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0000-0003-3945-3923
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Publisher: Wiley
Date: 02-1988
DOI: 10.1113/JPHYSIOL.1988.SP016950
Abstract: 1. The effects of I.V. infusions of 6.7-19.3 mmol hydrochloric acid/kg on fetal renal function were studied in fourteen chronically catheterized fetal sheep aged 121-143 days. Infusion of acid caused arterial pH and plasma bicarbonate levels to fall (P less than 0.0005, P less than 0.001). These remained low for the next 3 h. Plasma chloride levels increased (P less than 0.0005). There were no other changes in plasma electrolytes nor in plasma osmolality. 2. Fetal glomerular filtration rate did not change the fractional reabsorptions of sodium, chloride and phosphate all decreased (P less than 0.005). Initially urine volume did not change but urinary osmolality increased (P less than 0.0005). Fetal urinary pH fell abruptly, titratable acid excretion increased, urinary ammonium excretion increased (P less than 0.0005) but urinary bicarbonate excretion remained unchanged. Thus, net acid excretion increased significantly (P less than 0.0005). 3. Twenty-six hours after infusion of acid, fetal arterial pH, bicarbonate levels, urinary pH, titratable acid and ammonium excretion were no different from control. Net acid excretion was still increased (P less than 0.05), urine flow rate was less (P less than 0.01) and urinary osmolality still increased (P less than 0.05). 4. There were no differences in arterial blood gases nor in pH of four fetuses which died during or shortly after infusion of acid. However, prior to acid infusion they were already excreting significantly greater amounts of phosphate (P less than 0.01), ammonium and titratable acid (P less than 0.02). Thus the fetal kidney responds to a metabolic acidosis by excreting more acid and by generating more bicarbonate, but this response is limited.
Publisher: S. Karger AG
Date: 1989
DOI: 10.1159/000242933
Abstract: Renal function was measured in fetal sheep, in neonates following delivery by caesarean section, and in lambs in the first week of life. The most marked changes in renal function following delivery were an increase in glomerular filtration rate from 4.59 ± 0.27 ml/min (n = 13) to 6.94 ± 1.00 ml/min (n = 12), a decrease in urine flow, sodium and osmolar excretion rates and an increase in urinary osmolality. Fractional sodium reabsorption increased from 95.5 ± 0.79% (n = 13) in the fetus to 99.4 ± 0.14% (n = 12, p 0.001) in lambs aged 24 h or more fractional osmolar reabsorption rose from fetal levels of 92.3 ± 0.84% (n = 13) to 96.5 ± 0.52% ( n = 11 p 0.001) in lambs aged 24h or more. Potassium excretion and fractional potassium reabsorption did not alter after birth. Urinary osmolality increased from 175 ± 20.4 mosm/kg H sup /sup O (n = 14) to 524 ± 45.6 mosm/kg H sup /sup O (n = 16 p 0.001) in lambs aged 24 h or more, and free water clearance decreased from 0.308 ± 0.06 ml/min (n = 13) to-0.067 ± 0.03 ml/min (n = 15 p 0.001). Since the above changes occurred within 24 h of delivery, they represent rapid adjustments by the kidney to lack of a placental supply of fluid and electrolytes.
Publisher: Springer Science and Business Media LLC
Date: 02-2000
DOI: 10.1203/00006450-200002000-00014
Abstract: To determine if alterations in arterial pressure influenced fetal heart rate variability (HRV), experiments were carried out in chronically catheterized fetal sheep aged 128-138 d. Arterial pressure was raised or lowered by intravenous infusion of phenylephrine or sodium nitroprusside, and the effects on heart rate (HR) and HRV were measured (HRV, as the coefficient of variation (CV) in mean pulse interval or by power spectral analysis). Experiments were carried out before and during beta-adrenoceptor blockade with propranolol or before and during cardiac vagal blockade with atropine. There were positive relationships between mean arterial pressure and HRV (slope = 0.074+/-0.001, r = 0.81+/-0.06, p<0.001, measured as the CV of pulse interval) and between mean arterial pressure and power spectral density (slope = 4+/-0.5, r = 0.89+/-0.02, p<0.001) in the frequency range 0.04-0.08 Hz. Beta-adrenoceptor blockade had no effect on these relationships, but they were abolished by cardiac vagal blockade. The sigmoid relationship between fetal HR and mean arterial pressure, i.e. the cardiac baroreflex, was affected, however, by blockade of cardiac sympathetics and abolished by blockade of cardiac vagal activity. Thus, fetal HRV was affected by alterations in arterial pressure, and these effects depended on the integrity of the cardiac vagus, not on alterations in cardiac sympathetic activity. Therefore, although baroreflex control of fetal HR depends on the integrity of both sympathetic and parasympathetic efferent pathways, baroreceptor-induced changes in HRV depend only on the cardiac vagus.
Publisher: Wiley
Date: 05-03-2009
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Physiological Society
Date: 03-2005
DOI: 10.1152/AJPREGU.00556.2004
Abstract: In 17 fetal sheep aged 129 days, the effects of large-dose infusions of cortisol (72.1 mg/day for 2–3 days) on proliferation, binucleation, and hypertrophy of cardiac myocytes, cardiac expression of angiotensinogen, angiotensin receptor subtypes 1 and 2, Glut-1, glucocorticoid and mineralocorticoid receptors, proteins of the MAPK pathways and calcineurin were studied. Cortisol levels were 8.7 ± 2.3 nM (SE) in 8 control and 1,028 ± 189 nM in 9 treated fetuses ( P 0.001). Cortisol had no effect on myocyte binucleation. Left ventricular free wall (LVFW) uni- and binucleated myocytes were larger in cortisol-treated fetuses ( P 0.001, P 0.05). Cortisol-treated fetuses had higher right ventricular free wall (RVFW) and LVFW angiotensinogen (Aogen) mRNA levels (treated: 2.30 ± 0.37, n = 8 and 2.05 ± 0.45, n = 7 vs. control: 0.94 ± 0.12, n = 8 and 0.67 ± 0.09, n = 7, P 0.02). Levels of the glucose transporter Glut-1 mRNA were lower in the LVFW of treated fetuses (0.83 ± 0.23 vs. 1.47 ± 0.30 in control, P 0.05, n = 7, 8). The higher the cortisol level, the greater the Aogen mRNA level (RVFW, r = 0.61, P 0.01, n = 16 LVFW, r = 0.83, P 0.0003, n = 14). There were no other changes in mRNA levels nor in levels of extracellular kinase, JNK, p38, their phosphorylated forms, and calcineurin. Thus high levels of cortisol such as occur after birth do not affect fetal cardiac myocyte binucleation or number but are associated with higher levels of ventricular Aogen mRNA, lower levels of Glut-1 mRNA, and hypertrophy of LVFW myocytes. These effects could impact on postnatal cardiac development.
Publisher: Portland Press Ltd.
Date: 04-1972
DOI: 10.1042/CS0420479
Abstract: 1. Determinations of plasma renin activity (PRA), plasma renin concentration (PRC) and renin substrate (RS) were made on single plasma s les from thirty-four women at various stages of pregnancy. Comparisons were made with non-pregnant control subjects. 2. All three variables were elevated above controls throughout pregnancy, but whereas the mean value of PRA was equally high between the first and the second halves of pregnancy, PRC was higher in the first and RS higher in the second half of pregnancy. 3. Kinetic studies indicated that, in spite of high concentrations of RS in late pregnancy, the renin-renin substrate reaction remains substrate dependent when proceeding at physiological pH values. 4. No differences in enzyme-substrate affinity were detected between the plasmas of pregnant and non-pregnant women. 5. In each of three deliveries RS was lower in the foetus than in the mother but PRA and PRC did not display consistent gradients. 6. PRC in uterine venous blood was slightly lower (P = 0·05) than in peripheral blood during caesarian section at term. 7. On deriving PRC from PRA by using the Michaelis-Menten equation, a physiologically inactive component in maternal PRC became apparent. It is suggested that this component is activated by the acid treatment used in the direct PRC methodology. Its concentration is highest in early pregnancy and circumstantial evidence suggests that it originates from foetal chorion.
Publisher: Elsevier
Date: 2023
Publisher: Wiley
Date: 05-2002
DOI: 10.1113/EPH8702339
Abstract: The acute and long-term effects of blockade of nitric oxide (NO) production were studied in six chronically catheterised fetal sheep aged from 116 and 118 days six untreated fetal sheep received injections of saline. Injection of 10 mg (kg maternal body wt)(-1) of the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine (NOLA) to the fetus, caused an immediate rise in fetal mean arterial pressure (MAP, P < 0.005) and a reflex fall in fetal heart rate (FHR, P < 0.001). Plasma renin concentration (PRC) fell from 8.4 +/- 3.3 to 1.5 +/- 0.3 ng ml(-1) h(-1) (P < 0.001) and was dependent on MAP (P = 0.001). Glomerular filtration rate (GFR) tended to increase, but renal blood flow (RBF) velocity decreased (P < 0.001). Thus filtration fraction (FF) increased (P < 0.025). Urine flow and sodium excretion increased (P < 0.001 for both). Fractional sodium reabsorption decreased (P < 0.05). In fetuses treated with NOLA, arterial pressure was found to affect glomerular haemodynamics and renal tubular handling of sodium. No such relationships were observed in untreated fetuses. The vascular responses to acetylcholine tended to be less (P = 0.07) and the responses to noradrenaline were enhanced in NOLA-treated fetuses. There were no changes in untreated fetuses. Fetuses were then injected twice daily with either 5 mg kg(-1) NOLA or saline for the next 2 days. On the 4th day, injection of 10 mg kg(-1) NOLA did not have any effects on MAP, FHR or renal function. However, the pressor responses to angiotensin II (Ang II) were enhanced (P < 0.005), as was the response to noradrenaline but to a lesser extent. It is concluded that endothelial production of NO maintains normal fetal blood pressure, renal vascular resistance and fetal renal function. When NO production was blocked by repeated injections of NOLA, other vasodilator pathways took over the maintenance of cardiovascular and renal vascular tone. However, alterations in both cardiovascular and renal function were still present. That is, there was increased pressor sensitivity to exogenous Ang II and unmasking of effects of arterial pressure on glomerular and tubular function.
Publisher: Wiley
Date: 04-1981
DOI: 10.1111/J.1440-1681.1981.TB00141.X
Abstract: 1. In adult conscious sheep the pressor actions of infused angiotensin II were prevented by the concomitant intravenous infusions of sodium nitroprusside. The effect of such intravenous infusions of angiotensin II on the cardiac baroreflex response to transient rises in arterial pressure caused by intravenous phenylephrine was studied. 2. Intravenous infusion of angiotensin II caused a reduction in pulse interval in the absence of any change in arterial pressure. It also caused a reduction in baroreflex sensitivity measured by determining the relation between pulse interval and systolic pressure during the rise in pressure caused by injection of phenylephrine. 3. After administration of the converting enzyme inhibitor (captopril) the mean baroreflex sensitivity of 3 of 4 pregnant ewes increased. 4. It is concluded that high levels of angiotensin II can modify the cardiac baroreceptor reflex response so that the heart rate is inappropriately high for a given systolic pressure and that it reduces the sensitivity of the cardiac baroreflex response to transient changes in arterial pressure.
Publisher: SAGE Publications
Date: 26-03-2015
Abstract: The newborn circulating, cardiac and renal renin–angiotensin systems (RASs) are essential for blood pressure control, and for cardiac and renal development. If cardiac and renal RASs are immature this may contribute to cardiovascular compromise in preterm infants. This study measured mRNA expression of cardiac and renal RAS components in preterm, glucocorticoid (GC) exposed preterm, and term piglets. Renal and cardiac RAS mRNA levels were measured using real-time polymerase chain reaction (PCR). Genes studied were: (pro)renin receptor, renin, angiotensinogen, angiotensin converting enzyme (ACE), ACE2, angiotensin type 1 receptor (AT 1 R) and angiotensin type 2 receptor (AT 2 R). All the genes studied were expressed in the kidney neither renin nor AT 2 R mRNA were detected in the heart. There were no gestational changes in (pro)renin receptor, renin, ACE or AT 1 R mRNA levels. Right ventricular angiotensinogen mRNA levels in females were lower in preterm animals than at term, and GC exposure increased levels in male piglets. Renal angiotensinogen mRNA levels in female term piglets were lower than females from both preterm groups, and lower than male term piglets. Left ventricular ACE2 mRNA expression was lower in GC treated preterm piglets. Renal AT 2 R mRNA abundance was highest in GC treated preterm piglets, and the AT 1 R/AT 2 R ratio was increased at term. Preterm cardiac and renal RAS mRNA levels were similar to term piglets, suggesting that immaturity of these RASs does not contribute to preterm cardiovascular compromise. Since preterm expression of both renal and cardiac angiotensin II-AT 1 R is similar to term animals, cardiovascular dysfunction in the sick preterm human neonate might be effectively treated by agents acting on their RASs.
Publisher: Wiley
Date: 04-1970
DOI: 10.1111/J.1471-0528.1970.TB03531.X
Abstract: There are several methods to extract and measure glycogen in animal tissues. Glycogen is extracted with or without homogenization by using cold Perchloric Acid (PCA). Three procedures were compared to determine glycogen fractions in rat liver at different physiological states. The present study was conducted on two groups of rats, one group of five rats were fed standard rodent laboratory food and were marked as controls, and another five rats were starved overnight (15 hour) as cases. The glycogen fractions were extracted and measured by using three methods: classical homogenization, total-glycogen-fractionation and homogenization-free protocols. The data of homogenization methods showed that following 15 hour starvation, total glycogen decreased (36.4±1.9 vs. 27.7±2.5, p=0.01) and the change occurred entirely in Acid Soluble Glycogen (ASG) (32.0±1.1 vs. 22.7±2.5, p=0.01), while Acid Insoluble Glycogen (AIG) did not change significantly (4.9±0.9 vs. 4.6±0.3, p=0.7). Similar results were achieved by using the method of total-glycogen-fractionation. Homogenization-free procedure indicated that ASG and AIG fractions compromise about 2/3 and 1/3 of total glycogen and the changes occurred in both ASG (24.4±2.6 vs. 16.7±0.4, p<0.05) and AIG fraction (8.7±0.8 vs. 7.1±0.3, p=0.05). The findings of 'homogenization assay method' indicate that ASG is the major portion of liver glycogen and is more metabolically active form. The same results were obtained by using 'total-glycogen-fractionation method'. 'Homogenization-free method' gave different results, because AIG has been contaminated with ASG fraction. In both 'homogenization' and 'homogenization-free' methods ASG must be extracted at least twice to prevent contamination of AIG with ASG.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2021
DOI: 10.1038/S41419-021-03898-Z
Abstract: FURIN is a pro-protein convertase previously shown to be important for placental syncytialisation (Zhou et al. [1]), a process of cell fusion whereby placental cytotrophoblast cells fuse to form a multinucleated syncytium. This finding has been broadly accepted however, we have evidence suggesting the contrary. Spontaneously syncytialising term primary human trophoblast cells and BeWo choriocarcinoma cells were treated with either FURIN siRNA or negative control siRNA or the protease inhibitor, DEC-RVKR-CMK, or vehicle. Cells were then left to either spontaneously syncytialise (primary trophoblasts) or were induced to syncytialise with forskolin (BeWo). Effects on syncytialisation were measured by determining human chorionic gonadotrophin secretion and E-cadherin protein levels. We showed that FURIN is not important for syncytialisation in either cell type. However, in primary trophoblasts another protease also inhibited by DEC-RVKR-CMK, may be involved. Our results directly contrast with those published by Zhou et al. Zhou et al. however, used first trimester villous explants to study syncytialisation, and we used term primary trophoblasts. Therefore, we suggest that FURIN may be involved in syncytialisation of first trimester trophoblasts, but not term trophoblasts. What is more concerning is that our results using BeWo cells do not agree with their results, even though for the most part, we used the same experimental design. It is unclear why these experiments yielded different results, however we wanted to draw attention to simple differences in measuring syncytialisation or flaws in method reporting (including omission of cell line source and passage numbers, siRNA concentration and protein molecular weights) and choice of immunoblot loading controls, that could impact on experimental outcomes. Our study shows that careful reporting of methods by authors and thorough scrutiny by referees are vital. Furthermore, a universal benchmark for measuring syncytialisation is required so that various studies of syncytialisation can be validated.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1999
DOI: 10.1097/00005344-199912000-00008
Abstract: Adrenocorticotropic hormone (ACTH 5 microg/kg/ day) infused into 10 pregnant ewes (gestation age, 127-139 days) for 72 h caused an increase in arterial pressure within 1-2 h (p < 0.05), which was sustained for the rest of the experiment. Cardiac output was increased at 24 h (p < 0.05). Total peripheral resistance did not change. There were no changes in four pregnant ewes infused with 0.15 M saline at the same rate for 72 h. In ACTH-treated pregnant ewes, a relation between arterial pressure and plasma renin activity observed in nontreated pregnant ewes (r = 0.71 p = 0.0005) was no longer evident. Compared with nonsurgical pregnant ewes, total angiotensin II (Ang II)-receptor density in the uterine artery was decreased in ewes that had previously had surgery (p = 0.015) and further reduced in ACTH-treated ewes (p < 0.0005). This was due to a reduction in the AT2-receptor density, which was inversely related to plasma cortisol levels (r = 0.73 p < 0.03). AT1-receptor density and the affinities of the AT1 and AT2 receptors were unchanged. The correlation between plasma cortisol and AT2-receptor density in uterine blood vessels may partly explain why these receptors are downregulated after surgery.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1999
DOI: 10.1097/00005344-199912000-00009
Abstract: The effects of intravenous (i.v.) infusions of 62.5 microg/h of angiotensin II (Ang II) on maternal arterial pressure (MMAP), cardiac output (CO), and uteroplacental blood flow (UPF) were studied in 11 chronically catheterized pregnant ewes and their fetuses. Over the first 4 h of infusion, MMAP (p < 0.01) increased and CO decreased (p < 0.05). UPF and fetal PO2, PCO2, and pH were unchanged. After 16-24 h, MMAP increased further (p < 0.05-p < 0.005) UPF decreased (p < 0.05), and vascular resistance increased (p < 0.05). Fetal arterial PO2 decreased and PCO2 increased (p < 0.001 p < 0.05). There were correlations between fetal arterial PO2 and UPF (r = 0.6 p < 0.00005 n = 81), pH and UPF (r = 0.39 p < 0.0003 n = 81) and a negative correlation between PCO2 and UPF (r = -0.5 p < 0.00005 n = 81). Infusions of 33 microg/h of noradrenaline initially caused a decrease in UPF. In the longer term, UPF was unchanged, as was UVR. There were no changes in fetal blood gases or pH, but there was a correlation between fetal arterial PO2 and UPF (r = 0.48 p < 0.01 n = 27). The short-term effects of Ang II and noradrenaline on UPF and UVR are similar to effects reported previously. The finding that long-term infusions of Ang II caused a reduction in UPF and compromised fetal gas exchange was unexpected. Thus the protective effect of reduced vascular reactivity of the uteroplacental circulation to Ang II is only a transient phenomenon.
Publisher: S. Karger AG
Date: 1979
DOI: 10.1159/000241150
Abstract: The association between fetal arterial pressure and fetal plasma renin activity (PRA) was studied in 30 fetal lambs prepared acutely, but studied i in utero /i . There was a negative correlation between resting fetal arterial pressure and resting fetal PRA (p 0.05). Fetal hypotension caused by intravenous infusion of sodium nitroprusside was associated with increases in fetal PRA. Fetal hypertension caused by intravenous infusion of phenylephrine to the fetus was associated with a decrease in fetal PRA. Maternal hypotension caused by infusion of sodium nitroprusside to the mother, and maternal hypertension caused by maternal infusion of phenylephrine caused an increase in fetal blood pressure and a fall in fetal PRA. It is concluded that the liypertensive response of the fetus to these changes in maternal blood pressure was not initiated by the fetal renin-angiotensin system. Isoprenaline caused a rise in fetal PRA. In 11 of 28 infusions this increase in fetal PRA occurred even though diastolic pressure was increased. It is concluded that there is a β-adrenergic receptor in the fetal kidney which can release renin. The increase in fetal PRA with intravenous isoprenaline was blocked by propanolol. Infusions of adrenaline were not associated with increases in fetal PRA.
Publisher: Wiley
Date: 04-1969
DOI: 10.1038/ICB.1969.26
Abstract: In this article, we report two life-threatening anaphylactic shocks by an antiseptic coated central venous catheter (CVC) within a 6-month period in our cancer center. Anaphylactic shock was preceded immediately after insertion of a central venous catheter (CVC) coated with silver sulphadiazine and chlorhexidine acetate (Blue FlexTip(®) ARROWg(+)ard Blue(®), 14Ga, Arrow International, Inc. USA). Though antiseptic coated CVC anaphylaxis has been reported in Japan, Europe and America, to our knowledge, this is first reported in China. We present these rare cases to remind clinicians about hypersensitivity to chlorhexidine that could potentially be life-threatening.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1969
Abstract: Excretion of renin into urine was studied using specific assay methods in normal subjects and hospital patients. Urinary renin output and renal clearance of renin varied widely among normal subjects but remained similar over months in any one subject. Renin clearance was significantly less in normal males (range 12 to 893 ml/24 hours) than females (79 to 3,149 ml/24 hours), but no reason for this was established. In normal subjects renin excretion did not show a diurnal variation and was not directly dependent upon creatinine clearance, protein clearance, plasma renin levels, or sodium or water output. Fivefold elevations in plasma renin level induced by natriuretic therapy increased renin excretion twofold and caused renin clearance to fall to 43% of control without a change in creatinine clearance. Total protein excretion did not change with this elevation in plasma renin level. Excess renin excretion did not occur in patients with proteinuria unless plasma levels were grossly elevated. The findings suggest that renin is filtered and selectively reabsorbed. No diagnostic application is apparent.
Publisher: Elsevier BV
Date: 05-2002
DOI: 10.1016/S0167-0115(02)00002-2
Abstract: Iodinated angiotensin II (Ang II) and its analogues are often assumed to have equal affinities for AT(1) and AT(2) receptor subtypes. However, using saturation and competition binding assays in several tissues from pregnant, nonpregnant, and fetal sheep, we found the affinity of 125I[Sar(1)Ile(8)] Ang II for Ang II receptors was different (P<0.05) between tissue types. The dissociation constants (Kd) and half maximal displacements of [Sar(1)Ile(8)] Ang II (Sar IC(50)) were directly related (P<0.05) to proportions of AT(1) receptors, and inversely related (P<0.05) to proportions of AT(2) receptors in tissues from all groups combined, in tissues from in idual groups (pregnant, nonpregnant or fetal), and in some in idual tissues (uterine arteries and aortae). This suggests that 125I[Sar(1)Ile(8)] Ang II has a different affinity for AT(1) and AT(2) receptors in ovine tissues. The Kds of 125I[Sar(1)Ile(8)] Ang II for "pure" populations of AT(1) and AT(2) receptors were 1.2 and 0.3 nM, respectively, i.e. affinity was four-fold higher for AT(2) receptors. We corrected the measured proportions of the receptor subtypes using their fractional occupancies. In tissues which contained at least 10% of each receptor subtype, the corrected proportions were significantly altered (P<0.05), even in some tissues, to the extent of being reversed.
