the RSNA baroreflex curve. Idazoxan treatment only partially reversed the hypotension after alpha-MNA and had no effect on any of the baroreflex curves. Both alpha-MNA and rilmenidine injected into the RVLM of rabbits produce renal sympathetic inhibition, but differences in the location of the baroreflex curve and the pattern of effects on burst litude and frequency suggest different mechanisms of action. The effects of idazoxan suggest that rilmenidine acts via imidazoline receptors. Since 2-MI reversed the actions of alpha-MNA and also rilmenidine, this suggests that alpha2-adrenoceptor hypotension can be produced in the rabbit RVLM and that rilmenidine may activate alpha2-adrenoceptors, possibly as a result of activating imidazoline receptors.
Publisher: American Physiological Society
Date: 02-2003
DOI: 10.1152/AJPREGU.00351.2002
Abstract: In this study, we examined the effect of excitatory amino acid (EAA) receptor blockade in the rostral ventrolateral medulla (RVLM) on the renal sympathetic baroreflex in conscious rabbits. Rabbits were implanted with guide cannulas for bilateral microinjections into the RVLM (+2 to +3 mm from the obex, n = 8) or into the intermediate ventrolateral medulla (IVLM 0 to +1 mm from the obex, n = 5) and with an electrode for measuring renal sympathetic nerve activity (RSNA). After 7 days of recovery, microinjection of the EAA receptor antagonist kynurenate (10 nmol) into the RVLM did not affect resting RSNA or arterial pressure. Kynurenate decreased the gain of the RSNA baroreflex by 53% but did not change the reflex range. By contrast, injection of kynurenate into the IVLM increased resting arterial pressure and RSNA by 27 mmHg and 88%, respectively, but did not alter the RSNA baroreflex gain or range. Pentobarbital sodium anesthesia attenuated the gain and range of the RSNA baroreflex by 78 and 40%, respectively. Under these conditions, microinjection of kynurenate into the RVLM did not cause any further change in the gain of this reflex. These results suggest that endogenous EAA neurotransmitters in the RVLM are important in modulating the sympathetic baroreflex in conscious rabbits. Anesthesia can mask the functional significance of EAAs in the RVLM in modulating the baroreflexes, which may explain why previous studies in anesthetized animals found no effect of blocking EAA receptors in the RVLM on sympathetic baroreflexes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2014
DOI: 10.1161/HYPERTENSIONAHA.113.02498
Abstract: Exposure to maternal obesity or a maternal diet rich in fat during development may have adverse outcomes in offspring, such as the development of obesity and hypertension. The present study examined the effect of a maternal high-fat diet (m-HFD) on offspring blood pressure and renal sympathetic nerve activity, responses to stress, and sensitivity to central administration of leptin and ghrelin. Offspring of New Zealand white rabbits fed a 13% HFD were slightly heavier than offspring from mothers fed a 4% maternal normal fat diet ( P .05) but had 64% greater fat pad mass ( P =0.015). Mean arterial pressure, heart rate, and renal sympathetic nerve activity at 4 months of age were 7%, 7%, and 24% greater, respectively ( P .001), in m-HFD compared with maternal normal fat diet rabbits, and the renal sympathetic nerve activity response to airjet stress was enhanced in the m-HFD group. m-HFD offspring had markedly elevated pressor and renal sympathetic nerve activity responses to intracerebroventricular leptin (5–100 µg) and enhanced sympathetic responses to intracerebroventricular ghrelin (1–5 nmol). In contrast, there was resistance to the anorexic effects of intracerebroventricular leptin and less neuronal activation as detected by Fos immunohistochemistry in the arcuate (−57% P .001) and paraventricular (−37% P .05) nuclei of the hypothalamus in m-HFD offspring compared with maternal normal fat diet rabbits. We conclude that offspring from mothers consuming an HFD exhibit an adverse cardiovascular profile in adulthood because of altered central hypothalamic sensitivity to leptin and ghrelin.