Publisher: S. Karger AG
Date: 1989
DOI: 10.1159/000243126
Abstract: Integrated electromyographic, electrocortical (ECoG) and electro-ocular activity were recorded in 13 chronically prepared fetal sheep (130–145 days). Fetal movements and the rate of habituation to repeated suffusions of cold saline against the fetal skin were recorded. Experiments were repeated during an intravenous infusion of noradrenaline to the fetus (0.4 μg/kg estimated fetal weight/min) and during hypoxia induced by altering the oxygen content of the inspired air to the ewe to 9%. Repeated stimulation with cold saline resulted in an increase in fetal movements (p = 0.009). The number of stimuli for habituation was similar in high-voltage and in low-voltage ECoG activity. The rate of fetal habituation was significantly faster during the infusion of noradrenaline compared with control measurements (p = 0.009). During hypoxia, the number of spontaneous fetal movements prior to stimulation decreased (p = 0.002). Habituation rates were also faster during hypoxemia compared with control measurements (p = 0.003). These findings may help to explain the rapid habituation rates seen in some human fetuses in at ‘at risk’ Pregnancies.
Publisher: Public Library of Science (PLoS)
Date: 09-07-2013
Publisher: American Physiological Society
Date: 10-2005
DOI: 10.1152/AJPREGU.00055.2005
Abstract: These experiments examined whether renal growth and the fetal renin-angiotensin system could be stimulated by infusion of amino acids and whether chronic amino acid infusions restored glomerulotubular balance, which had been disrupted during 4-h infusions. Five fetal sheep aged 122 ± 1 days gestation received an infusion of alanine, glycine, proline and serine in 0.15 M saline at 0.22 mmol/min for 7 days. Six control fetuses were given saline at the same rate (5 ml/h). Kidney wet weights after amino acid infusion were 28% larger than control fetuses ( P 0.05), and renal angiotensinogen mRNA levels were ∼2.6-fold higher ( P 0.005). Circulating renin levels and renal renin mRNA levels were suppressed ( P 0.05), and renal renin protein levels tended to be lower. Arterial pressure was increased, and there was a marked, sustained natriuresis and diuresis. Glomerular filtration rate and filtered sodium were ∼two-fold higher throughout infusion ( P 0.05). Fractional proximal sodium reabsorption, suppressed at 4 h (from 73.4 ± 6.5 to 53.7 ± 10.2%), did not return to control levels (36.1 ± 3.4% on day 7, P 0.05). Distal sodium reabsorption was markedly increased (from 79 ± 25 to 261 ± 75 μmol/min by day 7, P 0.005), but this was not sufficient to restore glomerulotubular balance. The resultant high rates of sodium excretion led to hyponatremia and polyhydramnios. In conclusion, long-term amino acid infusions increased renal angiotensinogen gene expression, kidney weight, and distal nephron sodium reabsorptive capacity but failed to restore proximal and total glomerulotubular balance.
Publisher: Canadian Science Publishing
Date: 06-2007
DOI: 10.1139/Y07-047
Abstract: We imposed a sustained reduction in glucose supply to late-gestation fetal sheep to see whether the reduction in glucose and insulin levels affected renal growth, renin expression and synthesis, and renal function. Maternal glucose concentrations were lowered to 1.7–1.9 mmol/L for 12–13 days by i.v. insulin infusion (n = 9, 121 days gestation, term = 150 days). Control ewes (n = 7) received vehicle. Maternal and fetal glucose concentrations were 40% and 31% lower than in controls (p 0.001), respectively. Fetal plasma insulin levels fell 36% ± 7% by day 7 (p 0.05) IGF-I levels were unchanged. Arterial PO 2 and pH increased and PCO 2 fell (p 0.05). Renal function was largely unaffected. Longitudinal growth was 28% slower and spleen weights were 36% smaller (p 0.05) body and kidney weights were not affected. Renal renin levels and renin, angiotensinogen, and angiotensin receptor mRNA levels were similar to those of controls. Plasma renin levels increased from 2.1 ± 0.6 to 7.6 ± 2.8 ng angiotensin I·mL –1 ·h –1 (p = 0.01). Thus reductions in fetal glucose and insulin levels in late gestation that were sufficient to retard skeletal growth had no effect on kidney growth or function or the renal renin–angiotensin system, possibly because IGF-I levels were not reduced. There was, however, increased activity of the circulating renin–angiotensin system similar to that seen during insulin-induced hypoglycaemia.
Publisher: OMICS Publishing Group
Date: 2015
Publisher: American Physiological Society
Date: 05-1992
DOI: 10.1152/AJPREGU.1992.262.5.R754
Abstract: After control measurements had been made, 15 chronically catheterized pregnant ewes (gestational age 123-141 days) were given 15 mg of captopril intravenously followed by an infusion of 6 mg/h. These doses blocked the pressor responses of both ewes and fetuses to 5 micrograms of angiotensin I. After captopril, maternal mean arterial pressure fell from 94 +/- 3.5 to 88 +/- 3.6 (SE) mmHg (P less than 0.0001) and pulse interval fell (P = 0.008). Maternal flow to the cotyledons fell from 766 +/- 118 to 525 +/- 77 ml/min (P = 0.002), as did flow to the remainder of the maternal placenta, i.e., the caruncles and their underlying myoendometrium (control flow 188 +/- 35 ml/min, flow 10-15 min after captopril 166 +/- 36.1 ml/min P = 0.021). Flow to the rest of the myometrium did not change. Fetal arterial pressure fell from 46.9 +/- 1.6 to 44.1 +/- 1.6 mmHg (P less than 0.009), and fetal placental blood flow fell from 639.9 +/- 93.2 to 413.1 +/- 53.9 ml/min (P = 0.025). Flow to the fetal membranes declined also, from 53.2 +/- 6.5 to 35.6 +/- 3.3 ml/min (P less than 0.005). Maternal and fetal renal blood flows and fetal adrenal blood flows were unchanged. Fetal arterial PO2 was initially 19.5 +/- 0.8 mmHg after captopril, it was 17.7 +/- 0.9 mmHg (P = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.PLACENTA.2011.09.020
Abstract: The renin-angiotensin system (RAS) is thought to regulate placentation, however, the expression and localization of RAS pathways in early gestation human placenta is not known. Here we describe the expression of prorenin (REN), (pro)renin receptor (ATP6AP2), angiotensinogen (AGT), angiotensin-converting enzyme 1 and 2 (ACE ACE2), angiotensin II type 1 and 2 receptors (AGTR1 AGTR2) and angiotensin 1-7 receptor (MAS1), as well as the angiogenic factor, vascular endothelial growth factor (VEGF), and transforming growth factor-β1 (TGF-β1), in early gestation (6-16 weeks) and term (>37 weeks) human placentae. We also describe the location of all of the key RAS proteins in the early gestation placentae. The highest levels of REN, ATP6AP2, AGT, AGTR1 and ACE2 mRNAs were found in early gestation, whereas ACE1 mRNA was highest at term. AGTR2 and MAS1 mRNA expression were low to undetectable in all s les. REN, ATP6AP2 and AGTR1 mRNA levels were correlated with VEGF expression, but not with TGF-β1 mRNA. In early gestation placentae, prorenin, (pro)renin receptor and the angiotensin II type 1 receptor (AT(1)R) were localized to extravillous trophoblast cells, suggesting they play a key role in trophoblast migration. ACE2 in syncytiotrophoblasts could regulate release of Ang 1-7 into the maternal circulation contributing to the vasodilation of the maternal vasculature. ACE was only found in fetal vascular endothelium and may specifically target the growing fetal placental vessels. Because REN, ATP6AP2 and AGTR1 show strong correlations with expression of VEGF this pathway is likely to be important in placental angiogenesis.
Publisher: Wiley
Date: 11-1989
DOI: 10.1111/J.1440-1681.1989.TB01525.X
Abstract: 1. If the fetal sheep is in sodium balance, then the net intake of sodium is equal to the sum of the losses of sodium in fetal urine and lung liquid plus the rate of deposition of sodium with growth. 2. In seven fetal sheep with oesophageal ligation net sodium intake was 23.1 +/- 2.8 (s.e.m.) mumols/min per kg 11.8 +/- 1.4 mumols/min per kg was excreted by the lungs and 8.7 +/- 2.3 mumol/min per kg was excreted by the kidneys. The excretion of sodium by the lungs accounted for 52.8 +/- 4.8% of the total amount of sodium the excretion of sodium by the kidneys accounted for 34.9 +/- 5.4% and the calculated variable, that is, sodium deposited due to growth was 12.3 +/- 1.4%. 3. All but one fetus excreted more sodium from the lungs than from the kidneys. There was no relationship between the clearance of sodium by the lungs and net sodium intake but there was a direct relationship between renal sodium clearance and net sodium intake (r = 0.92, P less than 0.005). This suggests that fetal urinary sodium excretion is dependent upon net sodium intake by the fetus. This animal model shows that normally there must be sodium fluxes from allantoic and/or amniotic cavities to either the fetus or the ewe.
Publisher: Springer Science and Business Media LLC
Date: 10-1994
DOI: 10.1203/00006450-199410000-00017
Abstract: To determine the cause of the transient natriuresis in lambs within 1-2 h of birth, renal function and blood volume (BV) were measured in nine chronically catheterized fetal sheep aged 139-145 d before and after delivery by cesarean section. After delivery, sodium excretion increased 8-fold. This was due to a transient rise in glomerular filtration rate (by 39 +/- 21%, p < 0.02) and a fall in fractional reabsorption of sodium by the proximal tubule from 63.4 +/- 2.5% to 53.4 +/- 3.4% (p < 0.01). The distal tubule failed to compensate fully for this fall, because fractional reabsorption by the distal tubule rose from 35.5 +/- 2.4% to only 41.6 +/- 2.2% (p < 0.05). The extent of the natriuresis did not depend on the lamb's initial BV per kg at birth. However, the amount of fluid excreted and the clearance of sodium during a 45-min period within the first 1-1.25 h after birth were approximately equal to the fall in BV that occurred during this time. Thus, most of the fall in BV that occurs after delivery is due to renal salt and water losses. Because the natriuresis was greater if the lamb's arterial pressure rose after birth, it is possible that a high arterial pressure in the immediate newborn period could result in salt and volume depletion.
Publisher: Elsevier BV
Date: 12-1972
DOI: 10.1016/0005-2744(72)90090-3
Abstract: Although an association between air pollution and adverse systemic health effects has been known for years, the effect of pollutants on neurodevelopment has been underappreciated. Recent evidence suggests a possible link between air pollution and neurocognitive impairment and behavioral disorders in children, however, the exact nature of this relationship remains poorly understood. Infants and children are uniquely vulnerable due to the potential for exposure in both the fetal and postnatal environments during critical periods in development. Carbon monoxide (CO), a common component of indoor and outdoor air pollution, can cross the placenta to gain access to the fetal circulation and the developing brain. Thus, CO is of particular interest as a known neurotoxin and a potential public health threat. Here we review overt CO toxicity and the policies regulating CO exposure, detail the evidence suggesting a potential link between CO-associated ambient air pollution, tobacco smoke, and learning and behavioral abnormalities in children, describe the effects of subclinical CO exposure on the brain during development, and provide mechanistic insight into a potential connection between CO exposure and neurodevelopmental outcome. CO can disrupt a number of critical processes in the developing brain, providing a better understanding of how this specific neurotoxin may impair neurodevelopment. However, further investigation is needed to better define the effects of perinatal CO exposure on the immature brain. Current policies regarding CO standards were established based on evidence of cardiovascular risk in adults with pre-existing comorbidities. Thus, recent and emerging data highlighted in this review regarding CO exposure in the fetus and developing child may be important to consider when the standards and guidelines are evaluated and revised in the future.
Publisher: Wiley
Date: 03-1983
DOI: 10.1113/JPHYSIOL.1983.SP014568
Abstract: Angiotensin II inhibits baroreceptor-evoked activity in cardiac vagal motoneurones. Because angiotensin III [( des-1-Asp ]angiotensin II) is a less potent pressor agent than angiotensin II, and has been reported not to share some of the actions of angiotensin II within the central nervous system, its influence on central vagal pathways was examined here. In unanaesthetized sheep equipressor doses of angiotensins II and III similarly inhibited the baroreceptor-cardioinhibitory reflex, a reflex which is almost wholly dependent on cardiac vagal activity. In anaesthetized dogs, equipressor doses of angiotensin II and III were equally effective in inhibiting the cardiac vagal activity usually evoked by rises in arterial pressure. This was established by direct recordings of activity in single cardiac vagal efferent nerve fibres. Direct recordings from single baroreceptor nerves in anaesthetized dogs showed that the angiotensins do not depress the receptor responses to elevations in blood pressure. It is concluded that equipressor doses of angiotensin III and angiotensin II inhibit central vagal pathways to the same extent.
Publisher: Wiley
Date: 08-1995
DOI: 10.1111/J.1440-1681.1995.TB02057.X
Abstract: 1. From studies in chronically catheterized fetal sheep and other species, it can be shown that the renin-angiotensin system (RAS) is active during intra-uterine life. Levels of angiotensin II (AII) in fetal sheep are similar to maternal. 2. The fetal RAS plays a role in maintenance of arterial pressure. The extent to which it does so depends on the level of activity of the system. 3. The distribution of renin within the fetal rat kidney is much more widespread than in the adult. The fetal kidney, like other vascular beds has high levels of the AT2 angiotensin receptor subtype. With maturation the proportion of the AT1 receptor subtype increases. 4. Blockade of the fetal RAS with angiotensin converting enzyme (ACE) inhibitors or with the non-peptide AII antagonist (losartan) caused a fall in fetal glomerular filtration rate (GFR) and a rise in renal blood flow (RBF). AII reverses the fall in GFR even though RBF decreases. 5. The fraction of the filtered sodium load reabsorbed by the proximal tubule was not affected when the fetal RAS was blocked by captopril or losartan. High doses of infused AII had no effect on renal reabsorption of sodium, in the short term, but in the long term depressed fractional proximal reabsorption. 6. Only in high doses does AII stimulate the secretion of aldosterone from the fetal adrenal.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: American Physiological Society
Date: 04-2001
DOI: 10.1152/AJPREGU.2001.280.4.R1045
Abstract: This study examined the hypothesis that the development of hydrops fetalis after asphyxia in the 0.6 gestation sheep fetus would be associated with activation of the fetal renin-angiotensin system (RAS). Fetuses were randomly assigned to either sham occlusion ( n = 7) or to 30 min of asphyxia induced by complete umbilical cord occlusion for 30 min ( n = 8). Asphyxia led to severe bradycardia and hypotension that resolved after release of occlusion. After occlusion, plasma renin concentration was significantly increased in the asphyxia group compared with controls ( P 0.005) after 3 min (16.3 ± 5.3 vs. 4.1 ± 1.3 ng · ml −1 · h −1 ), and 72 h (30.6 ± 6.3 vs. 3.7 ± 1.2 ng · ml −1 · h −1 ). Renal renin concentrations and mRNA levels were significantly greater in the asphyxia group after 72 h of recovery. All fetuses in the asphyxia group showed generalized tissue edema, ascites, and pleural effusions after 72 h of recovery. In conclusion, asphyxia in the preterm fetus caused sustained activation of the RAS, which was associated with hydrops fetalis.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/459818
Abstract: The intrauterine renin angiotensin system (RAS) is implicated in placentation and labour onset. Here we investigate whether promoter methylation of RAS genes changes with gestation or labour and if it affects gene expression. Early gestation amnion and placenta were studied, as were term amnion, decidua, and placenta collected before labour (at elective caesarean section) or after spontaneous labour and delivery. The expression and degree of methylation of the prorenin receptor ( ATP6AP2 ), angiotensin converting enzyme ( ACE ), angiotensin II type 1 receptor ( AGTR1 ), and two proteases that can activate prorenin (kallikrein, KLK1 , and cathepsin D, CTSD ) were measured by qPCR and a DNA methylation array. There was no effect of gestation or labour on the methylation of RAS genes and CTSD . Amnion and decidua displayed strong correlations between the percent hypermethylation of RAS genes and CTSD , suggestive of global methylation. There were no correlations between the degree of methylation and mRNA abundance of any genes studied. KLK1 was the most methylated gene and the proportion of hypermethylated KLK1 alleles was lower in placenta than decidua. The presence of intermediate methylated alleles of KLK1 in early gestation placenta and in amnion after labour suggests that KLK1 methylation is uniquely dynamic in these tissues.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2017
DOI: 10.1158/1538-7445.AM2017-4136
Abstract: Endometrial cancer is the most common gynaecological malignancy and its incidence is increasing. Tissue renin angiotensin systems (RAS) are known to stimulate angiogenesis, cell proliferation and migration. All of these actions potentiate cancer growth and spread. We have previously demonstrated that endometrioid endometrial cancers express both prorenin and prorenin receptor ((P)RR) mRNA and have significantly greater levels of these proteins than normal adjacent endometrial tissue. Prorenin acting via the (P)RR can activate both RAS dependent and independent signalling pathways. Therefore we hypothesized that endometrial cancer growth can be inhibited by drugs that block Ang II/AT1R interactions and prorenin/(P)RR mediated signaling pathways. To determine the functional role of (P)RR in endometrial cancer growth, we used siRNA transfection to knock down (P)RR expression in three endometrial cancer cell lines (Ishikawa, HEC-1A and AN3CA) at 24h, 48h, 72h & 96h. The effect of RAS blockers on cell viability was also assessed by Resazurin assay at 48h in the three endometrial cancer cell lines. All three of the endometrial cancer cell lines examined (Ishikawa, HEC-1A and AN3CA) expressed (P)RR and prorenin mRNA, however levels of (P)RR were much higher in Ishikawa cells. Transfection of the three cell lines with a (P)RR siRNA resulted in 90% knockdown of (P)RR mRNA expression and reduced the cell viability of both Ishikawa and AN3CA but not HEC-1A cells, as measured by a resazurin assay after 48h incubation. Aliskiren (a renin inhibitor) inhibited Ishikawa cell growth by 20%. There was no effect of Aliskiren on cell viability in HEC-1A and AN3CA cell lines. Perindoprilat (an ACE inhibitor) and Losartan (an angiotensin II type 1 receptor (AT1R) inhibitor) had no effect on cell viability in any cell line. Another AT1R antagonist, telmisartan, which also acts as a selective agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ), did however significantly reduce cell viability in all cell lines (Ishikawa 75%, HEC-1A 50% and AN3CA 60%). Removal of the prorenin receptor inhibits the growth and development of some endometrial cancer cell lines. Only telmisartan, which has properties additional to Ang II antagonism, was effective in inhibiting endometrial cancer cell growth. (P)RR knockdown and telmisartan are therefore potential therapeutic drugs for the treatment of endometrial cancer. Citation Format: Riazuddin Mohammed, Sarah J. Delforce, Yu Wang, Nicole M. Verrills, Eugenie R. Lumbers, Kirsty G. Pringle. Effect of prorenin receptor PRR knock down and telmisartan on endometrial cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017 2017 Apr 1-5 Washington, DC. Philadelphia (PA): AACR Cancer Res 2017 (13 Suppl):Abstract nr 4136. doi:10.1158/1538-7445.AM2017-4136
Publisher: American Physiological Society
Date: 10-2012
DOI: 10.1152/AJPREGU.00010.2012
Abstract: Low systemic blood flow occurs in up to 30% of infants born at less than 30 wk gestation. It is associated with increased morbidity and mortality, and current treatments are ineffective in 40% of cases. The aim of this study was to assess the ability of the preterm heart to respond to the acute shifts in preload and afterload that occur at the time of birth. Myocardial and coronary vascular function was assessed using an isolated working heart model in term (115 days) and preterm (92 days) piglets. Cardiac output/kg body wt in preterm hearts was ∼50% lower than that of term hearts ( P = 0.001). Pressure development was similar in term and preterm hearts. Elevations in preload increased cardiac output and aortic flow similarly in term and preterm hearts, demonstrating significant preload “reserve”. By contrast, elevations in afterload markedly depressed aortic flow, with a greater proportion of cardiac output being distributed to coronary flow in preterm hearts at high afterloads. The demands of increased workload were associated with greater increases in coronary flow in preterm hearts compared with term hearts. In preterm hearts, exposure to maternal glucocorticoids resulted in increased aortic flow when afterload was below 25 mmHg. These data suggest the preterm heart lacks the functional capacity to acutely adapt to postnatal afterload. To maximize systemic blood flow in preterm infants, treatments limiting afterload, while harnessing significant preload reserve, should be further explored.
Publisher: Hindawi Limited
Date: 25-02-2014
Abstract: There are fetal sex-associated differences in the circulating maternal renin-angiotensin system (RAS) in early pregnancy. Plasma prorenin, angiotensin (Ang) II, Ang 1-7 and angiotensin-converting enzyme (ACE) concentrations were measured at 15 weeks' gestation in 131 women with uncomplicated pregnancies from the Adelaide SCOPE cohort. Uterine and umbilical artery Doppler sonography was performed at 20 weeks' gestation. At 15 weeks, women bearing female fetuses had higher maternal Ang II concentrations (p = 0.017) and lower Ang 1-7 to Ang II ratios (p = 0.016) than women bearing males. In women with male fetuses, Ang II positively correlated with birth weight (p = 0.028) and prorenin negatively correlated with placental weight (p = 0.014). Female fetuses had higher umbilical artery resistance indices (p = 0.019) that were related to maternal prorenin concentrations (p = 0.007). In early human pregnancy, the maternal RAS is influenced by fetal sex. The lower Ang 1-7 to Ang II ratios in women with female fetuses may contribute to the lower maternal peripheral microvascular flow as described previously and the lack of any positive effect of Ang II on fetal growth, as seen in women with male fetuses.
Publisher: Elsevier
Date: 2023
Publisher: Wiley
Date: 12-2014
DOI: 10.14814/PHY2.12245
Publisher: Wiley
Date: 27-01-2011
DOI: 10.1111/J.1440-1681.2010.05473.X
Abstract: 1. The aim of the present study was to test the hypothesis that the renin response to mechanisms activated by haemorrhage is programmed by exposure to maternal renal dysfunction. 2. In 26-27-day-old lambs born to ewes that had reduced renal function (STNxL, n=10) and lambs born to ewes with normal renal function (ConL, n=6), 1.6 mL/kg per min of blood was removed over 10 min. 3. Under basal conditions, the STNxL group had increased mean arterial pressure (P < 0.05). In response to haemorrhage, mean arterial pressure decreased in the STNxL group (P < 0.001), but there was no significant change in the ConL group. 4. Although plasma renin level increased in both groups (P < 0.05), the peak response was reduced and delayed in the STNxL group. In contrast, the rise in arginine vasopressin (AVP) level was similar in both groups and occurred over the same time course. At 24 h, both plasma renin and AVP level were the same as those measured before haemorrhage in both groups. Kidney renin level was similar in the two groups. 5. The attenuated renin response to haemorrhage in the STNxL group might explain the inability to maintain arterial pressure after haemorrhage. The results of the present study suggest that the renin response of the postnatal kidney to reductions in blood volume can be affected by the intrauterine environment. If these changes persist into adulthood, it suggests that permanent programming has occurred. Thus, the ability of an in idual to respond to acute severe reductions in blood volume might be determined during intrauterine life.
Publisher: American Physiological Society
Date: 04-1994
DOI: 10.1152/AJPHEART.1994.266.4.H1395
Abstract: The effect on the fetal heart by inflating the fetal lungs with liquid or air while the animal was being maintained in utero by its normal placental circulation was investigated in 10 healthy, chronically catheterized fetal sheep of gestational age 126-137 days. It was found that initial attempts to inflate the lungs with volumes of air as small as 10 ml (i.e., with less than a predicted normal tidal volume) caused abrupt, powerful slowing of the fetal heart with, usually, an associated hypotension. Inflations with similarly small volumes of saline were ineffective. Atropine pretreatment abolished the cardiac slowing caused by the air inflations, indicating the operation of a neural reflex. An analysis of the pressure changes induced by the air and liquid inflations in airway, intrathoracic and intra-amniotic pressures showed that the cardiac slowing was primarily related to the level of mechanical stress applied across the fetal airway.
Publisher: Frontiers Media SA
Date: 10-09-2019
Publisher: Impact Journals, LLC
Date: 04-2022
Publisher: Wiley
Date: 03-1990
DOI: 10.1113/EXPPHYSIOL.1990.SP003395
Abstract: Excretion of organic acids and bases was studied in twelve fetal sheep aged 120-140 days. There was no significant plasma protein binding of the organic anion, p-aminohippurate (PAH), nor of the organic cation, [14C]tetraethylammonium (TEA). There was a significant amount of acetyl-PAH (20 +/- 3%) in fetal urine but none could be detected in fetal plasma. The fractional excretion of unconjugated PAH was less than one, i.e. there was net reabsorption of 31.7 +/- 3.9% of the filtered load of unconjugated PAH. Since there was no acetyl-PAH in fetal plasma it is concluded that all acetyl-PAH in fetal urine occurred as a result of metabolism of PAH and secretion of the metabolite into the tubular lumen. The rate of excretion of acetyl-PAH in fetal urine varied from 0 to 14.0 micrograms min-1. Thus unconjugated PAH is filtered and there is net reabsorption in addition, PAH is metabolized and enters the urine via tubular mechanisms. The fractional excretion of PAH was unaffected by I.V. administration of penicillin either acutely or chronically. The clearance of [14C]TEA was significantly greater than the glomerular filtration rate (GFR). The mean fractional excretion of [14C]TEA was 5.4 +/- 0.17. Thus 80.7 +/- 0.63% of the excreted TEA was secreted. The clearance of TEA was related to body weight (P less than 0.001) but the fractional excretion of TEA declined with gestation age, probably because GFR increased at a greater rate than the rate at which the secretory pathways increase their activity. It is concluded that those pathways that excrete organic anions like PAH into the urine mature much later (probably after birth) than those pathways responsible for the tubular secretion of organic bases.
Publisher: Wiley
Date: 27-11-2018
DOI: 10.1111/NEP.13520
Publisher: Frontiers Media SA
Date: 20-05-2021
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.PLACENTA.2012.12.018
Abstract: The placental renin-angiotensin system (RAS) is involved in placentation. We have shown that prorenin mRNA (REN) is expressed in a first trimester trophoblast cell line (HTR-8/SVneo) but not in a choriocarcinoma cell line (BeWo). We attempted to stimulate RAS expression in these cells by cAMP, 5'-aza-2'-deoxycytidine (AZA an inhibitor of methylation), cAMP and AZA combined, and the sex steroids medroxyprogesterone acetate (MPA) and estradiol-17β (E(2)) with and without cAMP. RAS mRNAs were measured by qPCR and prorenin concentration in supernatants measured by an ELISA. In HTR-8/SVneo cells, all treatments increased REN expression compared to controls and cAMP + AZA combined was more effective than either treatment alone. Prorenin levels in supernatants were similarly upregulated. In HTR-8/SVneo cells, angiotensinogen (AGT) mRNA expression was increased by MPA + E(2) either with or without cAMP. AGT expression was also significantly increased by AZA. BeWo cells did not express REN or prorenin and it was not inducible with any treatment. AGT expression was significantly increased with AZA, the combination of cAMP + AZA, and MPA + E(2) + cAMP treatments. Since cAMP, AZA, cAMP and AZA combined, or MPA and E(2) with and without cAMP in HTR-8/SVneo cells, a cell line most similar in its RAS expression to the in vivo placenta, these factors may affect placental RAS activity. Surprisingly, these treatments also induced AGT expression in BeWo cells. Whether they are involved in regulating AGT in choriocarcinomas in vivo remains to be determined.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2014
Publisher: Wiley
Date: 09-1974
DOI: 10.1113/JPHYSIOL.1974.SP010672
Abstract: 1. Plasma renin (measured as rate of formation of angiotensin I ng/ml.hr(-1) in the presence of added substrate at pH 7.5 and 37 degrees C) was much lower in recently nephrectomized foetal, new-born and older lambs than in intact siblings or other similar lambs.2. Angiotensin II-like concentrations were measured using a superfusion technique in an extracorporeal circuit. Resting concentrations in acute experiments under anaesthesia were deduced by comparison of carotid blood of intact lambs with that from recently nephrectomized lambs.3. Angiotensin II-like activity (mean +/- S.E. of mean, 315 +/- 117 pg/ml.) was readily detectable in foetal blood at 123-138 days gestation. The highest concentrations (mean +/- S.E. of mean 839 +/- 96 pg/ml.) were found in lambs less than 8 hr old, delivered vaginally. The lowest concentrations of angiotensin II-like activity occurred in lambs delivered by Caesarean section (mean +/- S.E. of mean < 123 +/- 12 pg/ml.). Concentrations declined with post-natal age.4. Hypovolaemia as a result of haemorrhage evoked an increase in angiotensin II-like concentrations in foetus, new-born lambs and adult sheep. The greatest increase of angiotensin-like concentrations was seen in new-born lambs. This rise was associated with increase of plasma renin.5. The rise of arterial pressure during bilateral carotid occlusion in new-born lambs was accompanied by an increase of angiotensin II-like concentration.6. It is concluded that the renin-angiotensin system is functional and can be stimulated during intra-uterine life. The increase of angiotensin II-like concentration following parturition is probably transient and associated with the trauma of delivery. This contrasts with observations made in the rabbit which suggest that full functional maturity of the renin angiotensin system is delayed until the second week of life.
Publisher: Wiley
Date: 03-1999
DOI: 10.1111/J.1469-7793.1999.555AC.X
Abstract: 1. The cardiac baroreflex was measured in four non-pregnant and six pregnant ewes before and during beta-adrenoreceptor blockade with propranolol and before and during vagal blockade with atropine. Arterial pressure was raised by phenylephrine and lowered by sodium nitroprusside. The relationships between mean arterial pressure (MAP) and heart rate (HR), between MAP and heart rate variability (HRV) measured as the coefficient of variation (c.v.) of the mean pulse interval (PI), and between MAP and HRV measured by power spectral analysis were determined. 2. The MAP-HR relationship showed that in pregnant ewes the gain of the cardiac baroreflex was reduced when compared with non-pregnant ewes. Threshold and saturation pressures were higher, maximum achievable HR was lower and there was a decrease in the operating range. 3. V-shaped relationships were obtained between MAP and HRV (measured as the c.v. of PI) and between MAP and power spectral density in the frequency range 0.04-0. 08 Hz. Using selective autonomic blockade the negative, or downward, slope of the V shape was shown to be a measure of baroreceptor-induced, sympathetically mediated effects on HRV. The upward, or positive, slope of the V shape was a measure of baroreceptor-induced, vagally mediated effects. Similar results were also obtained from the cardiac power spectrum, but it was less sensitive. The MAP at which the two slopes intersected was the same as the resting MAP. 4. In pregnant ewes, the slope of the downward limb of the V-shaped relationship between HRV (when measured as the c.v. of PI) and MAP was less than in non-pregnant ewes. 5. The relationship between MAP and the coefficient of variation of the mean pulse interval can therefore be used to measure the degree to which baroreceptor-induced sympathetic and parasympathetic activity affects the heart. 6. The resting MAP is the pressure at which the net effect of these sympathetic and parasympathetic influences on the heart is at a minimum. Studies of both the MAP-HR and MAP-HRV relationships in pregnant and non-pregnant sheep show that in pregnant sheep, there is attenuation of baroreceptor-mediated sympathetic effects on the heart.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2013
Publisher: Wiley
Date: 02-2022
DOI: 10.1002/PRP2.922
Abstract: Why a systems analysis view of this pandemic? The current pandemic has inflicted almost unimaginable grief, sorrow, loss, and terror at a global scale. One of the great ironies with the COVID‐19 pandemic, particularly early on, is counter intuitive. The speed at which specialized basic and clinical sciences described the details of the damage to humans in COVID‐19 disease has been impressive. Equally, the development of vaccines in an amazingly short time interval has been extraordinary. However, what has been less well understood has been the fundamental elements that underpin the progression of COVID‐19 in an in idual and in populations. We have used systems analysis approaches with human physiology and pharmacology to explore the fundamental underpinnings of COVID‐19 disease. Pharmacology powerfully captures the thermodynamic characteristics of molecular binding with an exogenous entity such as a virus and its consequences on the living processes well described by human physiology. Thus, we have documented the passage of SARS‐CoV‐2 from infection of a single cell to species jump, to tropism, variant emergence and widespread population infection. During the course of this review, the recurrent observation was the efficiency and simplicity of one critical function of this virus. The lethality of SARS‐CoV‐2 is due primarily to its ability to possess and use a variable surface for binding to a specific human target with high affinity. This binding liberates Gibbs free energy (GFE) such that it satisfies the criteria for thermodynamic spontaneity. Its binding is the prelude to human host cellular entry and replication by the appropriation of host cell constituent molecules that have been produced with a prior energy investment by the host cell. It is also a binding that permits viral tropism to lead to high levels of distribution across populations with newly formed virions. This thermodynamic spontaneity is repeated endlessly as infection of a single host cell spreads to bystander cells, to tissues, to humans in close proximity and then to global populations. The principal antagonism of this process comes from SARS‐CoV‐2 itself, with its relentless changing of its viral surface configuration, associated with the inevitable emergence of variants better configured to resist immune sequestration and importantly with a greater affinity for the host target and higher infectivity. The great value of this physiological and pharmacological perspective is that it reveals the fundamental thermodynamic underpinnings of SARS‐CoV‐2 infection.
Publisher: Wiley
Date: 05-1993
DOI: 10.1111/J.1365-2141.1993.TB03029.X
Abstract: Transplacental passage of the low molecular weight dermatan sulphate Desmin 370 was investigated in pregnant sheep, using 125I-labelled Desmin 370 to optimize the sensitivity of the study. Chronically catheterized cross-bred pregnant ewes at approximately 120 d gestation received 3700 kBq 125I-labelled Desmin 370 with 1 mg/kg carrier unlabelled Desmin 370 intravenously. Early clearance from the maternal circulation was biexponential, and the volume of distribution corresponded closely with the theoretical value for distribution in total body water. Soon after injection low levels of radioactivity were detected in the fetal circulation and accumulated over the next 2 h, so that as the concentration of 125I-Desmin 370 in the maternal circulation declined with time the fetal level of radiolabel rose to represent a significant concentration in relation to that in the mother. Radioactivity was also excreted into the fetal urine. However, while 50% of the radiolabelled material present in maternal plasma 150 min post-injection was intact Desmin 370 and the remaining 50% represented degradation products, fetal urine contained only these fragments. By contrast, intact Desmin 370 was readily excreted into fetal urine after direct introduction to the fetal circulation. Thus molecules of intact Desmin 370 with anticoagulant activity cannot cross the ovine placenta, and low molecular weight dermatan sulphates may be valuable for prophylaxis and treatment of thrombotic disease during pregnancy.
Publisher: Public Library of Science (PLoS)
Date: 26-03-2014
Publisher: Elsevier BV
Date: 05-1986
DOI: 10.1016/0165-1838(86)90049-4
Abstract: The effects of hypoxia on the potential for the vagus to slow the heart, and on resting heart rate, were compared in anesthetized, vagotomized adult and fetal sheep, and in a chronically catheterized fetus in utero. In adults, the action of the cardiac vagus was potentiated at and below an arterial pO2 in the range 13-27 mm Hg. In contrast, in the fetus and the neonate, vagal action was not potentiated as pO2 fell through this range to 10-12 mm Hg. Below 10-12 mm Hg baseline heart rate fell markedly, and the effect of the cardiac vagus on heart rate was diminished, but its effect on pulse interval was not consistently changed. It is concluded that potentiation of vagal action during hypoxia occurs in adult but not fetal sheep and the bradycardia seen in the fetus during severe hypoxia is probably due to direct myocardial depression.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2016
DOI: 10.1038/PR.2016.156
Abstract: The preterm newborn is at high risk of developing cardiovascular compromise during the first day of life and this is associated with increased risk of brain injury. Standard treatments are volume expansion and administration of inotropes, typically dopamine and/or dobutamine, but there is limited evidence that inotropes improve clinical outcomes. This study investigated the efficacy of dopamine and dobutamine for the treatment of cardiovascular compromise in the preterm newborn using a piglet model. Preterm and term piglets were assigned to either dopamine, dobutamine or control infusions. Heart rate, left ventricular contractility, cardiac output, blood pressure, and cerebral and regional blood flows were measured during baseline, low (10 µg/kg/h), and high (20 µg/kg/h) dose infusions. At baseline, preterm piglets had lower cardiac contractility, cardiac output, blood pressure, and cerebral blood flow compared to term piglets. The response of preterm piglets to either dopamine or dobutamine administration was less than in term piglets. In both preterm and term piglets, cardiac output and cerebral blood flow were unaltered by either inotrope. In order to provide better cardiovascular support, it may be necessary to develop treatments that target receptors with a more mature profile than adrenoceptors in the preterm newborn.
Publisher: Wiley
Date: 02-1996
DOI: 10.1111/J.1440-1681.1996.TB02583.X
Abstract: 1. The angiotensin type 1 (AT1) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125-132 days gestation). Losartan reduced the fetal systolic (P <0.01) and diastolic (P <0.01) pressor response to 5 microg angiotensin II (AngII) i.v. from 27.4 +/- 1.5 to 7.4+/-0.9 and from 17.5 +/- 1.3 to 5.4 +/- 0.6 mmHg, respectively, after 1 h and to 6.1 +/- 0.5 and 4.4 +/- 0.5 mmHg, respectively, after 2 h. Maternal pressor responses to 5 microg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P <0.05) after losartan administration, but fetal heart rate did not change. 2. Fetal haematocrit increased (P <0.05), fetal PO2 decreased (P <0.01), PCO2 did not change and pH decreased (P <0.01), as did plasma bicarbonate levels (P <0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. 3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P <0.01) and an increase in blood flow (P <0.05). Glomerular filtration rate decreased (P <0.05) thus, filtration fraction decreased (P <0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P <0.01) and became negative. Urine flow decreased (P <0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium: potassium ratio decreased (P <0.05). There was a decrease in lung liquid flow (P <0.05) following losartan. 4. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT1 receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels.
Publisher: Oxford University Press (OUP)
Date: 28-07-2018
Abstract: Are any microRNAs (miRNAs) that target the placental renin-angiotensin system (RAS) in the human placenta suppressed in early gestation? Overall, 21 miRNAs with predicted RAS mRNA targets were less abundant in early versus term placentae and nine were more highly expressed. Regulation of human placental RAS expression could alter placental development and therefore normal pregnancy outcome. The expression of genes encoding prorenin (REN), angiotensinogen, (pro)renin receptor, angiotensin converting enzyme 2, and the angiotensin II type 1 receptor are highest in early gestation, at a time when oxygen tension is at its lowest. Studies have shown that the human placental RAS is sensitive to oxygen, as are some miRNAs that regulate RAS mRNAs. We propose that in early pregnancy, the prevailing low O2 tension, by suppression of levels of miRNAs that target RAS mRNAs, results in increased expression of RAS mRNAs and encoded proteins. As gestation proceeds and the prevailing oxygen tension rises, abundance of these miRNAs increases, and placental RAS mRNA expression is suppressed. The expression of miRNAs was compared in human placentae collected in early (10-11 weeks n = 7) and mid-gestation (14-18 weeks n = 8) with placenta collected at term (38-40 weeks n = 8). Expression of placental miRNAs in women with early (29-35.1 weeks n = 8) or late-onset pre-ecl sia (PE) (>34-weeks gestation n = 8) and gestational age matched preterm (31.6-35.1 weeks n = 8) and term normotensive controls were also compared. Agilent Human miRNA microarray v19 was used to detect up to 2006 miRNAs in four placentae from each group. Statistically different levels of expression were determined and refined using predictive modelling. Placental miRNAs predicted to target RAS mRNAs were identified in three databases. Differences detected on the array were confirmed for some miRNAs by semi-quantitative RT-PCR (qPCR, n = 7-8 for all groups). Two differentially expressed miRNAs that were known to target human renal REN mRNA (miR-181a-5p and miR-663) were transfected into human HTR-8/SVneo trophoblast cells to examine their effect on placental REN expression and prorenin levels. In early gestation placentae, 186 miRNAs were differentially expressed compared with term placentae (109 increased, 77 decreased). Thirty of the differentially expressed miRNAs were predicted to target RAS components. In mid-gestation placentae, 117 miRNAs were differentially expressed compared with term placentae (69 increased, 48 decreased). Of these, 19 had RAS mRNAs as predicted targets. Eight miRNAs that were lower in early gestation and predicted to target RAS mRNAs were confirmed by qPCR. All showed an increase during gestation and could influence the transgestational profile of the human placental RAS. Additionally, on the array, three miRNAs predicted to target RAS mRNAs (miR-892c-3p, miR-378c and miR-514b-3p) were overexpressed in placentae from women with late-onset PE (P = 3.6E-10, P = 1.8E-05, P = 5.3E-06 respectively). miR-663, which suppresses renal REN mRNA expression, was overexpressed in early-onset PE placentae as determined by qRT-PCR analysis (P = 0.014). Transfection of miR-181a-5p and miR-663 into HTR-8/SVneo trophoblast cells suppressed REN mRNA expression (P = 0.05) and prorenin protein production (P = 0.001). Data can be found via GEO accession number GSE109832. Further validation that the differentially expressed miRNAs do indeed directly target RAS mRNAs and affect placental development and function is required. This study is limited by the small s le size. Therefore independent validation in a larger cohort is required. We propose that suppression of miRNAs that target the placental RAS in early gestation is partly responsible for the increase in RAS expression at this time, in order to promote placental development. Later in pregnancy, we have detected overexpression of several miRNAs in placentae from women with PE. These may prove to be biomarkers for early detection of women at risk of developing PE. Since the placenta produces at least two miRNAs that were found in the kidney to target REN mRNA, and that also target placental REN mRNA, the escape of these miRNAs into the maternal circulation in excess amounts could affect maternal renal REN mRNA production and thereby disturb maternal fluid and electrolyte homoeostasis. This work was supported by the National Health and Medical Research Council, Australia (APP1043537). K.G.P. is supported by an Australian Research Council Future Fellowship (FT150100179). C.T.R. is supported by a Lloyd Cox Professorial Research Fellowship from the University of Adelaide. F.Z.M. is supported by a National Heart Foundation Future Leader Fellowship and Baker Heart and Diabetes Institute Fellowship. The authors declare that they have no competing interests.
Publisher: Frontiers Media SA
Date: 09-01-2018
Publisher: Elsevier
Date: 2020
Publisher: Oxford University Press (OUP)
Date: 06-02-2019
Abstract: Human placental renin-angiotensin system (RAS) expression is highest in early gestation, at a time when placental oxygen tension is at its lowest (1-3%), and promotes placental development. Some miRNAs predicted to target RAS mRNAs are downregulated in early gestation. We tested the hypothesis that low oxygen suppresses expression of miRNAs that target placental RAS mRNAs, thus increasing concentrations of RAS mRNAs. HTR-8/SVneo cells were cultured in 1, 5 and 20% oxygen for 48 h. Differences in miRNA expression were measured on an Affymetrix miRNA microarray (n = 3/group). Those predicted to target RAS mRNAs, or that were decreased in early gestation, were confirmed by qPCR (n = 9/group). RAS protein levels were assessed by ELISAs or immuno-blotting. Microarray analysis identified four miRNAs predicted to target RAS mRNAs that were differentially expressed between 1 and 5% oxygen. Using qPCR, 15 miRNAs that target the RAS were measured in HTR-8/SVneo cells. Five miRNAs were downregulated in 1% compared with 5% oxygen. Expression of a number of RAS mRNAs (ATP6AP2, AGT, ACE and AGTR1) were increased in either, or both, 1 and 5% oxygen compared with 20% oxygen. AGT protein levels were increased in 1% oxygen compared with 5%. Further validation is needed to confirm that these miRNAs target RAS mRNAs directly and that placental development is partly regulated by oxygen-sensitive miRNAs that target RAS mRNAs. Since placental oxygen tension changes across gestation, changes in expression of these miRNAs may contribute to the transgestational changes in placental RAS expression and the resulting effects on placental development.
Publisher: Elsevier BV
Date: 04-1999
DOI: 10.1016/S0167-0115(99)00026-9
Abstract: The object of this review is to describe the role of the renin-angiotensin system in control of aldosterone secretion. The review focuses on the roles of the circulating renin-angiotensin (RAS) system, the activity of which is determined predominantly by control of renin secretion from the kidney and on the role of the intra-adrenal RAS. Angiotensin can bind to two types of G protein coupled receptors, the AT1 and AT2 receptors. Both receptors are found on cells from the zona glomerulosa, the site of aldosterone synthesis. Angiotensin II acting via the AT1 receptor stimulates the synthesis of aldosterone at early and late steps in the pathway. Its effect on aldosterone is influenced by a number of other factors such as plasma potassium levels, sodium status, other peptides such as ANP and adrenomedullin and proadrenomedullin N-terminal peptide. All components of the RAS are found in the adrenal gland. The activity of this intra-adrenal RAS is unmasked and lified in nephrectomised animals. Aldosterone controls sodium transport across epithelial cells, but recently novel effects on the heart have been described.
Publisher: American Physiological Society
Date: 12-1996
DOI: 10.1152/AJPREGU.1996.271.6.R1691
Abstract: In 16 chronically catheterized fetal sheep the effects of reducing and restoring maternal renal blood flow (RBF) and thus inducing and reversing hypertension were studied in uninephrectomized pregnant ewes controls were 3 fetuses that were carried by uninephrectomized ewes in which RBF was not reduced and that did not become hypertensive. Within 24-72 h of maternal RBF reduction, fetal arterial PO2 had fallen (P 0.001) and PCO2 had increased (P 0.025) fetal arterial pressure also increased (P 0.005). These effects persisted, despite restoration of maternal RBF and reversal of maternal hypertension. Within 24-72 h of reduction of maternal RBF, fetal urine flow had increased (P 0.005), and it remained elevated over the first 3 h after RBF was restored 24-72 h later it was lower (P 0.025) and returned to control levels. The excretion of sodium, potassium, and chloride showed a similar increase when maternal RBF was reduced (P 0.001), with return to control values 24-72 h after RBF had been restored. Fetal glomerular filtration rate did not change thus the natriuresis and diuresis that occurred were due to reduced tubular solute and water reabsorption (P 0.025). These changes in fetal renal function may be related, in part, to changes in fetal PO2 and PCO2, but they are most likely due to reduced maternal renal function due to the restriction in maternal RBF, inasmuch as they were reversed when RBF was restored.