Publisher: Frontiers Media SA
Date: 2011
Publisher: Frontiers Media SA
Date: 02-12-2014
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S0165-0270(03)00121-3
Abstract: A major difficulty of recording from peripheral sympathetic nerves is that microvolt values reflect characteristics of the recording conditions and limit comparisons between different experimental groups. In this study we assessed methods of calibrating renal sympathetic nerve activity (RSNA) in conscious rabbits. Calibration values were obtained from maximum RSNA responses to nasopharyngeal stimulation, airjet stress or unloading baroreceptors. Curves relating RSNA to blood pressure were produced by raising and lowering blood pressure with vasoactive drugs. To assess whether normalization would eliminate differences between RSNA curves which were most likely due to recording conditions, rabbits were first ided into two groups with high or low basal microvolt levels of RSNA, then again into two groups with high or low heart rate. In both cases, curves were similar if values were normalized by nasopharyngeal stimulation or by the upper plateau value. In hypertensive rabbits, where the baroreflex is suppressed, only the nasopharyngeal method showed this attenuated pattern. This method also eliminated the 50% decay in basal RSNA measured over 5 weeks. We conclude that expressing RSNA in terms of the maximum response to nasopharyngeal stimulation provides a calibration method suitable for comparing nerve activity over the long term as well as showing valid differences in baroreflex curves between different experimental groups.
Publisher: Springer Science and Business Media LLC
Date: 05-05-2020
Publisher: Medknow
Date: 2020
Publisher: Elsevier BV
Date: 02-2002
DOI: 10.1016/S0167-0115(01)00332-9
Abstract: The 16-kDa polypeptide hormone, leptin along with the neurotransmitters noradrenaline and serotonin (5-HT) have important physiological roles in the regulation of a number of neuroendocrine actions particularly feeding. Leptin receptor mRNA and immunoreactivity has been reported in various brain regions, while recent studies suggest that leptin is released from the human brain. This study investigated the interactions between leptinergic and neurotransmitter systems of the rat brain in vitro. Techniques were established to simultaneously monitor the release of endogenous noradrenaline and its metabolite 3,4 dihydroxyphenylglycol (DHPG), and 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) from the rat brain. The neuromodulatory action of leptin (0.2 and 3 nM) on the overflow of noradrenaline and DHPG from the medulla and hypothalamus was examined. The effect of leptin on 5-HT and 5-HIAA overflow from the hypothalamus was also investigated. Administration of 0.2 and 3 nM leptin significantly increased medullary noradrenaline overflow to 172% and 174% of basal levels, respectively. Leptin had no significant effect on hypothalamic noradrenaline overflow, while leptin perfusion induced a significant increase in 5-HIAA overflow from the hypothalamus. This study lends support to the notion of a complex interaction of the leptinergic and brain neurotransmitters involved in the control of feeding and energy metabolism.
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0306-4522(02)00337-8
Abstract: Sympathetic hyperactivity in rats with heart failure is associated with increased extracellular noradrenaline in the hypothalamic paraventricular nucleus at rest. However, it is unknown how this nucleus responds to stressful stimuli. In the present study we therefore examined the basal and stress-induced release of noradrenaline in the paraventricular nucleus of conscious Sprague-Dawley rats with heart failure measured by in vivo microdialysis. Basal noradrenaline concentration in the paraventricular nucleus of rats with heart failure was more than double that in sham-operated controls. Immobilization stress decreases noradrenaline levels in the paraventricular nucleus of rats with heart failure to 57% of baseline, while it increased in sham-operated controls to 228%. However, serum corticosterone was similarly elevated at 30 and 90 min post-stress in both experimental groups. We have shown that heart failure causes an impairment of the central noradrenergic system's response to acute sympatho-excitation but does not affect the hypothalamo-pituitary-adrenocortical response.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2004
DOI: 10.1097/00004872-200411000-00008
Abstract: To determine the suitability of a new logistic curve fitting procedure to measure the diurnal rates of transition from the active to the asleep periods separately. We applied this method to 24-h telemetry recordings of systolic, mean, diastolic arterial pressure (SAP, MAP, DAP, respectively), heart rate (HR) and locomotor activity of normotensive Sprague-Dawley rats (SDR) and spontaneously hypertensive rats (SHR). There was a similar pattern of higher awake and lower sleep values (16 +/- 1 mmHg SAP, 77 +/- 2 bpm HR and 40 +/- 2 units activity) in SHR. In SDR, awake-asleep differences were less for SAP (9 +/- 1 mmHg) but similar for HR (83 +/- 2 bpm). In SHR, while the blood pressure patterns were symmetrical, the rate of rise in activity and HR during arousal was more rapid than the rate of decline during the dark to light transition. By contrast in SDR, the arousal rate of increase in blood pressure and HR was much less than the rate of decline. Thus SHR have an exaggerated arousal surge in DAP compared with SDR. Double logistic provides a better fit than Cosinor or square wave and better estimates of day-night differences than partial Fourier. Analysis of 24-h recordings by a new logistic curve method reveals distinct asymmetric circadian patterns of cardiovascular and activity changes in rats. The greater surge in arousal blood pressure in SHR is not associated with differences in HR or activity changes and may be inherent to the underlying mechanisms contributing to the hypertension in SHR.
Publisher: MDPI AG
Date: 14-06-2016
DOI: 10.3390/NU8060364
Publisher: Wiley
Date: 02-09-2017
DOI: 10.1002/OBY.21962
Abstract: Because sympathetic nervous system activity plays a detrimental role in metabolic and cardiovascular health, this study compared the effects of a centrally acting sympatholytic agent, the effects of a weight loss (WL) program using a low-calorie diet, and the effects of a combination of both. Young (18-30 years) male subjects with overweight (BMI > 25 kg/m WL occurred in the WL and WL + M groups (-7.6 ± 1.9 kg, P < 0.001 in both). MSNA and systolic blood pressure decreased similarly in the WL, M, and WL + M groups (by ∼10 bursts/min, P < 0.001, and by ∼9 mm Hg, P < 0.05). All other parameters for the WL, C, and M groups remained unchanged. In the WL + M group, decreased total cholesterol (-0.78 ± 0.23 mmol/L, P < 0.001), decreased low-density lipoprotein cholesterol (-0.49 ± 0.16 mmol/L, P < 0.01), decreased insulin (-6.5 ± 2.8 mmol/L, P < 0.05), and attenuated glomerular hyperfiltration (-19 ± 5 mL/min, P < 0.01) occurred. The combination of moxonidine with a WL program has beneficial effects on aspects of the metabolic profile and end organ damage in young males with overweight.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2019
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.
Publisher: Public Library of Science (PLoS)
Date: 17-07-2015
Publisher: Oxford University Press (OUP)
Date: 05-2010
DOI: 10.1038/AJH.2010.12
Abstract: Abnormal circadian variation of blood pressure (BP) increases cardiovascular risk. In this study, we examined the influence of angiotensin AT(1A) receptors on circadian BP variation, and specifically on its behavioral activity-related and -unrelated components. BP and locomotor activity were recorded by radiotelemetry in AT(1A)-receptor knockout mice (AT(1A)(-/-)) and their wild-type controls (AT(1A)(+/+)) placed on a normal-salt diet (NSD) or high-salt diet (HSD, 3.1% Na). The 24-h BP was lower in AT(1A)(-/-) than AT(1A)(+/+) mice on a NSD (92 +/- 2 and 118 +/- 2 mm Hg, respectively), whereas the day-night BP difference (DeltaDNBP) was similar between groups (11 +/- 2 and 12 +/- 1 mm Hg, respectively). HSD increased BP by 20 +/- 2 mm Hg and DeltaDNBP by 7 +/- 1 mm Hg in AT(1A)(-/-) mice, without affecting these parameters much in AT(1A)(+/+) mice. The DeltaDNBP increase in AT(1A)(-/-) mice was caused by nondipping BP during the inactive late-dark period. Conversely, BP rise associated with circadian behavioral activation during the early dark period was not altered by HSD in AT(1A)(-/-) mice. The BP change associated with spontaneous ultradian activity-inactivity bouts was also similar between strains on HSD as was the BP rise associated with induced (cage-switch) behavioral activity. Ganglionic or alpha(1)-adrenergic blockade decreased BP in both strains HSD did not affect this response in AT(1A)(-/-), but abolished it in AT(1A)(+/+) mice. AT(1A)-receptor deficiency, when combined with HSD, can increase circadian BP difference in mice. This increase is mediated principally by activity-unrelated factors, such as the nonsuppressibility of basal resting sympathetic tone by HSD, thus suggesting a form of salt-/volume-dependent hypertension.