Publisher: Elsevier BV
Date: 06-2001
DOI: 10.1016/S0167-0115(01)00242-7
Abstract: Previously, we showed that uterine arteries from late gestation pregnant ewes infused intravenously with angiotensin II (Ang II) for 24 h, displayed heightened responsiveness to Ang II in vitro. Furthermore, we found that a small population of ewes with a "preecl sia-like" disorder also displayed this. Therefore, we have investigated the density and affinity of Ang II receptor subtypes in the uterine arteries from these groups. Ang II receptor binding was measured using 125I [Sar1Ile8] Ang II. Proportions of AT1 and AT2 receptors were determined by inhibiting 125I [Sar1Ile8] Ang II with losartan (AT1 antagonist) or PD 123319 (AT2 antagonist). Uterine arteries from 24-h Ang II-infused ewes had a lower proportion of AT2 receptors (56.2+/-2.3%) than control (saline-infused) ewes (84.1+/-1.0% P<0.05). The density of AT2 receptors was reduced (P<0.05) while the density of AT1 receptors was not different. Thus, 24-h infusions of Ang II selectively down-regulated AT2 receptors in the uterine artery, resulting in heightened Ang II reactivity. By contrast, the binding properties of Ang II receptor subtypes in uterine arteries from ewes with the "preecl sia-like" disorder were not different from control ewes.
Publisher: Wiley
Date: 09-1992
DOI: 10.1113/EXPPHYSIOL.1992.SP003637
Abstract: The aim of this study was to investigate the cardiovascular effects of exogenous cortisol in fetal sheep, (a) between 100 and 120 days of gestation when cortisol production is minimal and (b) after 130 days when endogenous plasma cortisol starts to rise. Chronically cannulated ovine fetuses (103-120 days, n = 9 130-137 days, n = 7), received sequentially a 24 h infusion of vehicle (0.9% sodium chloride) and a 24 h infusion of cortisol at 100 micrograms/h. Blood pressure and heart rate changes to bolus injections each of angiotensin II and noradrenaline (0.2, 0.5, 1.0, 2.0 micrograms) were measured before and after the saline and cortisol infusions. Fetuses in each age group, served as additional controls receiving 48 h saline infusions. In both immature and mature age groups, the cortisol infusion increased basal fetal blood cortisol concentrations by 33.7 and 35.4 nmol/l respectively. In the immature group, cortisol, but not saline, caused significant 14.3 and 15.3% increases in basal systolic and diastolic pressures respectively. Basal blood pressure was higher in the mature group, but did not increase further despite the increase in cortisol levels. Furthermore, vascular responsiveness to angiotensin II but not to noradrenaline was significantly enhanced following the cortisol infusion, at both ages. Fetal heart rate did not change following the cortisol infusion. Exogenous cortisol contributes to the regulation of fetal blood pressure in the immature fetus, when other mechanisms have not developed. Cortisol might achieve this, in part, by enhancing vascular sensitivity to angiotensin II.
Publisher: Wiley
Date: 30-11-2001
DOI: 10.1046/J.1440-1681.2001.03554.X
Abstract: 1. Brain sparing is a feature of intra-uterine growth retardation (IUGR). This implies that there is a redistribution of metabolic supply so that body growth slows to a greater extent than brain growth. 2. Intra-uterine growth retardation, as evidenced by a low birthweight for gestational age is a predisposing factor for hypertension, cardiovascular disease and diabetes mellitus in adult life. 3. In species like humans, nephrogenesis is complete before birth. In the rat, it is completed shortly after birth. In both species, it can be shown that either undernutrition or IUGR is associated with reduced nephron number. 4. It has been proposed that oligonephropathy results in hyperfiltration, which ultimately leads to glomerulosclerosis and hypertension. The renin-angiotensin system (RAS) is necessary for normal renal development and fetal renal function. In the rat, blockade of the RAS in the first weeks of life by pharmacological agents reduces glomerular number and has been shown to cause hypertension in adult life. Renal denervation reduces the activity of the fetal RAS and also causes abnormal development of the renin-secreting cells. 5. There is tonic renal sympathetic nerve activity in the late gestation fetal sheep. The level of renal sympathetic nerve activity (RSNA) is influenced by the fetal behavioural state. 6. However, interactions between the developing kidney and the developing sympathetic nervous system are poorly understood. On the one hand, renal innervation may be important in the provision of neurotrophic factors that stimulate the development of the RAS and kidney. On the other, high levels of RSNA associated with circulating catecholamines and vasopressin may cause vasoconstriction and limit nephrogenesis. This latter effect could be a predisposing factor to adult hypertension and cardiovascular disease.
Publisher: Wiley
Date: 14-08-2000
DOI: 10.1046/J.1440-1681.2000.03305.X
Abstract: 1. The effects of cold saline (25 mL) injected over the fetal skin on fetal heart rate (HR) and HR variability (HRV), measured as the coefficient of variation (CV) in pulse interval (PI) and by power spectral analysis (PSA), were measured in 10 chronically catheterized fetal sheep aged 140-144 days. To determine the extent to which effects on HR and HRV were mediated by the sympathoadrenal neuroendocrine axis and the cardiac vagus, experiments were performed before and after beta-adrenoreceptor blockade with propranolol (n = 12 fetuses) or before and after cardiac vagal blockade with atropine (n = 4 fetuses). 2. Injection of ice-cold saline over the skin caused an immediate rise in mean arterial pressure (MAP) from 46+/-1 to 55+/-1 mmHg (P < 0.001) and HR from 156+/-2 to 182+/-2 b.p.m. (P < 0.001). Heart rate variability, measured as CV of PI, rose from 3.5+/-0.2 to 8.0+/-0.2% (P < 0.001) and total power spectral density (PSD) increased from 78+/-6 to 278+/-16 units (P < 0.001) as measured by PSA. Within 100s, MAP, HR and HRV had returned to baseline. 3. Beta-adrenoreceptor blockade abolished all these changes in HR, HRV and PSD, but had no effect on changes in MAP. Atropine had no demonstrable effect on the responses to cold. 4. Therefore, the increase in fetal MAP, HR and HRV that occurred with stimulation of peripheral thermoreceptors was the result of increased activity of the sympathetic nervous system. Alterations in efferent cardiac vagal tone were not involved in the cardiac response to cold.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.PREGHY.2013.04.053
Abstract: To see if urinary angiotensinogen (uAGT)/creatinine and other urinary components of the RAS could be used to detect renal disease in pregnancy, as renal disease predisposes to preecl sia. Plasma and urinary prorenin, ACE and AGT (iRAS) were measured by ELISA. Urinary active renin levels were measured enzymatically (9 males, 10 non pregnant, 61 Australian Indigenous pregnant women). No relationships between plasma RAS and iRAS were found. In non-pregnant females plasma AGT levels were inversely related to protein and albumin/creatinine (r=-0.72, P=0.019, n=10 r=-0.65, P=0.042, n=10). In pregnancy, plasma ACE levels were related to protein/creatinine (r=0.29, P=0.036, n=54). Urinary protein/creatinine was not related to iRAS activity (males and non-pregnant females) but in pregnancy was related to prorenin and active renin/creatinine (r=0.45, P=0.02, n=26 r=0.47, P<0.001, n=50). Urinary albumin/creatinine was related to uAGT and active renin/creatinine in pregnancy (r=0.39, P=0.005, n=51 r=0.37, P=0.008, n=51). uACE/creatinine and uAGT/creatinine were related (r=0.52, P<0.001, n=51). Excretion of components of the iRAS is independent of plasma levels. Not only is uAGT/creatinine related to albumin/creatinine but there are similar relationships with other iRAS components. Measurement of the iRAS in human pregnancy may detect early stage renal disease, endemic in Indigenous Australians.
Publisher: American Physiological Society
Date: 05-2006
DOI: 10.1152/AJPRENAL.00241.2005
Abstract: Maternal renal disease is associated with high maternal and fetal morbidity. To establish an animal model to study renal dysfunction in pregnancy and its potential role in programming for renal disease and hypertension in adult life, a kidney was removed from each of 16 nonpregnant ewes, and a branch of the renal artery of the remaining kidney was ligated (STNx ewes). The 16 STNx and 15 intact ewes were time mated 2.5–17 mo later and studied at 119–132 days of gestation. STNx ewes demonstrated renal hypertrophy and glomerular hyperfiltration. They had higher diastolic arterial pressures ( P 0.05) and larger left ventricles ( P 0.0005), drank more water ( P 0.01), were hypochloremic ( P 0.01) and hyperglycemic ( P 0.0005), and had higher plasma creatinine levels ( P 0.0005) than intact ewes. Effective renal plasma flows and glomerular filtration rates were lower ( P 0.01) and protein excretion was greater ( P 0.05) in STNx than in intact ewes. Glomerulotubular balance was impaired in STNx ewes. Proximal tubular Na + reabsorption was reduced ( P 0.05), so Na + excretion was increased ( P 0.05). In STNx ewes, filtered K + loads were reduced ( P 0.005), but K + excretion was the same as in intact ewes. There was net K + secretion in STNx ewes in intact ewes, there was net reabsorption. Plasma renin and angiotensinogen concentrations in STNx and intact ewes were similar, so the hypertension in STNx ewes was not renin dependent. STNx fetuses grew normally, and their blood gases, blood pressure, and heart rates were normal. These alterations in maternal fluid and electrolyte balance and the potential risk of maternal salt depletion or hyperkalemia may adversely affect the fetus.
Publisher: Cambridge University Press (CUP)
Date: 30-08-2013
Publisher: Wiley
Date: 2007
DOI: 10.1002/JGM.1039
Abstract: Development of effective and durable gene therapy for treatment of the respiratory manifestations of cystic fibrosis remains a formidable challenge. Obstacles include difficulty in achieving efficient gene transfer to mature airway epithelium and the need to stably transduce self-renewing epithelial progenitor cells in order to avoid loss of transgene expression through epithelial turnover. Targeting the developing airway epithelium during fetal life offers the prospect of circumventing these challenges. In the current study we investigated vesicular stomatitis virus glycoprotein (VSVg)-pseudotyped HIV-1-derived lentivirus vector-mediated gene transfer to the airway epithelium of mid-gestation fetal lambs, both in vitro and in vivo. In the in vitro studies epithelial sheet explants and lung organ culture were used to examine transduction of the proximal and more distal airway epithelium, respectively. For the in vivo studies, vector was delivered directly into the proximal airway. We found that even during the early pseudoglandular and canalicular phases of lung development, occurring through mid-gestation, the proximal bronchial airway epithelium was relatively mature and highly resistant to lentivirus-mediated transduction. In contrast, the more distal bronchiolar airway epithelium was relatively permissive for transduction although the absolute levels achieved remained low. This result is promising as the bronchiolar airway epithelium is a major site of pathology in the cystic fibrosis airway, and much higher levels of transduction are likely to be achieved by developing strategies that increase the amount of vector reaching the more distal airway after intratracheal delivery.
Publisher: The Endocrine Society
Date: 2012
DOI: 10.1210/EN.2011-1316
Abstract: The maternal decidua expresses the genes of the renin-angiotensin system (RAS). Human decidua was collected at term either before labor (i.e. cesarean delivery) or after spontaneous labor. The mRNA for prorenin (REN), prorenin receptor (ATP6AP2), angiotensinogen (AGT), angiotensin-converting enzymes 1 and 2 (ACE1 and ACE2), angiotensin II type 1 receptor (AGTR1), and angiotensin 1–7 receptor (MAS1) were measured by quantitative real-time RT-PCR. Decidual explants were cultured in duplicate for 24 and 48 h, and all RAS mRNA, and the secretion of prorenin, angiotensin II, and angiotensin 1–7 was measured using quantitative real-time RT-PCR, ELISA, and radioimmunoassay, respectively. In the decidua collected before labor, REN mRNA levels were higher if the fetus was female. In addition, REN, ATP6AP2, AGT, and MAS1 mRNA abundance was greater in decidual explants collected from women carrying a female fetus, as was prorenin protein. After 24 h, ACE1 mRNA was higher in the decidual explants from women with a male fetus, whereas after 48 h, both ACE1 and ACE2 mRNA was higher in decidual explants from women with a female fetus. Angiotensin II was present in all explants, but angiotensin 1–7 levels often registered below the lower limits of sensitivity for the assay. After labor, decidua, when compared with nonlaboring decidua, demonstrated lower REN expression when the fetus was female. Therefore, the maternal decidual RAS is regulated in a sex-specific manner, suggesting that it may function differently when the fetus is male than when it is female.
Publisher: Bioscientifica
Date: 2017
DOI: 10.1530/EC-16-0082
Abstract: A dysfunctional endometrial renin–angiotensin system (RAS) could aid the growth and spread of endometrial cancer. To determine if the RAS is altered in endometrial cancer, we measured RAS gene expression and protein levels in 30 human formalin-fixed, paraffin-embedded (FFPE) endometrioid carcinomas and their adjacent endometrium. All components of the RAS were expressed in most tumours and in adjacent endometrium mRNA levels of (pro)renin receptor ( ATP6AP2 ), angiotensin II type 1 receptor ( AGTR1 ), angiotensin-converting enzyme ( ACE1 ) and angiotensin-converting enzyme 2 ( ACE2 ) mRNA levels were greater in tumour tissue than adjacent non-cancerous endometrium ( P = 0.023, 0.008, 0.004 and 0.046, respectively). Prorenin, ATP6AP2, AGTR1, AGTR2 and ACE2 proteins were abundantly expressed in both cancerous and adjacent non-cancerous endometrium. Staining was most intense in cancerous glandular epithelium. One potential target of the endometrial RAS, transforming growth factor beta-1 ( TGFB1 ), which is essential for epithelial-to-mesenchymal transition, was also upregulated in endometrial cancer tissue ( P = 0.001). Interestingly, TGFB1 was strongly correlated with RAS expression and was upregulated in tumour tissue. This study is the first to characterise the mRNA and protein expression of all RAS components in cancerous and adjacent non-cancerous endometrium. The greater expression of ATP6AP2 , AGTR1 and ACE1 , key elements of the pro-angiogenic roliferative arm of the RAS, suggests that the RAS plays a role in the growth and spread of endometrial cancer. Therefore, existing drugs that inhibit the RAS and which are used to treat hypertension may have potential as treatments for endometrial cancer.
Publisher: Springer Science and Business Media LLC
Date: 1972
DOI: 10.1007/BF00589136
Abstract: The present study evaluated the effects of job stress, including organisational system to self-rated depression through a panel study of male municipal firefighters in the Republic of Korea. A panel of 186 municipal firefighters reported self-rated depressive symptoms according to the Beck Depression Inventory (BDI). The effects of job stress were evaluated using the Korea Occupational Stress Scale, taken one year earlier and classified by the median value. Panel members were classified into Depression or Control groups according to BDI scores, with a cut-off level of 'over mild depression' in a follow-up survey. The Depression group included 17 (9.1%) workers. Firefighters who scored high on occupational system had an 8.3 times greater risk of being assigned to the Depression group than those who had not (adjusted odds ratio [OR] = 8.03, 95% confidence interval (CI) = [1.73-37.22]). In contrast, job stress from a 'difficult physical environment' revealed negative risks related to being classified in the Depression group (AOR = 0.20, 95% CI = [0.04-0.92]). Although the healthy worker effect may be involved, job stress based on perceptions of organisational system was a strong risk factor for depression. A comprehensive approach should be considered that encompasses social issues when assessing or mental health in high-risk groups, as well as the practical issue of physiochemical hazards.
Publisher: American Physiological Society
Date: 10-2003
DOI: 10.1152/AJPREGU.00252.2003
Abstract: Fetal behavior, renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were studied 1-3 days after surgery in seven fetal sheep (aged 127-136 days). Five behavioral states were defined from chart recordings of electrocortical (electrocorticographic ECoG) activity and eye, limb, and breathing movements. Most records were of high-voltage ECoG (HV) or low-voltage (LV) ECoG with breathing (LV B ) 6.7 ± 1.7% were LV ECoG with no breathing (LV 0 ). RSNA was lower in LV 0 ( P 0.001) and greater in LV B than in HV ( P 0.05). MAP was lower in both LV states than in HV and when the fetuses went from LV to HV ( P 0.001 to P 0.03). HR was highest in HV ( P 0.001). In HV and LV B and when the fetus went from LV to HV, MAP and HR were inversely related ( P = 0.012-0.003). In LV B and from LV to HV there were direct relationships between MAP and RSNA ( P = 0.0014, P = 0.08), and when the fetus went from LV to HV there was also an inverse relationship between HR and RSNA ( P = 0.02). Thus fetal RSNA, MAP, and HR are affected by behavioral state as is fetal cardiovascular control. The increase in RSNA during fetal breathing showed that there was an altered level of fetal RSNA associated with fetal breathing activity.
Publisher: Frontiers Media SA
Date: 31-01-2019
Publisher: Bioscientifica
Date: 09-2019
DOI: 10.1530/REP-18-0633
Abstract: Fetal growth restriction (FGR) is a pregnancy complication wherein the foetus fails to reach its growth potential. The renin–angiotensin system (RAS) is a critical regulator of placental function, controlling trophoblast proliferation, angiogenesis and blood flow. The RAS significantly influences uteroplacental blood flow through the balance of its vasoconstrictive and vasodilatory pathways. Although the RAS is known to be dysregulated in placentae from women with preecl sia, the expression of the RAS has not yet been studied in pregnancies compromised by FGR alone. This study investigated the mRNA expression and protein levels of RAS components in placentae from pregnancies compromised by FGR. Angiotensin II type 1 receptor ( AGTR1 ) and angiotensin-converting enzyme 2 ( ACE2 ) mRNA levels were reduced in FGR placentae compared with control ( P = 0.012 and 0.018 respectively). Neprilysin ( NEP ) mRNA expression was lower in FGR placentae compared with control ( P = 0.004). mRNA levels of angiotensinogen ( AGT ) tended to be higher in FGR placentae compared with control ( P = 0.090). Expression of prorenin, AGT, angiotensin-converting enzyme (ACE) or ACE2 proteins were similar in control and FGR placentae. The renin-AGT reaction is a first order reaction so levels of expression of placental AGT determine levels of Ang II. Decreasing levels of ACE2 and/or NEP by limiting the production of Ang-(1-7), which is a vasodilator, and increasing placental Ang II levels (vasoconstrictor) may result in an imbalance between the vasoconstrictor and vasodilator arms of the placental RAS. Ultimately this dysregulation of the placental RAS could lead to reduced placental perfusion that is evident in FGR.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2018
Publisher: Wiley
Date: 04-01-2000
DOI: 10.1046/J.1440-1681.2000.03207.X
Abstract: 1. To measure the renal contribution to acid–base homeostasis during hypoxia (not associated with hypercapnia) and in response to the subsequent mild metabolic acidosis and to determine the effects of this hypoxia on the renal handling of sodium, studies were performed in six chronically catheterized foetal sheep (129–138 days gestation) before, during and for 1 h after a 2 h period of hypoxia. 2. Hypoxia was induced in the conscious ewe by infusing nitrogen into the trachea. Foetal arterial oxygen tension fell to 12.0 ± 0.6 mmHg ( P 0.001). Carbon dioxide tension fell during hypoxia ( P 0.001) and was still somewhat reduced in the recovery period ( P 0.005). Arterial pH fell progressively to 7.19 ± 0.08 in the recovery period ( P 0.05). Plasma bicarbonate concentrations fell ( P 0.001) and lactate rose ( P 0.001). 3. Urinary pH and the excretion rates of bicarbonate, titratable acid, ammonium and net acid did not change during hypoxia. Ammonium excretion and, hence, generation of new bicarbonate increased in the recovery period ( P 0.05). 4. Renal sodium excretion progressively increased and was greatest after normoxia was restored ( P 0.05). This natriuresis was due to a fall in the reabsorption of sodium by the proximal tubule ( P 0.05). Proximal reabsorption of sodium was directly related to foetal pH ( P 0.0001) and bicarbonate reabsorption ( P 0.001). 5. It was concluded that: (i) the foetal kidneys began to contribute to the maintenance of acid–base balance within the first hour of recovery from a 2 h episode of hypocapnic hypoxia, even though the acidosis was relatively mild and (ii) a reduction in bicarbonate reabsorption was probably the most important factor that limited sodium reabsorption by the renal tubule during this experiment.
Publisher: Frontiers Media SA
Date: 16-07-2020
Publisher: Cambridge University Press (CUP)
Date: 17-01-2019
DOI: 10.1017/S204017441800079X
Abstract: Adverse pregnancy outcomes including prematurity and low birth weight (LBW) have been associated with life-long chronic disease risk for the infant. Stress during pregnancy increases the risk of adverse pregnancy outcomes. Many studies have reported the incidence of adverse pregnancy outcomes in Indigenous populations and a smaller number of studies have measured rates of stress and depression in these populations. This study sought to examine the potential association between stress during pregnancy and the rate of adverse pregnancy outcomes in Australian Indigenous women residing in rural and remote communities in New South Wales. This study found a higher rate of post-traumatic stress disorder, depression and anxiety symptoms during pregnancy than the general population. There was also a higher incidence of prematurity and LBW deliveries. Unfortunately, missing post-traumatic stress disorder and depressive symptomatology data impeded the examination of associations of interest. This was largely due to the highly sensitive nature of the issues under investigation, and the need to ensure adequate levels of trust between Indigenous women and research staff before disclosure and recording of sensitive research data. We were unable to demonstrate a significant association between the level of stress and the incidence of adverse pregnancy outcomes at this stage. We recommend this longitudinal study continue until complete data sets are available. Future research in this area should ensure prioritization of building trust in participants and overestimating s le size to ensure no undue pressure is placed upon an already stressed participant.
Publisher: Wiley
Date: 11-1989
DOI: 10.1111/J.1440-1681.1989.TB01527.X
Abstract: 1. Infusions of hyperosmotic mannitol to the ewe caused a rise in fetal arterial pressure in 17 chronically catheterized fetal sheep aged 120-140 days. The fetal heart slowed in 13 out of 17 of these fetuses. The rise in pressure occurred before there was any rise in fetal urinary osmolality. 2. In seven fetal sheep combined alpha- and beta-adrenoceptor and muscarinic blockade delayed the onset of the rise in blood pressure and no bradycardia was observed. It is concluded that the hypertension was due in part to increased activity of the sympatho-adrenal system, and that any reflex bradycardia that occurred was mediated by the vagus. 3. In three other fetal sheep aged 125-131 days, the cardiovascular responses elicited by infusion of hyperosmotic mannitol to the ewe were not blocked by a specific vasopressin antagonist. Thus vasopressin could not be responsible for either the initial rise in pressure nor the delayed hypertensive response that was not blocked by alpha- and beta-adrenoceptor blockade. 4. Fetal blood volume was maintained even though the changes in plasma osmolality and electrolytes were indicative of a fall in blood volume. Thus changes that threaten maintenance of fetal blood volume seem to induce increased solute and water transport across the placenta or from the extracorporeal fluid compartments.
Publisher: Wiley
Date: 2009
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.PREGHY.2013.04.063
Abstract: The intrarenal renin angiotensin system (iRAS) may be activated in normal pregnancy. Failure of activation may predispose to preecl sia. Urinary angiotensinogen/creatinine (uAGT/creat), albumin and protein/creat were measured in 10 non-pregnant and 17 pregnant non-Indigenous women and 61 Indigenous pregnant women (in whom other components of iRAS were also measured). uAGT/creat was higher in pregnancy (18.2±3.2μg/mmol, n=9 vs. 1.1±0.3μg/mmol, P=0.001, n=10). Women with clinical proteinuria and/or preecl sia had low uAGT/creat (n=3). Hypertensive women had normal high uAGT/creat (n=4). Indigenous pregnant women had higher protein/creat (P=0.01) and lower uAGT/creat (2.9±1.0μg/mmol, P=0.010, n=51) than non-Indigenous pregnant women. Indigenous women were classified based on a uAGT/creat of 2.0μg/mmol (n=12). Only low uAGT/creat Indigenous pregnant women had correlations between uAGT/creat and albumin/creat (r=0.367, P=0.027), renin/creat and albumin or protein/creat (r=0.493, P=0.002, r=0.603, P<0.001). uAGT/creat levels fell with gestation (r=-0.329, P=0.047) while Cystatin C increased (r=0.592, P=0.000). The iRAS is activated in normal pregnancy. This is not the case in women with proteinuria reecl sia or in many Indigenous women who have higher urinary protein/creat. Therefore a low uAGT/creat in pregnancy may indicate impaired renal function and be associated with an increased risk of preecl sia.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2015
Publisher: Wiley
Date: 08-11-2008
DOI: 10.1113/EXPPHYSIOL.2007.039149
Abstract: Effects of altered maternal salt intake between 122 and 127 days gestation (term is 150 days) were studied in eight fetuses carried by ewes which had renal insufficiency caused by subtotal nephrectomy (STNxF) and seven fetuses carried by intact ewes (IntF). Plasma sodium and osmolality were increased in ewes with subtotal nephrectomy on a high-salt intake (0.17 m NaCl in place of drinking water for 5 days P < 0.05). The STNxF had normal body weights. A high maternal salt intake did not affect fetal blood pressure or heart rate. Plasma osmolality was higher in STNxF (P < 0.001), and plasma sodium and osmolality were increased by high salt (P < 0.001 and P < 0.04, respectively). The STNxF had higher urinary osmolalities (P = 0.002), which were also increased by a high maternal salt intake (P = 0.03). Renal blood flow fell in STNxF in response to a high maternal salt intake, but increased in IntF (P = 0.003). In STNxF but not IntF, glomerular filtration rate and urinary protein excretion were positively related to fetal plasma renin levels (P < or = 0.01). It is concluded that the salt intake of pregnant ewes with renal insufficiency affects maternal and fetal osmolar balance, fetal plasma sodium and fetal renal function. Since STNxF also had altered renal haemodynamic responses to high maternal salt and evidence of renin-dependent glomerular filtration and protein excretion, we suggest that interactions between dietary salt and pre-existing maternal renal disease impair glomerular integrity and function in the fetus.
Publisher: Bioscientifica
Date: 11-2021
DOI: 10.1530/REP-20-0650
Abstract: This study aimed to determine if the (pro)renin receptor (ATP6AP2) changes the cellular profile of choriocarcinomas from cytotrophoblast cells to terminally syncytialised cells and ascertain whether this impacts the invasive potential of choriocarcinoma cells. Additionally, we aimed to confirm that FURIN and/or site 1 protease (MBTPS1) cleave soluble ATP6AP2 (sATP6AP2) in BeWo choriocarcinoma cells and determine whether sATP6AP2 levels reflect the cellular profile of choriocarcinomas. BeWo choriocarcinoma cells were treated with ATP6AP2 siRNA, FURIN siRNA, DEC-RVKR-CMK (to inhibit FURIN activity), or PF 429242 (to inhibit MBTPS1 activity). Cells were also treated with forskolin, to induce syncytialisation, or vehicle and incubated for 48 h before collection of cells and supernatants. Syncytialisation was assessed by measuring hCG secretion (by ELISA) and E-cadherin protein levels (by immunoblot and immunocytochemistry). Cellular invasion was measured using the xCELLigence real-time cell analysis system and secreted sATP6AP2 levels measured by ELISA. Forskolin successfully induced syncytialisation and significantly increased both BeWo choriocarcinoma cell invasion ( P 0.0001) and sATP6AP2 levels ( P = 0.02). Treatment with ATP6AP2 siRNA significantly inhibited syncytialisation (decreased hCG secretion ( P = 0.005), the percent of nuclei in syncytia ( P = 0.05)), forskolin-induced invasion ( P = 0.046), and sATP6AP2 levels ( P 0.0001). FURIN siRNA and DEC-RVKR-CMK significantly decreased sATP6AP2 levels (both P 0.0001). In conclusion, ATP6AP2 is important for syncytialisation of choriocarcinoma cells and thereby limits choriocarcinoma cell invasion. We postulate that sATP6AP2 could be used as a biomarker measuring the invasive potential of choriocarcinomas. Additionally, we confirmed that FURIN, not MBTPS1, cleaves sATP6AP2 in BeWo cells, but other proteases (inhibited by DEC-RVKR-CMK) may also be involved.
Publisher: Wiley
Date: 05-1997
DOI: 10.1111/J.1440-1681.1997.TB01198.X
Abstract: 1. Hypertension secondary to renal disease was studied in non-pregnant and pregnant ewes to determine whether there were any changes in arterial pressure and the distribution of cardiac output and, in particular, whether uteroplacental blood flow was affected. 2. In six non-pregnant, chronically catheterized, uninephrectomized ewes, a reduction in renal blood flow (RBF) to 40-50% of control caused hypertension within 3 h. This was maintained for as long as RBF was reduced (72 h) and returned to control 24 h after the occluder around the renal artery was released. When this experiment was repeated in 16 uninephrectomized pregnant ewes (118-134 days gestation) hypertension occurred within 3 h and was sustained for as long as RBF was reduced (between 24 and 72 h). Arterial pressure returned to control within 24-72 h of restoring RBF. 3. Compared with non-pregnant ewes, pregnant ewes had similar arterial pressures, higher cardiac outputs (CO P < 0.001) and heart rates (HR P < 0.001), lower total peripheral resistances (TPR P < 0.001) and similar blood flows to brain, ovary, pancreas, kidney and spleen. Splenic vascular resistance (VR) was greater (P = 0.006), gut blood flow was greater (P < 0.05) and gut VR was less (P < 0.05). Myoendometrial blood flow/g was greater (P < 0.005) and myoendometrial VR was less (P = 0.006). 4. In pregnant sheep with renal clip hypertension, there was no change in CO and HR, but TPR increased (P < 0.01), as did plasma renin activity. Gut, brain, pancreatic and myoendometrial VR were increased as long as RBF was reduced in addition, myoendometrial VR remained high for the rest of the experiment. Placental blood flow was unchanged at 3 h 24-72 h later it was reduced (P < 0.05) and remained low. Placental VR was increased 24-72 h after RBF was restored when ewes were again normotensive. 5. Thus, one-clip, one-kidney renal hypertension in the pregnant ewe was due to increased TPR associated with a fall in uteroplacental blood flow that persisted even when RBF was restored and ewes were normotensive. This reduction in uteroplacental blood flow could account for the high foetal morbidity and mortality that occurs in pregnant women with renovascular hypertension.
Publisher: Wiley
Date: 04-1995
DOI: 10.1111/J.1476-5381.1995.TB13376.X
Abstract: 1. The transplacental transfers of three drugs (enalapril, captopril and losartan) which block the renin angiotensin system and have different lipophilicities were studied in chronically catheterized foetal sheep (125-139 days gestation). 2. The ability of the foeto-placental unit to convert enalapril to enalaprilat was studied in two chronically catheterized foetuses. Enalapril (3 mg kg-1, 7.9 mumol kg-1) given i.v. to the foetuses abolished the foetal pressor response to 5 micrograms angiotensin I (AI) in one foetus and attenuated the pressor response in the other. 3. Enalapril (100 mg, 5.7 mumol kg-1) given i.v. to the ewe (n = 5) abolished the maternal pressor response to 2.5 micrograms AI (n = 1) and attenuated the maternal pressor response to 5 micrograms AI (n = 5, P < 0.001). The foetal pressor response to 5 micrograms AI (n = 2) and 10 micrograms AI (n = 3) did not change. The maternal and foetal pressor responses to angiotensin II (AII n = 5) did not change. 4. Foetal pressor responses to 5 micrograms AI (n = 1) and 10 micrograms AI (n = 2) were attenuated within 11 min of their mothers (n = 3) being given i.v. captopril (15 mg, 1.5 mumol kg-1). Foetal pressor responses to 5 micrograms AII (n = 1) and to 10 micrograms AII (n = 2) did not change. 5. Losartan (100 mg, kg-1, 21.7 mumol kg-1) given i.v. to the foetus (n = 9) attenuated the foetal pressor response to 5 micrograms AII (P < 0.001) but the maternal pressor response to 5 micrograms AII did not change. 6. Losartan (100 mg, 21.7 MICROmol kg-1) given i.v. to the ewe (n = 5) attenuated the maternal pressor response to 5 microg AII (P <0.002) but the foetal pressor response to 5 microg AII did not change.7. It is concluded that the foeto-placental unit of the sheep can metabolize enalapril to enalaprilat.Captopril readily crosses the sheep placenta but enalapril and losartan do not. Thus, the transplacental transfer of these drugs does not parallel their lipid solubilities. Furthermore the results show that AT1 receptors are important in mediating the vasoconstrictor effects of AII in the foetus.
Publisher: Wiley
Date: 15-07-1996
DOI: 10.1113/JPHYSIOL.1996.SP021504
Abstract: 1. In nine chronically catheterized fetuses in which all lung liquid was drained continuously from the time of surgery, the effects of continuous drainage of fetal urine for 1 week on fetal renal function, lung liquid production and salt and water balance were studied. Fetal wellbeing, as judged by fetal growth, urinary osmolality, blood gas status, arterial pressure and heart rate, was not adversely affected by urine drainage. The ewes, however, drank more water when fetal urine was drained. Thus. fetal plasma and urinary osmolalities declined (P < 0.25 and P < 0.05). 2. Fetal glomerular filtration rate fell from 75 +/- 4 ml kg-1 h-1 (+/- S.E.M., n = 9) before drainage to 54 +/- 7 ml kg-1 h-1 after drainage (n = 7 P < 0.005), and fetal renal sodium excretion also declined (P < 0.05). However, the excretion of sodium in lung liquid did not decrease and the fetal renin-angiotensin system was not activated. Fetal extracellular volume (561 +/- 44 ml kg-1, n = 7) and the calculated net sodium transfer (0.76 mmol kg-1 h-1, n = 6) and fluid transfer (15 +/- 2 ml kg-1 h-1, n = 8) to the fetus did not change. 3. It is concluded that overall fetal salt and water balance were maintained when all fetal urine and lung liquid were drained from fetal sheep in late gestation. Since drainage of urine and lung liquid considerably reduced the amniotic and allantoic fluids, transfer across the placenta and extraplacental membranes was able to compensate for the absence of these fluids. In response to the loss of sodium during drainage, fetal renal sodium conservation was about 11% of the total sodium conservation by the materno-fetal unit.
Publisher: Frontiers Media SA
Date: 08-2023
DOI: 10.3389/FCELL.2023.1212898
Abstract: The (pro)renin receptor ((P)RR also known as ATP6AP2 ) is a multifunctional receptor. The (P)RR activates the tissue renin-angiotensin system (RAS) and is also involved in regulating integral intracellular pathways such as V-ATPase and Wnt/β-catenin signalling. Given this, the (P)RR may be associated with essential pathways in placentation, however its role within the context of pregnancy remains poorly characterised. The first trimester/extravillous trophoblast cell line, HTR-8/SVneo, underwent an siRNA knockdown where they were incubated for 24 h with a negative control siRNA or siRNA targeting ATP6AP2 mRNA. xCELLigence real-time cell analysis was performed to assess the effect of ATP6AP2 mRNA knockdown on HTR-8/SVneo cell proliferation, migration, and invasion. In subsequent experiments, GFP-encoding lentiviral packaged gene-constructs were used to knockdown (P)RR expression in the trophectoderm of C57/BL6/CBA-F1 mouse blastocysts. Blastocysts were incubated for 6 h with vehicle (no-virus), control virus (non-targeting shRNA and GFP), or (P)RR-knockdown virus ((P)RR shRNA and GFP) before transfer into recipient pseudo-pregnant Swiss CD1 female mice. Fetal and placental tissues were collected and assessed at embryonic age (EA) 10 and 18. (P)RR levels were measured in the labyrinth zone of day 18 placentae and stereological Merz grid analysis was performed to determine the volumetric distribution of trophoblasts, fetal capillaries, and the maternal blood space. We showed that a reduction of ATP6AP2 expression in HTR-8/SVneo cells in vitro, impaired trophoblast proliferation, migration, and invasion. In vivo, decreasing placental labyrinth (P)RR expression adversely effected placental physiology, decreasing placental trophoblast number and total surface area available for exchange, while also increasing maternal blood space. Additionally, decreased (P)RR affected placental efficacy evident by the reduced fetal-placental weight ratio. Our study shows that the (P)RR is necessary for appropriate placental development and function.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.PLACENTA.2021.04.015
Abstract: The (pro)renin receptor ((P)RR) is a multi-functional protein that can be proteolytically cleaved and released in a soluble form (s(P)RR). Recently, the (P)RR and s(P)RR have become of interest in pregnancy and its associated pathologies. This is because the (P)RR not only activates tissue renin angiotensin systems, but it is also an integral component of vacuolar-ATPase, activates the wingless/integrated (Wnt)/β-catenin and extracellular signal regulated kinases 1 and 2/mitogen-activated protein kinase signalling pathways, and stabilises the β subunit of pyruvate dehydrogenase. Additionally, s(P)RR is detected in plasma and urine, and maternal plasma levels are elevated in pregnancy complications including fetal growth restriction, preecl sia and gestational diabetes mellitus. Therefore, s(P)RR has potential as a biomarker for these pregnancy pathologies. Preliminary functional findings suggest that s(P)RR may be important for regulating fluid balance, inflammation and blood pressure, all of which contribute to a successful pregnancy. The (P)RR and s(P)RR regulate pathways that are known to be important in maintaining pregnancy, however their role in the physiological context of pregnancy is poorly characterised. This review summarises the known and potential functions of the (P)RR and s(P)RR in pregnancy, and how their dysregulation may contribute to pregnancy complications. It also highlights the need for further research into the source and function of s(P)RR in pregnancy. Soluble (P)RR levels could be indicative of placental, kidney or liver dysfunction and therefore be a novel clinical biomarker, or therapeutic target, to improve the detection and treatment of pregnancy pathologies.
Publisher: Elsevier BV
Date: 07-1990
DOI: 10.1016/0028-2243(90)90054-5
Abstract: Fetal cardiovascular (CVS) changes, forelimb movements (FM) and rates of habituation to repeated stimulation, with suffusions of cold saline over the skin, were measured in 12 chronically catheterized fetal sheep aged 130-145 days. Stimulation of the fetuses caused a significant rise in heart rate (HR) (p less than 0.01) and blood pressure (BP) (p less than 0.001) and FM (p less than 0.01). When the ewe was given an intravenous (i.v.) infusion of ethanol which produced fetal ethanol levels of 87 +/- 1.1 mg/100 ml, the number of spontaneous FM decreased (p less than 0.05). After i.v. ethanol, repeated stimulation of the fetuses still caused an increase in FM (p less than 0.01) and a rise in HR (p less than 0.05) and BP (p less than 0.02) but the fetuses habituated more rapidly (7.25 +/- 1.28 stimuli) compared to control experiments performed prior to (21.5 +/- 3.57 stimuli) or after the ethanol (17.75 +/- 5.83, p less than 0.01). Fetal exposure to low concentrations of ethanol does affect the patterns of response and habituation of the developing fetal central nervous system.
Publisher: Elsevier BV
Date: 03-2002
DOI: 10.1016/S1440-2440(02)80294-8
Abstract: A pregnant woman participated in cycling events in the 2000 Olympics. Recently there was concern about the participation of a pregnant woman in the Australian netball team. More and more women are anxious to pursue sports during their pregnancies and to maintain condition. For the clinician or sports physician caring for women who want to maintain a high-level of physical activity there is no simple exercise prescription. It is probable that continuing exercise by women who are already conditioned will not result in foetal compromise, unless there are hidden or unknown complications of pregnancy. Pregnant women should probably exercise within limits that do not cause severe discomfort and should, as pregnancy progresses, be prepared to moderate the intensity and duration of their exercise programs to avoid risks and injury. It is probably not advisable for women to begin high intensity exercise programs when pregnant, although moderate exercise is beneficial to both mother and baby. The type of activity that is undertaken has to be taken into consideration and in particular the adverse effects of supine activity in late gestation recognised.
Publisher: Wiley
Date: 12-1974
DOI: 10.1113/JPHYSIOL.1974.SP010769
Abstract: 1. Plasma renin (measured in the presence of additional substrate) was significantly higher (10.7 +/- 1.1 S.E. of mean ng/ml.hr) in foetal lambs of 111-144 days gestation age (full term 147 days) than in their mothers (1.5 +/- 0.2 ng/ml.hr S.E. of mean, P < 0.001) but plasma angiotensin II concentrations were in the same range (ewe 47.3 +/- 6.6 S.E. of mean, foetus 47.4 +/- 14.1 S.E. of mean pg/ml.). The endogenous velocity of renin production by foetal plasma was also greater than that of maternal plasma.2. Foetal plasma [Na(+)] (137 +/- 0.8 S.E. of mean m-equiv/l.), was lower than that in the ewe (142 +/- 1.5 m-equiv/l. S.E. of mean, P < 0.01).3. Foetal plasma renin in lambs of less than 120 days gestation was lower (9.2 +/- 2.7 S.E. of mean ng/ml.hr) than that in lambs of over 130 days gestation (12.6 +/- 2.6 ng/ml.hr S.E. of mean, P < 0.01). Foetal plasma [K(+)] (3.8 +/- 0.1 S.E. of mean m-equiv/l.) was also lower in lambs of less than 120 days gestation than in those over 130 days (4.1 +/- 0.1 S.E. of mean m-equiv/l., P < 0.001).4. When small volumes of blood (</= 3% of blood volume) were withdrawn from foetal lambs, plasma renin increased. The% increase of plasma renin in hypoxaemic foetal lambs was significantly less (P < 0.05) than in control lambs. At the end of 60 min hypoxaemia, arterial pressure and plasma [K(+)] were significantly higher in hypoxaemic than in control foetal lambs.5. During foetal hypoxaemia, plasma angiotensin II concentration increased concurrently with plasma renin.6. Bilateral nephrectomy was performed in two foetal lambs. Plasma renin fell to very low levels and angiotensin II became undetectable.7. Adrenaline ( approximately .0.42 mug/min.kg I.V.) infused into the foetus did not alter foetal plasma renin. When adrenaline was infused into the ewe ( approximately 0.26 mug/min.kg) maternal plasma renin increased. Maternal infusion of adrenaline raised foetal plasma renin significantly more (P < 0.05) than foetal infusion.8. It is concluded that the foetal kidney is the major source of foetal renin in the last quarter of gestation and that renin release is stimulated by very small reductions of blood volume. Hypoxaemia does not augment renin release and cannot be responsible for high levels of renin and angiotensin associated with vaginal delivery.
Publisher: Wiley
Date: 09-2019
DOI: 10.14814/PHY2.14227
Publisher: Cambridge University Press (CUP)
Date: 08-11-2013
DOI: 10.1017/S2040174413000494
Abstract: Rates of chronic kidney disease (CKD) among Indigenous groups in Australia exceed non-Indigenous rates eight-fold. Using kidney volume as a surrogate for nephron number, we carried out a study to determine if Indigenous neonates have a smaller kidney volume (and thus a reduced nephron number) from birth compared with non-Indigenous neonates. We recruited term and preterm neonates ( weeks) at a tertiary care neonatal unit over a 12 months period. Preterm neonates were assessed (renal sonography and renal function measurement) at 32 weeks corrected age (CA) and again at 38 weeks CA when blood pressure was also measured. All term neonates were assessed in the first post-natal week, including renal sonography, renal function and blood pressure measurement. The primary outcome measured was total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) was a secondary outcome. Data was available for 44 preterm (11 Indigenous) and 39 term (13 Indigenous) neonates. TKV of Indigenous neonates was significantly lower at 32 weeks [12.0 (2.0) v. 15.4 (5.1) ml P =0.03] and 38 weeks CA [18.6 (4.0) v. 22.6 (5.9) ml P =0.04] respectively. Term Indigenous neonates also had smaller kidney volumes compared with non-Indigenous neonates. Despite a smaller kidney volume (and reduced nephron number), Indigenous neonates did not have a significantly lower eGFR. Indigenous neonates achieve similar eGFRs to Non-Indigenous neonates, presumably through a higher single nephron filtration rate. This places Indigenous neonates at a greater risk of long-term kidney damage later in life.
Publisher: American Physiological Society
Date: 03-2007
DOI: 10.1152/AJPREGU.00188.2006
Abstract: To determine the effects of chronic maternal renal insufficiency on fetal renal function, we studied nine fetuses whose mothers underwent subtotal nephrectomy at least 2 mo before mating (STNxF) and seven fetuses from intact ewes (IntF) (126–128 days of gestation, term 150 days). STNxF had lower hematocrit ( P 0.05), plasma chloride ( P 0.01), and creatinine levels ( P 0.01), and the length-to-width ratio of their kidneys was reduced ( P 0.05). They excreted twice as much urine ( P 0.05) and sodium ( P 0.01). Total ( P = 0.01) and proximal fractional sodium reabsorptions ( P 0.05) were lower in STNxF distal delivery of sodium ( P 0.05) and distal fractional sodium reabsorption ( P 0.05) were higher. They tended to have suppressed renin levels ( P = 0.06). Infusions of amino acids (alanine, glycine, proline, and serine at 0.32 mmol/min for 1 h and 0.64 mmol/min for 2 h intravenously), known to stimulate renal blood flow and glomerular filtration rate in fetal sheep, did so in IntF ( P 0.01). Arterial pressure also increased ( P 0.01). These effects were not observed in STNxF. In summary, chronic maternal renal insufficiency was associated with profound alterations in fetal renal excretion of fluid and electrolytes and impaired renal hemodynamic and glomerular responses to amino acid infusion. Whether these marked changes in the renal function of fetuses carried by STNx ewes are associated with alterations in renal function in postnatal or adult life remains to be determined.