Publisher: FapUNIFESP (SciELO)
Date: 09-2002
DOI: 10.1590/S0100-879X2002000900005
Abstract: There is a close association between the location of angiotensin (Ang) receptors and many important brain nuclei involved in the regulation of the cardiovascular system. The present review encompasses the physiological role of Ang II in the brainstem, particularly in relation to its influence on baroreflex control of the heart and kidney. Activation of AT1 receptors in the brainstem by fourth ventricle (4V) administration to conscious rabbits or local administration of Ang II into the rostral ventrolateral medulla (RVLM) of anesthetized rabbits acutely increases renal sympathetic nerve activity (RSNA) and RSNA baroreflex responses. Administration of the Ang antagonist Sarile into the RVLM of anesthetized rabbits blocked the effects of Ang II on the RSNA baroreflex, indicating that the RVLM is the major site of sympathoexcitatory action of Ang II given into the cerebrospinal fluid surrounding the brainstem. However, in conscious animals, blockade of endogenous Ang receptors in the brainstem by the 4V AT1 receptor antagonist losartan resulted in sympathoexcitation, suggesting an overall greater activity of endogenous Ang II within the sympathoinhibitory pathways. However, the RSNA response to airjet stress in conscious rabbits was markedly attenuated. While we found no effect of acute central Ang on heart rate baroreflexes, chronic 4V infusion inhibited the baroreflex and chronic losartan increased baroreflex gain. Thus, brainstem Ang II acutely alters sympathetic responses to specific afferent inputs thus forming part of a potentially important mechanism for the integration of autonomic response patterns. The sympathoexcitatory AT1 receptors appear to be activated during stress, surgery and anesthesia.
Publisher: Elsevier BV
Date: 09-1996
Abstract: Short-term (one week) and chronic (six week) cardiovascular effects of orally administered perindopril were examined in the rabbit to demonstrate if short-term results can predict chronic outcomes. In short-term treatment, five doses of perindopril were examined in random order separated by a one week recovery period in each of six rabbits. Two doses of perindopril which resulted in a moderate hypotensive effect (-14 mmHg) and no hypotensive effect, respectively, were then selected for long-term treatment. Each rabbit in the short-term study received perindopril in doses of 0.01, 0.06, 0.32, 1.8 and 10 mg kg-1 day-1 for a week at a time. Rabbits on long-term treatment received either 0.3 or 0.01 mg kg-1 day-1 perindopril for six weeks. All rabbits had their mean arterial blood pressure (MAP) and heart rate recorded throughout treatment. Plasma angiotensin I (AngI), perindoprilat, angiotensin converting enzyme (ACE) inhibition were also assayed. Perindopril treatment for one week produced a dose-dependent hypotensive effect with the threshold dose, 0.06 mg kg-1 day-1, producing a 6.5 +/- 1.8 mmHg fall in MAP. The highest dose (10.0 mg kg-1 day-1) produced a large fall in blood pressure of -29.6 +/- 4.2 mmHg. The 0.01 and 0.06 mg kg-1 day-1 doses of perindopril produced an average 2.65 fold increase in plasma AngI levels compared to the initial control. The three higher doses (0.32-10.0 mg kg-1 day-1) of perindopril produced an equivalent 5.7 fold increase in plasma AngI levels compared to the initial controls. However, over six weeks 0.01 mg kg-1 day-1 perindopril induced a similar decrease in MAP as the 30 fold higher dose (-9.3 mmHg compared to -11.7 mmHg,). This was in spite of a 3 fold difference in plasma perindoprilat concentrations between the high and low dose perindopril groups. Plasma ACE inhibition was > 80% with both doses of perindopril. The results indicate that while perindopril decreases MAP in a dose-dependent manner in short-term (one week) periods, over longer treatment times (six weeks) low concentrations of perindopril, non-hypotensive with short-term treatment, may be as anti-hypertensive as considerably higher doses.
Publisher: Wiley
Date: 28-08-2012
DOI: 10.1111/J.1440-1681.2011.05579.X
Abstract: 1. In the past 30 years the prevalence of obesity and overweight have doubled. It is now estimated that globally over 500 million adults are obese and a further billion adults are overweight. Obesity is a cardiovascular risk factor and some studies suggest that up to 70% of cases of essential hypertension may be attributable, in part, to obesity. Increasingly, evidence supports a view that obesity-related hypertension may be driven by altered hypothalamic signalling, which results in inappropriately high appetite and sympathetic nerve activity to the kidney. 2. In addition to the adult risk factors for obesity and hypertension, the environment encountered in early life may 'programme' the development of obesity, hypertension and cardiovascular disease. In particular, maternal obesity or high dietary fat intake in pregnancy may induce changes in fetal growth trajectories and predispose in iduals to develop obesity and related sequelae. 3. The mechanisms underlying the programming of obesity-related hypertension are becoming better understood. However, several issues require clarification, particularly with regard to the role of the placenta in transferring fatty acid to the fetal compartment, the impact of placental inflammation and cytokine production in obesity. 4. By understanding which factors are most associated with the development of obesity and hypertension in the offspring, we can focus therapeutic and behavioural interventions to most efficiently reduce the intergenerational propagation of the obesity cycle.