Publisher: American Physiological Society
Date: 02-1998
DOI: 10.1152/AJPREGU.1998.274.2.R445
Abstract: To study the effects of elevated maternal levels of adrenocorticotropic hormone (ACTH) on the fetus, nine chronically catheterized pregnant ewes (132 ± 0.9 days of gestation) were infused intravenously for 3 days with Synacthen (5 μg ⋅ kg −1 ⋅ day −1 ). Four ewes were given 0.15 M saline intravenously over the same period. ACTH induced hypertension in the ewe. Mean arterial pressure (MAP) increased from 101 ± 4.4 to 114 ± 3.9 mmHg at 48 h ( P 0.05) cardiac output increased from 8.6 ± 0.5 to 10.4 ± 1.0 l/min after 24 h ( P 0.05). Within 2–4 h, maternal cortisol levels increased from 24.6 ± 6.3 to 287 ± 30 nM ( P 0.05) and remained high. Fetal plasma cortisol levels increased from 20 ± 4.5 to 60 ± 4.5 nM ( P 0.05) within 2–4 h and then increased further. Fetal MAP was increased at 24 h. There was no effect on fetal blood gases or pH. Ewes became hyperglycemic and lactacidemic by 24 h ( P 0.05), and the fetuses were also hyperglycemic and lactacidemic ( P 0.05) at this time. There were no changes in fetuses carried by saline-infused ewes. Both ewes and fetuses had raised plasma osmolalities and, since hematocrit fell, retained fluid. Ewes became hypokalemic the fetuses did not, but there was an increase in fetal K excretion. Thus ACTH-induced hypertension in the ewe had minimal effects on fetal MAP, fetal blood gas status, and pH. The fetus, however, did show many of the other effects of maternal glucocorticoid and mineralocorticoid excess, partly because its cortisol levels were increased but also as a consequence of metabolic and endocrine changes in the ewe.
Publisher: Frontiers Media SA
Date: 07-06-2022
Publisher: American Physiological Society
Date: 07-1988
DOI: 10.1152/AJPRENAL.1988.255.1.F11
Abstract: The effects of maternal hyperglycemia on fetal renal function were investigated in 10 chronically catheterized fetal sheep after the infusion of 100 g of glucose into the ewe over 30 min. Fetal blood glucose levels rose (P less than 0.001) within 15 min of completing the glucose infusion from 15.75 +/- 2.8 to 195.4 +/- 18 (SE) mg/dl (n = 10). There was a significant increase in fetal glomerular filtration rate (P less than 0.05) from 2.73 +/- 0.41 to 3.65 +/- 0.40 (SE) ml/min (n = 10) within 1.5 h of the infusion of glucose into the ewe. Urine flow rate increased from 0.38 +/- 0.06 to 0.63 +/- 0.12 (SE) ml/min (n = 10, P less than 0.001), and sodium excretion increased from 18.42 +/- 7.21 to 38.4 +/- 13.7 (SE) mumol/min (n = 10, P less than 0.002) within 2.5 h of the infusion of glucose into the ewe. The fraction of the filtered load that was excreted (urine flow rate ided by glomerular filtration rate) also increased (P less than 0.01) as did the fraction of the osmolar load (P less than 0.002). Glycosuria occurred in all fetuses within 30 min of the infusion of glucose into the ewe, and glucose excretion reached 26.16 +/- 12.36 (SE) micrograms/min (n = 8) after 1.5 h. These findings of diuresis, natriuresis, and glycosuria in response to hyperglycemia are evidence that an increased delivery of fluid into the amniotic cavity might occur after a rise in fetal plasma glucose levels.
Publisher: Cambridge University Press (CUP)
Date: 16-05-2019
DOI: 10.1017/S2040174418000302
Abstract: Childhood obesity rates are higher among Indigenous compared with non-Indigenous Australian children. It has been hypothesized that early-life influences beginning with the intrauterine environment predict the development of obesity in the offspring. The aim of this paper was to assess, in 227 mother–child dyads from the Gomeroi gaaynggal cohort, associations between prematurity, Gestation Related-Optimal Weight (GROW) centiles, maternal adiposity (percentage body fat, visceral fat area), maternal non-fasting plasma glucose levels (measured at mean gestational age of 23.1 weeks) and offspring BMI and adiposity (abdominal circumference, subscapular skinfold thickness) in early childhood (mean age 23.4 months). Maternal non-fasting plasma glucose concentrations were positively associated with infant birth weight ( P =0.005) and GROW customized birth weight centiles ( P =0.008). There was a significant association between maternal percentage body fat ( P =0.02) and visceral fat area ( P =0.00) with infant body weight in early childhood. Body mass index (BMI) in early childhood was significantly higher in offspring born preterm compared with those born at term ( P =0.03). GROW customized birth weight centiles was significantly associated with body weight ( P =0.01), BMI ( P =0.007) and abdominal circumference ( P =0.039) at early childhood. Our findings suggest that being born preterm, large for gestational age or exposed to an obesogenic intrauterine environment and higher maternal non-fasting plasma glucose concentrations are associated with increased obesity risk in early childhood. Future strategies should aim to reduce the prevalence of overweight/obesity in women of child-bearing age and emphasize the importance of optimal glycemia during pregnancy, particularly in Indigenous women.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Wiley
Date: 09-1979
DOI: 10.1113/JPHYSIOL.1979.SP012915
Abstract: 1. Action potentials were recorded in single baroreceptor fibres dissected from the carotid sinus nerves in dogs during increases in blood pressure caused by I.V. injection of angiotensin II, and by I.V. injection of phenylephrine or inflation of an aortic balloon. Action potentials were recorded in single cardiac efferent fibres dissected from the right cervical vagus nerve in other dogs during increases in blood pressure caused by angiotensin II, and by phenylephrine or by inflation of an aortic balloon. 2. There was no difference in the discharge frequency of single carotid sinus baroreceptor fibres at any blood pressure when phenylephrine, balloon inflation, or angiotensin II were used to raise the pressure. 3. Activity in single cardiac vagal efferent fibres was increased when blood pressure was increased by phenylephrine or by inflation of an aortic balloon. However, when blood pressure rose by a comparable amount in response to angiotensin II, vagal firing decreased (three fibres), was little changed from control levels (four fibres), or increased less than it did in response to phenylephrine (one fibre). 4. It is concluded that while angiotensin II has no effect on baroreceptor sensitivity, it does inhibit vagal discharge which is evoked by stimulation of arterial baroreceptors.
Publisher: Portland Press Ltd.
Date: 02-1985
DOI: 10.1042/CS0680165
Abstract: 1. The effect of cold on vagal action at the heart was studied in sheep, dogs and an isolated guinea pig atrial preparation. 2. During cardiac output measurements in un-anaesthetized sheep, by the thermodilution method, bradycardia was evoked on injection of cold indicator in eight of 12 sheep studied. This bradycardia was consistently evoked when blood pressure was increased, but not at normal blood pressure levels. 3. In the guinea pig atrial preparation, which has one vagus nerve attached, bradycardia was evoked by electrical stimulation of the vagus nerve. When the preparation was cooled this bradycardia was potentiated. 4. In anaesthetized dogs, the cut peripheral end of one vagus was stimulated electrically at different frequencies. The linear relationship between pulse interval and vagal frequency was then compared at deep body temperatures of 35, 37, 39 and 41°C. This comparison showed that the vagus prolonged pulse interval more effectively when the animal was cool (35°C) than when it was warm (41°C).
Publisher: American Physiological Society
Date: 1998
DOI: 10.1152/AJPREGU.1998.274.1.R160
Abstract: Renal sympathetic nerve activity (RSNA) increases rapidly after delivery of term fetal sheep and parallels the rise in heart rate (HR) and arterial pressure. To examine the RSNA response at birth in immature lambs, experiments were performed in chronically instrumented preterm fetal sheep (118- to 125-day gestation, term 145 days) before and after delivery by cesarean section. HR remained unchanged from fetal values at 1 and 4 h after birth, whereas mean arterial blood pressure (MABP) decreased significantly ( P 0.05) by 4 h after delivery. RSNA significantly decreased after premature birth in all animals studied ( n = 6), achieving only 39 ± 17% of fetal RSNA ( P 0.05 all results are mean ± SE). Because cardiovascular function after premature birth is improved by the use of antenatal corticosteroids, we also tested the hypothesis that corticosteroid administration would evoke a more pronounced sympathetic response in prematurely delivered lambs ( n = 7, 118- to 125-day gestation). After maternal administration of dexamethasone (5 mg im, 48 and 24 h before delivery), RSNA increased after birth in six of seven fetuses to 166 ± 32% of the fetal RSNA value. Dexamethasone treatment also decreased the sensitivity of baroreflex-mediated changes in HR in response to increases in MABP. Because the sympathetic response at birth is depressed in preterm compared with term lambs, we performed an additional study ( n = 8) to determine if immature sheep are capable of mounting a sympathetic response to cold. In utero cooling produced rapid and sustained increases in MABP (20 ± 4%), HR (26 ± 6%), and RSNA (282 ± 72%) (all P 0.05), consistent with a generalized sympathoexcitation. These results suggest that sympathoexcitation is absent after premature delivery despite the presence of functional descending autonomic pathways. Furthermore, exogenous corticosteroids appear to have a maturational effect on the sympathetic response at birth, which may be one mechanism by which maternal steroid administration improves postnatal cardiovascular homeostasis.
Publisher: Wiley
Date: 08-09-2003
DOI: 10.1002/AR.A.10110
Abstract: Right (RVFW) and left (LVFW) ventricular free wall cardiac myocytes were collected from 25 fetal sheep aged 77-146 days gestation (term = 150 days gestation), six saline-infused catheterized fetal sheep (129 GD), and five lambs to measure gestational changes in uni- and binucleated cardiac myocyte numbers and cell volumes by confocal microscopy. At 77 days gestation, 2% of the myocytes were binucleated, which increased to 50% at 135 days gestation and 90% at 4-6 weeks after birth. RVFW uni- and binucleated myocytes were larger than those in the LVFW, and cell volumes of RVFW uni- and binucleated and LVFW binucleated myocytes (but not LVFW uninucleated myocytes) increased with gestation. Before birth, the approximate number of myocytes was greater in the LVFW than in the RVFW (P < 0.001). Before 110 GD, cardiac growth appeared to be due to myocyte hyperplasia, as approximate myocyte numbers and VFW weight increased at the same rate. After 110 days gestation, the approximate myocyte number/g VFW weight decreased, which suggests that myocyte hypertrophy, as well as hyperplasia, was occurring in association with the appearance of a greater proportion of binucleated cells after that time. By 4-6 weeks of age, there was marked hypertrophy of myocytes and an apparent reduction in myocyte number.
Publisher: Wiley
Date: 14-02-2006
DOI: 10.1111/J.1440-1681.2006.04346.X
Abstract: The effects of gestation on a-actin levels in vascular smooth muscle aortae were studied in 31 fetal sheep, aged 66-144 days (term=150 days). Aortae were collected post-mortem. 2. Aortae, carotid and femoral arteries from two groups of chronically catheterized fetal sheep (110-114 days) were also examined. One group was infused with cortisol (n=6 hydrocortisone sodium succinate, total dose 16.8 mg in 48 h) and the control group received saline (0.15 mol/L, 0.33 mL/h, n=7). 3. Vascular homogenate protein was separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and western transfer. a-Actin was identified using a monoclonal mouse anti-a actin antibody and standardized against tissue protein and DNA content. 4. Between 60 and 144 days gestation, there was an exponential increase in the a-actin content of vascular smooth muscle cells from fetal sheep aorta (P<0.0001). a-Actin concentration (densitometry units (U) relative to DNA 260 nm absorbance (Abs)) was significantly (P<0.05) higher in the aortae of cortisol-infused (12,601+/- 2,499 U/Abs) fetal sheep compared with those that were saline-infused (4,514+/-670 U/Abs). a-Actin (relative to DNA absorbance) of carotid and femoral vessels in cortisol-infused animals (20,659+/- 4,812 U/Abs) compared with those that were saline-infused (14,461+/- 2,645 U/Abs) was increased, but the difference was not significant. 5. Therefore, the a-actin concentration of the vascular smooth muscle of the aorta increases throughout gestation. Cortisol treatment is associated with further increases in a-actin concentration in the fetal aorta, indicating that the development of large conduit vessels can be altered by this glucocorticoid.
Publisher: Springer Science and Business Media LLC
Date: 07-2015
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.GHIR.2015.02.001
Abstract: Insulin-like growth factors (IGFs) are known to interact with the renin-angiotensin system (RAS). We previously demonstrated that administration of IGF1 to guinea pigs in early to mid pregnancy promotes placental function and fetal growth in mid to late gestation. Early administration of IGF2 had sustained, but not acute, effects on these parameters and also on placental structural differentiation. Here, we aimed to determine whether the IGFs interact with the placental RAS in early to mid gestation to modulate placental development and increase fetal growth and survival, and if IGF2 binding the IGF2R is implicated in the sustained effects of IGF2 treatment. At day 20 of pregnancy, guinea pigs were infused with 1m g/kg/day of IGF1, IGF2, (Leu27)IGF2 or vehicle for 18days and sacrificed on either day 62 (late pregnancy) or during the infusion period on day 35 (early-mid pregnancy). Placental structure at day 35 was analyzed using morphometric technique and expression of RAS genes in the placenta and placental and plasma renin activity were measured at both time points. Compared with vehicle at day 35 of gestation, IGF1 infusion reduced the total midsagittal cross-sectional area of the placenta (-17%, p = 0.02) and the labyrinth area (-22%, p = 0.014) but did not alter the labyrinth volume nor labyrinth:interlobium ratios. IGF2 treatment did not affect placental structure. IGF1 did not alter placental mRNA for any of the RAS genes quantified at day 35 (AGTR1, ACE, AGT, TGFB1) but increased TGFB1 expression by more than 16-fold (p = 0.005) at day 62. IGF2 increased placental expression of AGTR1 (+88%, p = 0.03) and decreased AGT (-73%, p = 0.01) compared with the vehicle-treated group at day 35, and both IGF2 and (Leu27)IGF2 increased expression of TGFB1 at day 62 by 9-fold (p = 0.016) and 6-fold (p = 0.019) respectively. Both IGFs increased the ratio of active:total placental renin protein (+22% p = 0.026 p = 0.038) compared to vehicle compared to vehicle at day 35 but not 62. At day 62, IGF2-treated mothers showed a marked increase in total plasma renin (+495%) and active renin (+359%) compared to vehicle but decreased the ratio of active to total renin by 41% (p = 0.042). (Leu27)IGF2-treated animals had higher levels of placental active renin (+73%, p = 0.001) and total renin (+71%, p = 0.001) compared with the vehicle control. The data obtained in the current study suggest the potential for alternate roles for the induction of the RAS after IGF treatment. IGF1 and 2 treatments increase the activation of prorenin to renin in the placenta, possibly due to increased protease activity. In addition, IGF2 treatment in early pregnancy may enhance the maternal adaptation to pregnancy through stimulation of renin in the kidney. The sustained effects on placental differentiation and function after IGF2 treatment suggest therapeutic potential for exogenous administration of IGFs in improving pregnancy outcomes.
Publisher: Elsevier BV
Date: 09-2007
Publisher: Wiley
Date: 15-08-1995
DOI: 10.1113/JPHYSIOL.1995.SP020867
Abstract: 1. Angiotensin II (AII) was infused I.V. into seven chronically catheterized fetal sheep (gestational age, 120-136 days). The effects of short-term infusions of 6 and 12 micrograms kg-1 h-1 for 1.5 h were compared with the effects of infusing 6 micrograms kg-1 h-1 for 3 or 5 days (long-term infusion). AII produced an immediate rise in fetal arterial blood pressure (P < 0.025). When infused for 3 or 5 days, 6 micrograms kg-1 h-1 AII caused a greater increase in arterial blood pressure (P < 0.05). 2. Infusions of 6 micrograms kg-1 h-1 AII for 1.5 h had no effect on fetal placental blood flow or on flow to the fetal membranes, but after AII infusion for 3 or 5 days both flows were reduced (P < 0.01 and P < 0.005, respectively). Fetal blood gas status and pH were maintained. The only change in fetal renal function observed with short-term infusions of AII was a rise in sodium excretion when 12 micrograms kg-1 h-1 AII was given (P < 0.05). Infusion of 6 micrograms kg-1 h-1 for 3 or 5 days also caused a rise in sodium excretion (P < 0.025) because total and proximal fractional sodium reabsorptions were depressed (P < 0.01). Infusions of AII had no effects on the volume of lung liquid produced or on its composition. 3. Administration of indomethacin to the ewe (10 mg kg-1) and to the fetus (12 mg kg-1), during the infusion of AII, caused a rise in maternal arterial pressure (P < 0.01) but no change in fetal arterial pressure. 4. After indomethacin, umbilicoplacental blood flow rose (P < 0.05), as did fetal arterial PO2 (P < 0.05). Fetal arterial PCO2, pH and bicarbonate levels fell (P < 0.01). Glomerular filtration rate (GFR) rose (P < 0.01) there was a natriuresis (P < 0.01), chloriuresis (P < 0.01) and a kaliuresis (P < 0.05) but urine flow rate did not change. Lung liquid flow fell (P < 0.01). 5. It is concluded that in the fetus, long-term infusions of AII at a constant dose rate cause a progressive rise in arterial pressure. In addition, effects of AII on placental blood flow and on renal function develop. Thus, short-term infusions of AII cannot be used to predict the renal and cardiovascular effects of sustained high levels of this peptide in the fetus.(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: American Physiological Society
Date: 04-2008
DOI: 10.1152/AJPREGU.00842.2006
Abstract: The effects of high salt intake on blood pressure and renal function were studied in nine subtotally nephrectomized pregnant ewes (STNxP) and seven intact pregnant ewes (IntP) in late gestation and in eight subtotally nephrectomized nonpregnant ewes (STNxNP) and seven intact nonpregnant ewes (IntNP). STNxP had higher mean arterial pressures ( P 0.02) and plasma creatinine levels ( P 0.001) than IntP. High salt (0.17 M NaCl as drinking water for 5 days) did not change blood pressure in either STNxP or IntP. STNxNP had higher mean arterial pressures ( P = 0.03) and plasma creatinine levels ( P 0.001) than IntNP. In STNxNP, blood pressure increased with high salt intake and there was a positive relationship between diastolic pressure and sodium balance ( r = 0.497, P = 0.05). This relationship was not present in IntNP, STNxP, or IntP. Because high salt intake did not cause an increase in blood pressure in STNxP, it is concluded that they were protected by pregnancy from further rises in blood pressure. The observed increase in glomerular filtration rate ( P 0.03) and depression of fractional proximal sodium reabsorption ( P = 0.003) that occurred in STNxP, but not in STNxNP, in response to high salt may have contributed to this protection. As well, the increased production of vasorelaxants in pregnancy may selectively protect against the occurrence of salt-sensitive hypertension in pregnancy.
Publisher: Wiley
Date: 08-1996
DOI: 10.1111/J.1440-1681.1996.TB01758.X
Abstract: 1. Renin gene expression was investigated in kidneys from 13 foetal and four adult sheep. 2. The levels of renal renin mRNA in foetuses were greater than those in adult sheep (P < 0.001). 3. There was no significant difference in renin mRNA levels between foetuses aged 91 and 134 days (term 150 days). 4. The levels of renin gene expression were higher (178 +/- 5 units P < 0.001) in foetuses at 142 days than levels in 91 (144 +/- 4 units) and 134 days old foetuses (146 +/- 6 units). 5. It is concluded that the high level of renin gene expression in the foetal kidney is responsible for the high levels of renin in the foetal circulation.
Publisher: Wiley
Date: 10-1985
DOI: 10.1113/JPHYSIOL.1985.SP015810
Abstract: The effects of infusions of angiotensin and vasopressin, in stepwise concentrations, on the cardiac baroreflex and on cardiac output were studied in seven adult unanaesthetized sheep and compared with those obtained with infusions of phenylephrine. Six animals were treated with the beta-adrenoceptor blocking drug, propranolol (in order to inhibit the effects of the sympathetic nervous system on the heart). One animal was not treated with propranolol. In those animals in which arterial pressure increased during infusion of vasopressin, the slope of the systolic pressure-pulse interval relation was greater than that seen when phenylephrine was used to increase arterial pressure. Compared with the cardiac response to pressor doses of phenylephrine, infusions of angiotensin were associated with a lesser degree of cardiac slowing and a lesser reduction in cardiac output. The effects of combined infusions of angiotensin and vasopressin on the cardiac baroreflex were studied. In five sheep which were infused with a pressor dose of angiotensin (1.1 microgram/min), the stimulatory effect of vasopressin (1.0 u./min) on pulse interval and its depressant effect on cardiac output were attenuated. In seven sheep infused with 0.5 u./min of vasopressin, I.V. infusion of angiotensin (0.2-5.0 micrograms), produced a progressive decrease in pulse interval and increase in cardiac output as the dose was increased. Therefore, angiotensin can offset the cardioinhibitory effects of vasopressin. Since cardiac sympathetic activity was blocked and neither drug has any direct chronotropic effect on the heart, it would appear that these interactions between the two drugs affect the cardiac vagus either at a peripheral or central level.
Publisher: S. Karger AG
Date: 1988
DOI: 10.1159/000242766
Abstract: Electrocortical (ECoG) and integrated electromyographic (EMG) activity was recorded in 6 chronically prepared fetal sheep (132–145 days). Recordings were made in fetuses prior to and during repeated vibroacoustic stimulation. In the undisturbed fetus, two patterns of ECoG activity were apparent high (HV) and low voltage (LV). The fetus responded to this broad spectrum stimulus during both LV and HV ECoG activity. In 18 of the 20 experiments, repeated stimulation was not associated with a change in the background ECoG activity. All fetuses responded at least once to the stimulus. Habituation of the EMG response was observed during both HV and LV ECoG activity. The rate of habituation was independent of the background ECoG activity and was unchanged when experiments were repeated at intervals of more than 3 days. These results show that fetal sheep also respond to vibroacoustic stimulation and with repetition habituation occurs.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.PLACENTA.2012.10.007
Abstract: This study aimed to determine the association of AGTR1 and AGTR2 polymorphisms with preecl sia and whether these are affected by environmental factors and fetal sex. Overall 3234 healthy nulliparous women, their partners and babies were recruited prospectively to the SCOPE study in Adelaide and Auckland. Data analyses were confined to 2121 Caucasian parent-infant trios, among whom 123 had preecl tic pregnancies. 1185 uncomplicated pregnancies served as controls. DNA was extracted from buffy coats and genotyped by utilizing the Sequenom MassARRAY system. Doppler sonography on the uterine arteries was performed at 20 weeks' gestation. Four polymorphisms in AGTR1 and AGTR2 genes, including AGTR1 A1166C, AGTR2 C4599A, AGTR2 A1675G and AGTR2 T1134C, were selected and significant associations were predominately observed for AGTR2 C4599A. When the cohort was stratified by maternal BMI, in women with BMI ≥ 25 kg/m(2), the AGTR2 C4599A AA genotype in mothers and neonates was associated with an increased risk for preecl sia compared with the CC genotype [adjusted OR 2.1 (95% CI 1.0-4.2) and adjusted OR 3.0 (95% CI 1.4-6.4), respectively]. In the same subset of women, paternal AGTR2 C4599A A allele was associated with an increased risk for preecl sia and uterine artery bilateral notching at 20 weeks' gestation compared with the C allele [adjusted OR 1.9 (95% CI 1.1-3.3) and adjusted OR 2.1 (95% CI 1.3-3.4), respectively]. AGTR2 C4599A in mothers, fathers and babies was associated with preecl sia and this association was only apparent in pregnancies in which the women had a BMI ≥ 25 kg/m(2), suggesting a gene-environment interaction.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2020
DOI: 10.1007/S00467-020-04554-Y
Abstract: We carried out a study to determine the impact of prematurity on kidney development in the first 2 years of life. In this prospective study, extremely preterm neonates (gestation 28 weeks) were recruited and underwent assessments at 6, 12, and 24 months of age. A cohort of neonates born term were also recruited and followed up for 24 months. The primary outcomes measured in this study were total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) albuminuria and blood pressure measurements (all provided as mean (standard deviation)) were the secondary outcomes. Fifty-three premature and 31 term neonates (control) were recruited. At the age of 24 months (corrected age), infants born preterm had significantly smaller TKV (56.1 (9.4) vs. 64.8 (10.2) mL P = 0.006). There was no difference in eGFR. These preterm infants were smaller (11.25 (1.53) vs. 12.9 (1.8) kg P = 0.002) and shorter (83.8 (3.0) vs. 86.3 (3.4) cm P = 0.02) when compared with the control group. At 6, 12, and 18 months respectively, preterm infants had, relative to their height, significantly smaller kidney volumes (0.54 (0.1) vs. 0.59 (0.1) mL/cm, P = 0.05 0.61 (0.1) vs.0.71 (0.1) mL/cm, P = 0.003 and 0.67 (0.1) vs.0.76 (0.1) mL/cm, P = 0.006). Relative to body length, TKV in premature infants is smaller. Since length reflects adult body proportions more accurately than BSA, TKV to height ratio may be a more important measure in the child. Despite smaller TKV (and therefore fewer nephrons), infants born prematurely achieve similar eGFRs in the first 24 months of life, probably due to single-nephron hyperfiltration.
Publisher: Elsevier
Date: 2000
Publisher: Springer Science and Business Media LLC
Date: 09-1987
DOI: 10.1203/00006450-198709000-00023
Abstract: In 10 chronically catheterized fetal sheep, the effects of 100 g of glucose infused (intravenous) to the pregnant ewe on lung liquid production and acid-base status were investigated. Maternal and fetal hyperglycemia occurred within 15 min of the infusion of glucose. There was a significant increase in fetal PCO2 from 41.67 +/- 1.00 to 46.89 +/- 1.83 mm Hg and a decrease in fetal arterial pH from 7.42 +/- 0.016 to 7.33 +/- 0.026 (n = 7). This acidosis was probably the result of fetal lactacidemia. There was also a decrease in fetal PO2 (p less than 0.001) following the infusion of glucose to the ewe. This, along with the acidosis, might account for the increased risk of unexplained fetal death in the diabetic pregnancy especially near term. Following the infusion of glucose to the ewe there was an increase in maternal plasma osmolality by 16 +/- 3.35 mosmol/kg (n = 9) and in fetal plasma osmolality by 14 +/- 2.64 mosmol/kg (n = 9 p less than 0.001). Fetal lung liquid production fell from 0.195 +/- 0.04 to 0.093 +/- 0.02 ml/min (n = 6 p less than 0.001). There was no change in the excretion of osmol by the lungs. The decreased lung liquid production was probably due to a decrease in the net movement of fluid across the pulmonary epithelium.
Publisher: Wiley
Date: 07-10-1999
DOI: 10.1046/J.1440-1681.1999.03127.X
Abstract: 1. To determine the importance of the kidneys in maintaining the normal volume and composition of foetal body fluids, measurements were made in 11 chronically catheterized foetuses (123-136 days) that had been bilaterally nephrectomized at least 5 days previously and compared with 10 intact foetuses (121-133 days). 2. The nephrectomized foetuses had reduced extracellular (ECV), blood, plasma and interstitial volumes per kg foetal weight (P < 0.005), reduced plasma chloride levels (P < 0.001) and were acidaemic, hypoxaemic and hypercapnaemic (P < 0.05) compared with intact foetuses. They also had reduced lung liquid production (P < 0.05) and reduced lung liquid sodium and osmolality levels (P < 0.05). Their arterial pressure was more variable between foetuses (P < 0.005) and was directly related to ECV/kg (P = 0.013). 3. To determine which of these changes were due to absence of the foetal renin-angiotensin system, seven chronically catheterized nephrectomized foetal sheep (124-132 days) were infused with replacement doses of angiotensin (Ang)II (1.5 micrograms/kg per h) for 3 days. Six nephrectomized foetuses were infused with 0.15 mol/L saline. 4. The AngII infusion was non-pressor. It prevented the fall in ECV that occurred in the control group (P < 0.05) and foetal plasma chloride concentration rose (P < 0.05). Blood gas status and lung liquid production rate did not change, but lung liquid sodium concentration fell (P < 0.05) and potassium concentration rose (P < 0.05). 5. Bolus injections of AngII (0.3-5 micrograms) were given to assess vascular sensitivity to AngII. This was not altered by either nephrectomy or AngII replacement. 6. It is concluded that the foetal kidneys are important for the maintenance of the normal volume and composition of foetal body fluids. Angiotensin II, perhaps because it promotes fluid transfer across the placenta, helps maintain foetal ECV and plasma chloride levels.
Publisher: Wiley
Date: 2001
DOI: 10.1111/J.1469-7793.2001.0253L.X
Abstract: While it is known that treatment with insulin-like growth factor I (IGF-I) stimulates growth of the fetal kidney, nothing is known about the short term or long term effects of IGF-I on fetal renal function. To investigate the acute effects of IGF-I on fetal renal function and on the activity of the fetal renin-angiotensin system, studies were carried out in 12 chronically catheterized fetal sheep aged 120 +/- 1 days, before and during a 4 h I.V. infusion of IGF-I at 80 ug h-1. Seven control fetuses were infused over the same period with vehicle (0.1% bovine serum albumin in 0.15 M saline). IGF-I infusion increased plasma IGF-I concentrations by about 80%. There was a small fall in arterial PO2 (P < 0.01), arterial PCO2 increased (P < 0.05), plasma lactate levels increased (P < 0.01) and arterial pH fell (P < 0.05). Fractional bicarbonate reabsorption increased and bicarbonate excretion decreased (P < 0.05). Infusions of IGF-I had no sustained effect on fetal arterial pressure. Glomerular filtration rate (GFR) did not change significantly during IGF-I infusion, but renal blood flow (RBF) fell (P < 0.05). Therefore filtration fraction relative to control values increased (P < 0.05), suggesting that efferent arteriolar vasoconstriction had occurred. IGF-I infusion led to an antidiuresis (P < 0.01), a rise in urinary osmolality (P < 0.05) and a fall in free water clearance (P < 0.01). Since fetal PO2 fell, it is probable that these effects were mediated by arginine vasopressin. The excretion rates of sodium, chloride and phosphate were all reduced by 4 h of infusion (P < 0.05), because their fractional reabsorption rates were all increased (sodium, P < 0.01 chloride, P < 0.01 and phosphate, P < 0.05). Plasma renin concentration increased by 275 +/- 52% during infusion of IGF-I (P < 0.005). Plasma renin activity also increased (P < 0.005), while circulating angiotensinogen concentrations fell (P < 0.05). In the adult, IGF-I increases both RBF and GFR, enhances tubular reabsorption and stimulates the renin-angiotensin system. In the fetus, however, it decreased RBF and had no effect on GFR, but was associated with enhanced tubular function and intense stimulation of renin secretion. Some of these effects of IGF-I on fetal renal function may be involved in maturation of the kidney in preparation for life after birth.
Publisher: Oxford University Press (OUP)
Date: 07-1970
DOI: 10.1093/CVR/4.3.312
Abstract: Intra-abdominal fibromatosis (IAF) is a benign mesenchymal lesion that can occur throughout the gastrointestinal tract. Although rare, it is the most common primary tumor of the mesentery and can develop at any age. We describe a rare case of primary IAF involving the mesentery and small bowel which clinically, macroscopically and histologically mimicked malignant gastrointestinal stromal tumor (GIST). This report highlights the fact that benign IAF can be misdiagnosed as a malignant GIST localized in the mesentery or arising from the intestinal wall. Their diagnostic discrimination is essential because of their very different biological behaviors and the fact that the introduction of effective therapies involving tyrosine kinase inhibitor STI571 (imatinib mesylate) has greatly changed the clinical approach to intra-abdominal stromal spindle cell tumors.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.PLACENTA.2012.05.001
Abstract: The renin-angiotensin system (RAS) is implicated in placentation. We determined which RAS pathways are present in two trophoblast cell lines (HTR-8/SVneo and BeWo cells) and the effects of cAMP, which stimulates renal renin. The effect of cAMP on RAS gene expression and on prorenin and angiotensin peptides in HTR-8/SVneo and BeWo cells were investigated. In HTR-8/SVneo cells, prorenin mRNA (REN) and protein, (pro)renin receptor (ATP6AP2) and angiotensin II type 1 receptor (AGTR1) were stimulated by cAMP (P < 0.05, P < 0.05, P < 0.001 and P < 0.05, respectively). HTR-8/SVneo cells also expressed angiotensinogen (AGT) and angiotensin converting enzyme 1 (ACE1), but did not express AGTR2 or ACE2 nor the Ang 1-7 receptor (MAS1). BeWo cells did not express REN, and REN was not inducible by cAMP, but cAMP increased ACE2 and MAS1 (both P < 0.05) and decreased AGT (P < 0.05). BeWo cells expressed AGT, ACE1, ACE2 and MAS1 but not ATP6AP2, AGTR1 nor AGTR2. There was net destruction of Ang II in media from HTR-8/SVneo and BeWo incubations and net production of Ang 1-7 by BeWo and untreated HTR-8/SVneo cells. HTR-8/SVneo cells express REN and produce prorenin as well as expressing other RAS genes likely to regulate Ang II/AT(1)R interactions and respond to cAMP, like renal renin-secreting cells. They are more similar to early gestation placentae and are therefore useful for studying effects of renin/ACE/Ang II/AT₁R on cell function. BeWo cells express the ACE2/Ang 1-7/Mas pathway, which is sensitive to cAMP and therefore are useful for studying the effects of ACE2/Ang 1-7/Mas on trophoblast function.
Publisher: Wiley
Date: 27-10-2013
Publisher: Elsevier
Date: 2000
Publisher: American Physiological Society
Date: 12-2021
DOI: 10.1152/AJPREGU.00211.2021
Abstract: Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound protein containing 805 amino acids. ACE2 shows approximately 42% sequence similarity to somatic ACE but has different biochemical activities. The key role of ACE2 is to catalyze the vasoconstrictor peptide angiotensin (ANG) II to Ang-(1–7), thus regulating the two major counterbalancing pathways of the renin-angiotensin system (RAS). In this way, ACE2 plays a protective role in end-organ damage by protecting tissues from the proinflammatory actions of ANG II. The circulating RAS is activated in normal pregnancy and is essential for maintaining fluid and electrolyte homeostasis and blood pressure. Renin-angiotensin systems are also found in the conceptus. In this review, we summarize the current knowledge on the regulation and function of circulating and uteroplacental ACE2 in uncomplicated and complicated pregnancies, including those affected by preecl sia and fetal growth restriction. Since ACE2 is the receptor for SARS-CoV-2, and COVID-19 in pregnancy is associated with more severe disease and increased risk of abnormal pregnancy outcomes, we also discuss the role of ACE2 in mediating some of these adverse consequences. We propose that dysregulation of ACE2 plays a critical role in the development of preecl sia, fetal growth restriction, and COVID-19-associated pregnancy pathologies and suggest that human recombinant soluble ACE2 could be a novel therapeutic to treat and/or prevent these pregnancy complications.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2013
DOI: 10.1038/JHH.2013.51
Abstract: There are fetal sex-specific differences in the balance between angiotensin (Ang) II and Ang-(1-7) in the maternal circulation during pregnancy. To determine whether at 15 weeks' gestation plasma levels of Ang II and Ang-(1-7), as well as levels of prorenin and Ang-converting enzyme (ACE), predicted the development of gestational hypertension (GH) or preecl sia (PreE) and were associated with estimates of fetal and maternal health, women who later developed GH (n=50) or PreE (n=50) were compared with body mass index-matched controls (n=100). Women who subsequently developed PreE or GH had increased Ang-(1-7) levels at 15 weeks' gestation compared with women with normal pregnancies. When separated by fetal sex, this difference was seen only in women carrying a female fetus. Prorenin and ACE concentrations were not useful biomarkers for the prediction of either PreE or GH at 15 weeks' gestation. Women with a male fetus who developed PreE and women who subsequently developed GH had increased blood pressures at 15 weeks' gestation compared with women with normal pregnancies, suggesting that these women were on an early trajectory for the development of hypertension. We propose that measurement of Ang-(1-7) during early gestation could be useful in predicting, those women who will go on to develop new-onset hypertension in pregnancy.
Publisher: Cambridge University Press (CUP)
Date: 15-04-2016
DOI: 10.1017/S204017441600009X
Abstract: Indigenous Australians have high rates of chronic diseases, the causes of which are complex and include social and environmental determinants. Early experiences in utero may also predispose to later-life disease development. The Gomeroi gaaynggal study was established to explore intrauterine origins of renal disease, diabetes and growth in order to inform the development of health programmes for Indigenous Australian women and children. Pregnant women are recruited from antenatal clinics in Tamworth, Newcastle and Walgett, New South Wales, Australia, by Indigenous research assistants. Measures are collected at three time points in pregnancy and from women and their children at up to eight time points in the child’s first 5 years. Measures of fetal renal development and function include ultrasound and biochemical biomarkers. Dietary intake, infant feeding and anthropometric measurements are collected. Standardized procedures and validated tools are used where available. Since 2010 the study has recruited over 230 women, and retained 66 postpartum. Recruitment is ongoing, and Gomeroi gaaynggal is currently the largest Indigenous pregnancy-through-early-childhood cohort internationally. Baseline median gestational age was 39.1 weeks (31.5–43.2, n =110), median birth weight was 3180 g (910–5430 g, n =110). Over one third (39.3%) of infants were admitted to special care or neonatal nursery. Nearly half of mothers (47.5%) reported tobacco smoking during pregnancy. Results of the study will contribute to knowledge about origins of chronic disease in Indigenous Australians and nutrition and growth of women and their offspring during pregnancy and postpartum. Study strengths include employment and capacity-building of Indigenous staff and the complementary ArtsHealth programme.
Publisher: SAGE Publications
Date: 03-10-2012
DOI: 10.5301/JN.5000220
Abstract: Low birth weight (LBW), defined as birth weight below 2,500 g, is an important risk factor for the development of hypertension and renal disease in adult life. LBW is associated with a reduced nephron number, which results in hyperfiltration. The objective of this study was to compare the glomerular filtration rates (GFRs) of LBW and normal-birth-weight (NBW) term infants relative to their kidney volumes. Term infants (born after 37 weeks of gestation) who had been admitted to Townsville Hospital's neonatal unit were recruited for this study. Serum cystatin C was used to calculate gfr. a kidney ultrasound was used to measure renal volume. all assessments were performed during the first week of life. Data from 39 infants (17 male, 22 female 13 LBW, 26 NBW) were analyzed. There were no significant differences in the median cystatin C (1.36 mg/L, inter quartile range [IQR] = 1.12 - 1.41, vs. 1.17 mg/L, IQR = 1.10 - 1.39 p = 0.39) and gestational age. There was no significant difference in the median GFR (53.0 ml/min per 1.73 m2, IQR = 50.8-66.9, vs. 63.2 ml/min per m2, IQR = 51.8-69.5 p = 0.39) between LBW and NBW infants, but LBW infants had smaller total renal volume compared with NBW infants (18.0 ± 4.7 mL vs. 24.4 ± 6.2 mL p = 0.002). Within 6 days, LBW infants achieved a similar GFR to NBW infants, despite 25% smaller kidney volumes. Thus, the single-nephron glomerular filtration rate must be increased in LBW infants. Prior to this study, it was unclear when hyperfiltration begins, but our results demonstrate that hyperfiltration begins in early life.
Publisher: CSIRO Publishing
Date: 1998
DOI: 10.1071/RD98063
Abstract: The aim of the study was to determine the amount of angiotensinogen expression and its protein product in fetal sheep liver and kidney in the last third of gestation. Angiotensinogen mRNA was measured by RNase protection assay and its protein levels were measured by radioimmunoassay. Levels were measured at 80, 95, 111, 125 and 139 days. Angiotensinogen mRNA was present in all fetal liver and kidney s les tested. The ratio of hepatic angiotensinogen mRNA/18 S rRNA increased by 100% (P .001) and angiotensinogen levels increased by 33% (P .001) in fetal sheep from 80 to 139 d. Over the same period the ratio of renal angiotensinogen mRNA/18 S rRNA increased by 170% (P .001) and renal angiotensinogen protein increased by 41% (P .001). The levels of angiotensinogen mRNA and its protein in the adult kidney were less than in kidneys of 139 d old fetuses (P .01). There was a direct relationship between levels of angiotensinogen mRNA and its protein in the liver (r = 0.53, P .01, n = 25) and in the kidney (r = 0.75, P .0001, n = 24). These findings demonstrate that there is a significant increase in both hepatic and renal angiotensinogen gene expression in the last third of gestation in the fetal sheep and that this increase is associated with an increase of angiotensinogen levels in both tissues. This increase in angiotensinogen in late gestation could influence the activity of both the intrarenal and circulating renin angiotensin systems.
Publisher: Frontiers Media SA
Date: 22-05-2020
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.PLACENTA.2017.03.007
Abstract: Tissue renin-angiotensin systems (RASs) are involved in tissue growth and development as they are important regulators of angiogenesis, cell proliferation and migration. The placental RAS is most highly expressed in early gestation, at a time when the oxygen tension within the conceptus is reduced, and plays a key role in placental growth and development. Similar to the placenta, tumour development relies on proliferation, angiogenesis and invasion in order to grow and metastasize. The RAS is known to be upregulated in a variety of solid tumours, including ovarian, endometrial, cervical, breast and prostate. This review explores the roles of oxygen and microRNAs in regulating the normal expression of the placental RAS, providing insight into regulation of its development as well as the development of disease states in which the RAS is overexpressed. We propose that the placental RAS is downregulated by microRNAs that are suppressed during the physiologically normal 'hypoxic' phase of early placentation. Suppression of these miRNAs allows the placental RAS to stimulate placental growth and angiogenesis. We propose that similar mechanisms may be at play in solid tumours, which are characterised by hypoxia.
Publisher: Wiley
Date: 12-1987
DOI: 10.1113/JPHYSIOL.1987.SP016834
Abstract: 1. In eleven chronically catheterized fetal sheep aged 124-142 days, hypotension caused by infusion of sodium nitroprusside (1.6-3.3 mg/h) and competitive antagonism of angiotensin II by saralasin (3.3 mg/h) both caused a fall in fetal urine flow (P less than 0.02 and P less than 0.05, respectively), and in sodium excretion (P less than 0.05 and P less than 0.01) because they both caused a fall in glomerular filtration rate (G.F.R., P less than 0.02 and P less than 0.01). Neither hypotension nor saralasin had any significant effect on fractional sodium reabsorption. Saralasin only caused a significant fall in systolic pressure (P = 0.05) while infusion of sodium nitroprusside caused a fall in both systolic and diastolic pressure (P less than 0.005 and P less than 0.02). 2. Frusemide (6 mg I.V) caused a marked natriuresis and diuresis (F = 24.9, P less than 0.005 and F = 30.5, P less than 0.005). This effect was maximal within 30 min. There was no change in fetal G.F.R. and there was a significant decrease in the fraction of the filtered sodium load that was reabsorbed (F = 10.44, P less than 0.0025). Fetal mean plasma renin activity (p.r.a.) rose progressively throughout (F = 9.3, P less than 0.005). When frusemide was given to fetal sheep which were hypotensive because they were infused with sodium nitroprusside, it still caused a diuresis (F = 5.73, P less than 0.025) and the fraction of the filtered sodium load that was reabsorbed decreased (F = 4.06, P less than 0.05) to a similar extent to that seen in animals given frusemide alone. On the other hand, frusemide was ineffective as a diuretic i.e. it had no effect on fractional sodium reabsorption, when given to fetal sheep which were infused with saralasin. 3. Injection of frusemide was associated with a significant rise in the diastolic pressures of hypotensive fetuses (P less than 0.05). Furthermore, when the infusion of saralasin was terminated 1.5 h after frusemide injection, blood pressure rose significantly (F = 11.19, P less than 0.0005 for systolic pressure and F = 7.15, P less than 0.005 for diastolic pressure) and p.r.a. fell (F = 4.78, P less than 0.025). 4. It is concluded that the fetal renin-angiotensin system can play a significant role in regulation of fetal blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: CSIRO Publishing
Date: 1995
DOI: 10.1071/RD9950415
Abstract: This review concentrated mainly on studies of intrauterine renal function carried out in chronically-catheterized fetal sheep. In sheep, as in primates, nephrogenesis is complete before birth. Studies in the rat and neonatal puppy provide insight into the functional development of the kidney, because these species are immature at birth and there is considerable postnatal renal development. Studies of the ovine fetus provide insight into the physiological role(s) of the kidneys during intrauterine life, albeit modified by changes related to maturation.
Publisher: S. Karger AG
Date: 1998
DOI: 10.1159/000013984
Abstract: To determine the effects of circulating noradrenaline on fetal renal function noradrenaline was infused intravenously into 7 chronically catheterised fetal sheep (127–138 days) at a dose (1 µg/kg/min) which resulted in plasma levels similar to those which occur during hypoxia. Fetal mean arterial pressure increased by approximately 14 mm Hg (p 0.001) and haematocrit rose (p 0.005). Glomerular filtration rate rose from 3.85 ± 0.47 (SEM) to 4.70 ± 0.50 ml/min (p 0.05) during the first hour and fractional reabsorption of sodium by the proximal tubule fell (p 0.05) during the second hour. Urine flow rate increased from 0.61 ± 0.13 to 1.18 ± 0.24 ml/min (p 0.001) and osmolar excretion increased from 78 ± 15 to 153 ± 36 µosm/min (p 0.005). By contrast lung liquid flow fell (p 0.05), but the increase in urine flow was much greater than the decline in lung liquid. These findings suggest that during hypoxia, noradrenaline may play an important role in the maintenance of urine flow and consequently amniotic fluid volume and, as suggested by others, in the distribution of fluid between the vascular and interstitial compartments.