Publisher: Frontiers Media SA
Date: 28-07-2016
Publisher: Wiley
Date: 09-1996
DOI: 10.1111/J.1440-1681.1996.TB02820.X
Abstract: 1. In a number of species, high concentrations of angiotensin II (AngII) receptors have been found in the rostral ventrolateral medulla (RVLM) in the hindbrain, which is an important region involved in the modulation of sympathetic vasomotor tone. The present review describes studies in which the contribution of angiotensin receptors in the brainstem to cardiovascular regulation, in particular sympathetic vasomotor reflexes, has been examined in conscious and anaesthetized rabbits. 2. In conscious rabbits, fourth ventricular infusions of AngII produced dose-dependent pressor responses as doses 400 times less than equipressor intravenous doses. Chronic baroreceptor denervation increased the sensitivity to AngII by 1000-fold. Administration of prazosin i.v. blocked the pressor response, suggesting that the mechanism involved sympathetic vasoconstriction. 3. The pattern of haemodynamic changes in response to AngII injected into the fourth ventricle (4V) involved decreased total peripheral conductance and mesenteric conductance, but a rise in hindlimb conductance. Sinoaortic denervation changed the hindlimb fall in conductance to an increase, suggesting that muscle vasomotor pathways were particularly inhibited by baroreceptor feedback mechanisms. 4. In anaesthetized rabbits, infusion of AngII into the RVLM increased blood pressure and transiently increased resting renal sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right and the upper plateau of the sympathetic reflex increase was markedly increased. 5. The pressor actions of 4V AngII were blocked by administration of a peptide antagonist injected into the RVLM or by the angiotensin AT(1) antagonist losartan injected into the 4V. These results suggest that mainly AT(1) receptors are involved and that the RVLM is a likely candidate site for the modulation of the renal sympathetic baroreflex. 6. Losartan administration into the 4V in conscious rabbits increased resting renal sympathetic tone and enhanced renal sympathetic baroreflex and chemoreflexes. 7. Our studies suggest that there are sympathoexcitatory AT(1) receptors in the RVLM accessible to AngII from the cerebrospinal fluid. In addition, an AT(1) receptor pathway normally inhibits the sympathoexcitation produced by baroreceptor unloading or chemoreceptor activation. The effect of losartan suggests that there is greater tonic activity within the sympathoinhibitory pathways. These two actions suggest that angiotensin receptors in the brainstem modulate sympathetic responses to specific afferent inputs, thus forming part of a potentially important mechanism for the integration of characteristic autonomic response patterns.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2013
DOI: 10.1161/HYPERTENSIONAHA.113.01701
Abstract: Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin–angiotensin system. Our aim was to determine the contribution of the renin–angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg IP) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg IP) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period ( P =0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA P =0.02) and 0.8-fold lower abundance of micro-RNA-181a ( P =0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium ( r =0.99 P =0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin–angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin–angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.
Publisher: American Physiological Society
Date: 10-2011
DOI: 10.1152/AJPREGU.00273.2011
Abstract: In humans, chronic stressors have long been recognized as potential causes for cardiac dysregulation. Despite this, the underlying mechanistic links responsible for this association are still poorly understood. The purpose of this study was to determine whether exposure to a paradigm of subchronic stress can provoke enduring changes on the heart rate of experimental rats and, if so, to reveal the autonomic and neural mechanisms that mediate these effects. The study was conducted on adult male Sprague-Dawley rats instrumented for telemetric recording of heart rate and locomotor activity. Animals were submitted to a subchronic stress protocol, consisting of a 1-h foot shock session on five consecutive days. Heart rate and locomotor activity were recorded continuously for 3 days before and for 6 days after the subchronic stress period. Subchronic foot shock produced significant and enduring reduction in heart rate both during the dark/active [Δ= −23 ± 3 beats per minute (bpm)] and light/inactive (Δ= −20 ± 3 bpm) phases of the circadian cycle, and a reduction in locomotor activity during the dark/active phase [Δ= −54 ± 6 counts per hour (cph)]. The bradycardic effect of subchronic stress was not related to a reduced locomotion. Selective sympathetic (atenolol) and vagal (methyl-scopolamine) blockades were performed to reveal which autonomic component was responsible for this effect. We found that the fall in heart rate persisted after subchronic stress in animals treated with atenolol (active phase Δ= −16 ± 3 bpm, inactive phase Δ= −19 ± 2 bpm), whereas vagal blockade with scopolamine transiently prevented this effect, suggesting that the bradycardia following subchronic stress was predominantly vagally mediated. Fluoxetine (selective serotonin reuptake inhibitor) and metyrapone (inhibitor of corticosterone synthesis) treatments did not affect heart rate changes but prevented the reduction in locomotion. We conclude that subchronic stress exposure in rats reduces heart rate via a rebound in vagal activation and that this effect is serotonin- and corticosterone-independent.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2001
DOI: 10.1097/00005344-200103000-00003
Abstract: The pressor region of the rostral ventrolateral medulla (RVLM) is a critical site in the sympathoinhibitory action of imidazoline receptor agonists as shown by studies in anesthetized animals. The aim of this study was to compare the importance of the RVLM in mediating the inhibitory action of rilmenidine on renal sympathetic nerve activity (RSNA) and arterial pressure in urethane-anesthetized rabbits (n = 11) and in conscious, chronically instrumented rabbits (n = 6). Bilateral microinjection of rilmenidine (4 nmol in 100 nl) into the RVLM caused a greater decrease in resting arterial pressure in anesthetized animals (-19 mm Hg) than in conscious animals (-8 mm Hg). By contrast, the decrease in resting RSNA evoked by rilmenidine was similar in conscious (-27%) and anesthetized (-36%) rabbits. Furthermore, rilmenidine microinjection into the RVLM was equally effective in inhibiting the RSNA baroreflex in both groups of animals. The upper plateau of the RSNA baroreflex decreased by 37% and 42%, and gain decreased by 41% and 44% after rilmenidine treatments in conscious and anesthetized rabbits, respectively. We conclude that the RVLM plays an equally important role in the inhibitory action of rilmenidine on RSNA in conscious and anesthetized rabbits either at rest or during baroreflex responses. A relatively moderate effect of rilmenidine on arterial pressure in conscious, chronically instrumented rabbits may relate to a lower level of sympathetic drive compared with anesthetized animals.
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.NEUROSCIENCE.2005.01.032
Abstract: We determined whether the cardiovascular actions of central anti-hypertensive agents clonidine and moxonidine are dependent on noradrenergic or serotonergic innervation of the rostral ventrolateral medulla (RVLM) in conscious rabbits. 6-Hydroxydopamine (6-OHDA) or 5,6-dihydroxytriptamine (5,6-DHT) was injected into the RVLM to deplete noradrenergic and serotonergic terminals respectively. One, 2 and 4 weeks later, responses to fourth ventricular (4V) clonidine (0.65 microg/kg) and moxonidine (0.44 microg/kg) were examined. Destruction of noradrenergic pathways in the RVLM by 6-OHDA reduced the hypotensive response to 4V moxonidine to 62%, 47% and 60% of that observed in vehicle treated rabbits at weeks 1, 2 and 4 respectively. The moxonidine induced bradycardia was similarly attenuated (to 46% of vehicle). Conversely, 6-OHDA had no effect on the hypotensive or bradycardic effects of 4V clonidine. Efaroxan (I(1)-imidazoline receptor/alpha(2)-adrenoceptor antagonist 3.5, 11, 35 microg/kg) and 2-methoxyidazoxan (alpha(2)-adrenoceptor antagonist 0.3, 0.9, 3 microg/kg) equally reversed the hypotension to 4V clonidine, suggesting a mainly alpha(2)-adrenoceptor mechanism. Efaroxan preferentially reversed responses to moxonidine in both vehicle and 5,6-DHT groups and in the 1st week after 6-OHDA, suggesting a mechanism involving mainly I(1)-imidazoline receptors. This selectivity was subsequently lost in the 2nd and 4th weeks when the remaining hypotension was mainly mediated by alpha(2)-adrenoceptors. Depletion of serotonergic terminals did not alter the responses to either agonist nor did it change the relative effectiveness of the antagonists. Western blots of RVLM tissues probed with imidazoline and alpha(2)-adrenoceptor antisera showed a pattern of bands close to that reported in other species. The main effect of 6-OHDA was an 18% lower level of the 42 kDa imidazoline protein (P<0.05). We conclude that the hypotensive and bradycardic actions of moxonidine but not clonidine are mediated through imidazoline receptors and are dependent on intact noradrenergic pathways within the RVLM. Furthermore, the noradrenergic innervation may be associated with a 42 kDa imidazoline receptor protein.
No related grants have been discovered for Geoffrey Head.