Publisher: CSIRO Publishing
Date: 1995
DOI: 10.1071/RD9951321
Abstract: To find out if the gestation-dependent increase in fetal oncotic pressure is responsible for the gestation-dependent increase in the capacity of the fetal proximal tubule to reabsorb sodium, the effects on renal function of increases in oncotic pressure were studied in 8 volume-expanded chronically catheterized fetal sheep aged 128 +/- 3 (s.e.) days. Fetal extracellular volume was expanded by infusion of 65 +/- 10.8 (s.e.) mliter kg-1 estimated body weight of 0-15 M saline. This caused a decrease in fetal plasma protein concentrations (P 0.01) fetal oncotic pressure decreased (P 0.05). A diuresis and natriuresis occurred, which was due not to an increase in glomerular filtration rate but to a decrease in the fraction of the filtered sodium load reabsorbed by the proximal tubule (P 0.05) and a decrease in the fraction of distally delivered sodium reabsorbed (P 0.01). Fetal plasma protein concentrations were then increased to greater than control levels (P 0.01) by infusion of maternal plasma (28 +/- 1.6 mliter kg-1) oncotic pressure was greater than after saline expansion (P 0.05) and similar to control. The fraction of the filtered sodium load reabsorbed by the proximal tubule remained depressed (P 0.01) relative to control, as did the fraction of distally delivered sodium that was reabsorbed (P 0.01). Thus the natriuresis and diuresis continued. There was, however, a small effect of oncotic pressure on proximal fractional sodium reabsorption that was unmasked by multiple regression analysis. Obviously, this effect was not sufficient to override other effects of volume expansion on fetal proximal tubular function. Therefore, the reduction in fetal proximal fractional sodium reabsorption in volume expansion was not due solely to a fall in fetal oncotic pressure. Furthermore, since infusion of maternal plasma caused a rise in fetal plasma protein concentrations that was similar to the increase that would occur between 128 and 148 days gestation, it is unlikely that any gestation-dependent increase in proximal fractional sodium reabsorption is due solely to the increase in fetal plasma protein concentrations and hence oncotic pressure.
Publisher: Oxford University Press (OUP)
Date: 23-04-2013
Publisher: Wiley
Date: 04-2002
DOI: 10.1113/JPHYSIOL.2001.013448
Abstract: Amino acid infusions increase renal blood flow (RBF) and glomerular filtration rate (GFR) and stimulate tubular reabsorption in adults. To characterize the effects of amino acids on fetal renal haemodynamics, tubular sodium reabsorption, acid-base homeostasis and plasma renin levels, 11 chronically catheterized fetal sheep aged 121 +/- 1 days (term ~150 days) were infused I.V. for 4 h with alanine, glycine, proline and serine (0.1, 0.1, 0.06 and 0.06 mmol min(-1), respectively) in 0.15 M saline at 0.165 ml min(-1). Eight control fetuses were given saline. During amino acid infusion, plasma amino acid levels increased up to 20-fold (P < 0.005). GFR increased by 50 +/- 8 % (P < 0.001) there was only a small transient increase in RBF. Proximal fractional sodium reabsorption fell from 74.6 +/- 2.9 to 55.5 +/- 5.4 % (P < 0.005). Distal sodium delivery increased, but a smaller percentage of this distal sodium load was reabsorbed (P < 0.005). Thus fractional sodium reabsorption fell from 95.5 +/- 0.9 to 81.4 +/- 2.0 % (P < 0.005). There was a large diuresis, natriuresis, kaliuresis and increase in osmolar excretion (P < 0.005). Plasma sodium and chloride concentrations fell (P < 0.005). Plasma osmolality did not change. Plasma renin levels fell (P < 0.05), cortisol levels increased (P < 0.05), and there was a compensated metabolic acidosis. Thus the fetal sheep kidney demonstrated a remarkable functional capacity to respond to amino acid infusion. The increase in filtration fraction and the lack of an increase in RBF suggest that efferent arteriolar vasoconstriction occurred, a very different response from the renal vasodilatation seen in adult animals.
Publisher: Elsevier BV
Date: 10-2000
DOI: 10.1016/S0014-2999(00)00698-1
Abstract: The renin angiotensin system is important in the regulation of fetal blood pressure. This study investigated the expression of angiotensin AT(1) and AT(2) receptors in the ovine fetal heart, aorta and umbilical artery, and how these receptors are affected by cortisol. Cortisol infusion into the fetus has previously been shown to cause an increase in fetal blood pressure. We hypothesised that this effect of cortisol is mediated by upregulation of the angiotensin AT(1) receptor. Binding studies performed on tissues with intact endothelium demonstrated both receptor subtypes in the fetal aorta and right ventricle, although the latter contained mainly angiotensin AT(2) receptors. In contrast, only angiotensin AT(1) receptors were found in the umbilical artery. Cortisol infusion into fetuses (3 mg/day for 3-5 days) caused a physiological increase in plasma cortisol levels to 29+/-4 nM. This was associated with an increase in systolic pressure (57.8+/-1.7 vs. 52.2+/-1.5 mm Hg, P<0.05), but cortisol had no effect on the density or affinity of angiotensin receptors, nor on the in vitro contractile responses of carotid and umbilical arterial rings to 5-microM angiotensin II. In conclusion, this study has demonstrated differential expression of angiotensin AT(1) and AT(2) receptors in the different regions of the ovine fetal cardiovascular system and that the angiotensin AT(1) receptor is functional. The lack of any effect of low doses of cortisol on these receptors and on the contractility of isolated fetal vessels to angiotensin II suggests cortisol acts by other mechanisms to raise fetal arterial pressure.
Publisher: Wiley
Date: 11-2003
Publisher: Wiley
Date: 13-01-2022
DOI: 10.1002/PRP2.911
Abstract: Infection of humans with SARS‐CoV‐2 virus causes a disease known colloquially as “COVID‐19” with symptoms ranging from asymptomatic to severe pneumonia. Initial pathology is due to the virus binding to the ACE‐2 protein on endothelial cells lining blood vessels and entering these cells in order to replicate. Viral replication causes oxidative stress due to elevated levels of reactive oxygen species. Many (~60%) of the infected people appear to have eliminated the virus from their body after 28 days and resume normal activity. However, a significant proportion (~40%) experience a variety of symptoms (loss of smell and/or taste, fatigue, cough, aching pain, “brain fog,” insomnia, shortness of breath, and tachycardia) after 12 weeks and are diagnosed with a syndrome named “LONG COVID.” Longitudinal clinical studies in a group of subjects who were infected with SARS‐CoV‐2 have been compared to a non‐infected matched group of subjects. A cohort of infected subjects can be identified by a battery of cytokine markers to have persistent, low level grade of inflammation and often self‐report two or more troubling symptoms. There is no drug that will relieve their symptoms effectively. It is hypothesized that drugs that activate the intracellular transcription factor, nuclear factor erythroid‐derived 2‐like 2 (NRF2) may increase the expression of enzymes to synthesize the intracellular antioxidant, glutathione that will quench free radicals causing oxidative stress. The hormone melatonin has been identified as an activator of NRF2 and a relatively safe chemical for most people to ingest chronically. Thus, it is an option for consideration of re‐purposing studies in “LONG COVID” subjects experiencing insomnia, depression, fatigue, and “brain fog” but not tachycardia. Appropriately designed clinical trials are required to evaluate melatonin.
Publisher: Elsevier BV
Date: 09-2017
Publisher: Wiley
Date: 19-03-2014
DOI: 10.1111/JPC.12528
Publisher: Elsevier BV
Date: 07-2011
Publisher: Elsevier BV
Date: 07-1997
DOI: 10.1016/S0014-2999(97)00167-2
Abstract: This study was undertaken to determine if changes in receptor density or affinity could account for the reduced vascular sensitivity to angiotensin II seen during pregnancy. Angiotensin receptor subtypes in the uterine arteries of non-pregnant, pregnant and postpartum ewes were investigated using saturation and competition receptor binding techniques with the specific receptor antagonists, losartan (DuP-753) and PD-123319 (S)1-[[4-(dimethylamino)-3-methylphenyl]-methyl]-5-(diphenylacetyl )-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid, ditrifluoroacetate, monohydrate). Receptor density and affinity of total angiotensin receptors, as well as the angiotensin AT1 and AT2 receptor subtypes in uterine arteries were compared with those in the mesenteric artery and aorta. The uterine artery contains both AT1 and AT2 receptor subtypes, whereas the mesenteric artery and aorta contain primarily the AT1 receptor subtype. In uterine arteries from pregnant sheep, angiotensin receptor density was increased because AT2 receptors were increased. AT1 receptor density was not altered. This change was not seen in the aorta. In the uterine artery, receptor affinity for [Sar1,Ile8]angiotensin II decreased in mid-gestation (IC50 7.7 +/- 1.2 x 10(-9) M) compared with non-pregnant ewes (IC50 3.0 +/- 0.6 x 10(-9) M, P = 0.006), and there was decreased affinity of angiotensin AT1 receptors for losartan during pregnancy (IC50 2.8 +/- 1.0 x 10(-4) M) compared with non-pregnant ewes (IC50 2.2 +/- 1.3 x 10(-6) M, P = 0.025). Our results show changes in the density and affinity of the angiotensin receptor subtypes in the uterine artery which could explain its reduced responsiveness to circulating angiotensin II during pregnancy.
Publisher: Oxford University Press (OUP)
Date: 14-03-2019
Abstract: In early gestation, the human placental renin-angiotensin system (RAS) is upregulated and plays a role in placental development. Among other functions, signalling through the angiotensin II type 1 receptor (AT1R) initiates proliferation. Many microRNAs (miRNAs) targeting placental RAS mRNAs are downregulated at this time. We propose that in early gestation miRNAs that target the placental RAS are downregulated, allowing for the increased RAS expression and proliferation required for adequate placentation. HTR-8/SVneo cells (an immortalized human trophoblast cell line) were used to assess the effect of nine miRNA mimics (at 0.08, 0.16, 0.32 and 0.64 ng/μL) on trophoblast cell proliferation and predicted RAS target mRNAs. The effect of the miRNA mimics on the rate of cell proliferation was assessed using the xCELLigence real-time cell analysis system over 48 h. Levels of miRNAs and predicted RAS target mRNAs were determined by RT-PCR (qPCR, n = 9/group). Statistically different levels of expression were determined (P < 0.05). All nine miRNA mimics significantly affected the proliferation rates of HTR-8/SVneo cells. Five of the miRNA mimics (miR-181a-5p (predicted to target: renin (REN), angiotensin converting enzyme (ACE)), miR-378 (REN, ACE), miR-663 (REN), miR-483-3p (ACE, ACE2, angiotensinogen (AGT), angiotensin II type 1 receptor (AGTR1)) and miR-514 (AGT)) were associated with a dose-dependent reduction in cell proliferation. Seven of the mimics significantly decreased expression of at least one of their predicted target RAS mRNAs. Our study shows that miRNAs targeting placental RAS mRNAs play a role in controlling trophoblast proliferation. As placentation is largely a process of proliferation, changes in expression of these miRNAs may be partly responsible for the expression of the placental RAS, proliferation and placentation.
Publisher: Elsevier BV
Date: 06-1968
DOI: 10.1016/0002-9378(68)90564-4
Abstract: [This corrects the article DOI: 10.1371/journal.pone.0170941.].
Publisher: Wiley
Date: 15-06-1995
DOI: 10.1113/JPHYSIOL.1995.SP020773
Abstract: 1. To determine the extracellular volume (ECV) in fetal sheep and its distribution between the plasma and interstitial spaces, ECV, blood volume (BV) and haematocrit were measured in ten chronically catheterized fetal sheep aged 121-133 days. Relationships with age, weight and other fetal variables, including glomerular filtration rate (GFR), were studied. 2. ECV was measured as the mean of the volumes of distribution of [3H]inulin and [14C]mannitol extrapolated to time zero. The time zero volume of distribution was 1506 +/- 79 ml (means +/- S.E.M.) for inulin and 1590 +/- 80 ml for mannitol. The ECV was 1548 +/- 79 ml (632 +/- 18 ml (kg fetal wt)-1). BV, measured using 51Cr-labelled red cells, was 351 +/- 27 ml (141 +/- 6 ml kg-1). Haematocrit, plasma volume and interstitial volume were 34 +/- 1%, 229 +/- 17 ml (92 +/- 3 ml kg-1) and 1319 +/- 63 ml (540 +/- 17 ml kg-1), respectively. 3. Interstitial volume per kilogram fell with increasing fetal weight (P = 0.026). BV per kilogram did not change with weight or age. 4. The plasma: interstitial volume ratio was 0.17 +/- 0.01. This ratio increased as fetal weight and age increased (P = 0.026 and P = 0.044), that is, the proportion of ECV that was contained outside the vascular compartment was lower in heavier or older fetuses. 5. Since GFR was 3.4 +/- 0.4 ml min-1, the entire fetal ECV was filtered by the fetal kidney only 3.1 +/- 0.3 times per day.
Publisher: Wiley
Date: 21-04-2017
Abstract: Preterm birth (PTB) is the single largest cause of death in infants and young children. The rate of PTB is significantly higher in male infants, particularly those that are born very preterm. Here we present evidence to suggest that the decidual renin-angiotensin system may play a role in inhibiting inflammation and maintaining the integrity of the fetal membranes during pregnancy, and that sex-specific alterations in the intrauterine RAS could contribute to the increased risk of PTB in male babies. Women carrying female fetuses have high levels of expression of decidual prorenin at term. Decidua from 'female' pregnancies also have greater expression of the anti-inflammatory angiotensin (Ang)-(1-7) pathway, than decidua from 'male' pregnancies, and have lower levels of the pro-inflammatory Ang II pathway. We propose that in 'female' pregnancies, the very high levels of decidual prorenin drive the anti-inflammatory Ang-(1-7) pathway, thus reducing the likelihood of PTB. In addition, the high levels of prorenin produced by the decidua in 'female' pregnancies are able to diffuse into the amnion and bind to the PRR. We postulate that PRR rorenin interactions, possibly through both angiotensin dependent and independent pathways, stimulate the production of ECM proteins, inhibit ECM degradation and prevent apoptosis, thus strengthening the amnion. Thus control of the inflammatory signature and the integrity of the fetal membranes prior to parturition may partly depend on the sexually determined activity of the decidual and amniotic renin-angiotensin system pathways.
Publisher: Elsevier BV
Date: 09-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1980
Abstract: Intravenous infusions of angiotensin II were given to conscious sheep. During these infusions, the pressor action of angiotensin was antagonized by concomitant infusion of sodium nitroprusside. Under these conditions, angiotensin produced a dose-dependent tachycardia. This dose-dependent tachycardia was not affected by propranolol and therefore it was not due to an action of angiotensin on sympathoadrenal mechanisms. The dose-dependent tachycardia was reduced by atropine, and abolished by increases in systolic pressure. We conclude that iv infusions of angiotensin cause a central, dose-dependent reduction in vagal tone. This action is normally antagonized by the baroreceptor reflex response to the hypertensive action of angiotensin. Therefore, in those conditions in which endogenous angiotensin production is increased and blood pressure is not elevated (e.g., sodium deficiency and pregnancy), angiotensin may influence heart rate.
Publisher: Springer Science and Business Media LLC
Date: 11-2011
DOI: 10.1038/PR.2011.482
Publisher: Wiley
Date: 02-2022
DOI: 10.1002/PRP2.917
Abstract: SARS‐CoV‐2 interacting with its receptor, angiotensin‐converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS‐CoV‐2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole‐body response to maintain tissue perfusion. Tissue and circulating renin‐angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT 1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang‐(1‐7) by the enzyme ACE2. Ang‐(1‐7) has effects that are contrary to Ang II‐AT 1 R mediated effects. Thus, destruction of ACE2 by SARS‐CoV‐2 results in loss of control of the pro‐inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS‐CoV‐2 that is responsible for the pathogenesis of COVID‐19.
Publisher: Wiley
Date: 09-1981
DOI: 10.1111/J.1440-1681.1981.TB00762.X
Abstract: 1. In anaesthetized mongrel dogs it was shown that intravertebral infusions of angiotensin II (2-4 ng/kg per min) increased mean arterial pressure by causing an increase in cardiac output, while infusions of 10 ng/kg per min increased mean arterial pressure through an effect on peripheral resistance. After intravenous clonidine, intravertebral angiotensin no longer had any stimulatory effect on cardiac output, but arterial pressure still increased to the same extent. 2. It is concluded that intravertebral angiotensin can increase arterial pressure by increasing either cardiac output or peripheral resistance. The effects of intravertebral angiotensin on cardiac output can be reduced by concomitant stimulation of baroreflex pathways but its effects on peripheral resistance are not so readily antagonized.
Publisher: American Physiological Society
Date: 04-1994
DOI: 10.1152/AJPREGU.1994.266.4.R1353
Abstract: Active and total (acid-activated) levels of a reninlike enzyme (hereafter called renin) were measured in plasma, tissues, and yolk sac fluid of pregnant and postpartum wallabies. Plasma active renin generated angiotensin I (ANG I) from sheep angiotensinogen at 14 +/- 1.3 (SE) ng.ml-1.h-1, whereas acid-activated renin generated ANG I at 33.3 +/- 2.5 ng.ml-1.h-1, i.e., 44.2 +/- 3.7% of renin in plasma was active, and 58 +/- 3.7% was inactive. Inactive renin levels were highest in pregnant animals (P = 0.05). Uterine renin was mainly inactive (95%) levels were 5.1 +/- 1.1 times plasma levels. The levels of renin in nonpregnant uteri were the same as those in pregnant uteri from the same animals. Uterine renin levels did not change with gestation. Pooled acid-activated yolk sac fluid generated ANG I at low rates (0.7 and 1.6 ng.ml-1.h-1) the acid-activated supernatant of a homogenate of pooled fetal membranes generated ANG I at 15 ng.g wet wt-1.h-1. Yolk sac fluid was strikingly different in electrolyte composition from maternal plasma. Its lower osmolality suggests that the membranes separating it from maternal plasma have a low permeability to water. Thus, although eutherian and marsupial mammals erged 136-164 million years ago, the wallaby, like many eutherian mammals, has inactive renin in blood, in the female reproductive tract, and in fetal membranes.
Publisher: Elsevier BV
Date: 12-1981
DOI: 10.1016/0034-5687(81)90126-2
Abstract: The effects of a pressor dose of angiotensin II on the respiratory pattern of chloralose anaesthetized mongrel dogs was studied. In addition, since the hypertensive action of angiotensin II stimulates baroreflex pathways, the effects on breathing of baroreceptor stimulation were examined using aortic balloon inflation and i.v. phenylephrine. In the baroreceptor-denervated dog, i.v. angiotensin II was associated with a reduction in both inspiratory and expiratory time while both inspiration and expiration proceeded more quickly. Thus breathing became deeper and more rapid. Most of these effects of angiotensin II were opposite to the effects of hypertension caused by phenylephrine and aortic balloon inflation. These two forms of hypertension caused an increase in inspiratory and expiratory time, a decrease in the rate at which inspiration proceeded and a fall in tidal volume. These effects were not seen in baroreceptor denervated animals. In the intact dog angiotensin II caused a marked vagal dependent fall in tidal volume and inspiratory time while the rates at which inspiration and expiration proceeded were unaffected. It is concluded that angiotensin II has three independent effects on respiration. These are a respiratory depressant effect due to stimulation of baroreflex pathways by its pressor action, a 'central' stimulatory effect and an effect on the vagal control of inspiratory time.
Publisher: BMJ
Date: 12-1972
Abstract: This study was to investigate the effect of soyabean isoflavones (SIF) on onset of puberty, serum hormone concentration, and gene expression in hypothalamus, pituitary and ovary of female Bama miniature pigs. Fifty five, 35-days old pigs were randomly assigned into 5 treatment groups consisting of 11 pigs per treatment. Results showed that dietary supplementation of varying dosage (0, 250, 500, and 1,250 mg/kg) of SIF induced puberty delay of the pigs with the age of puberty of pigs fed basal diet supplemented with 1,250 mg/kg SIF was significantly higher (p<0.05) compared to control. Supplementation of SIF or estradiol valerate (EV) reduced (p<0.05) serum gonadotrophin releasing hormone and luteinizing hormone concentration, but increased follicle-stimulating hormone concentration in pigs at 4 months of age. The expression of KiSS-1 metastasis-suppressor (KISS1), steroidogenic acute regulatory protein (StAR) and 3-beta-hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase (3β-HSD) was reduced (p<0.01) in SIF-supplemented groups. Expression of gonadotropin-releasing hormone receptor in the pituitary of miniature pigs was reduced (p<0.05) compared to the control when exposed to 250, 1,250 mg/kg SIF and EV. Pigs on 250 mg/kg SIF and EV also showed reduced (p<0.05) expression of cytochrome P450 19A1 compared to the control. Our results indicated that dietary supplementation of SIF induced puberty delay, which may be due to down-regulation of key genes that play vital roles in the synthesis of steroid hormones.
Publisher: S. Karger AG
Date: 1977
DOI: 10.1159/000240953
Abstract: High levels of angiotensin II were found in umbilical venous blood of babies delivered vaginally (40.3 pg·ml sup –– /sup sup /sup ) and vaginally with epidural anaesthesia (66.8 pg·ml sup ––1 /sup ) low levels of angiotensin II were found in umbilical venous blood of babies delivered by Caesarian section (7.5pg·ml sup ––1 /sup ) and in the peripheral blood of normal adults (7.92 pg·ml sup ––1 /sup ). There were no significant differences between these groups in the levels of plasma renin activity (PRA), although the mean values of PRA showed trends similar to those described for angiotensin II. It is suggested that the increase in PRA may account, in part, for the high levels in angiotensin II seen following vaginal delivery, but additional factors may also be involved.
Publisher: Oxford University Press (OUP)
Date: 25-04-2019
DOI: 10.1016/J.ESXM.2019.03.003
Abstract: Women’s choices for a sexual partner are influenced by numerous personal, cultural, social, political and religious factors, and may also include aspects of penile anatomy such as male circumcision (MC) status. To perform a systematic review examining (i) whether MC status influences women’s preference for sexual activity and the reasons for this, and (ii) whether women prefer MC for their sons. PRISMA-compliant searches were conducted of PubMed, Google Scholar, Embase, and the Cochrane Database of Systematic Reviews. Articles that met the inclusion criteria were rated for quality using the SIGN system. Database searches identified 29 publications with original data for inclusion, including 22 for aim (i) and 4 of these and 7 others pertaining to aim (ii). In the overwhelming majority of studies, women expressed a preference for the circumcised penis. The main reasons given for this preference were better appearance, better hygiene, reduced risk of infection, and enhanced sexual activity, including vaginal intercourse, manual stimulation, and fellatio. In studies that assessed mothers’ preference for MC of sons, health, disease prevention, and hygiene were cited as major reasons for this preference. Cultural differences in preference were evident among some of the studies examined. Nevertheless, a preference for a circumcised penis was seen in most populations regardless of the frequency of MC in the study setting. Women’s preferences generally favor the circumcised penis for sexual activity, hygiene, and lower risk of infection. The findings add to the already well-established health benefits favoring MC and provide important sociosexual information on an issue of widespread interest.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Wiley
Date: 10-1983
DOI: 10.1113/JPHYSIOL.1983.SP014902
Abstract: In six pregnant ewes a reduction in transplacental water transfer was produced by increasing maternal osmolality (by infusion of 180 g of mannitol in 500 ml of 0.15 M-sodium chloride) and the fetal renal responses to this reduction in water transfer were studied. These responses were compared with the renal responses of five other chronically catheterized fetal lambs whose mothers received I.V. infusions of 500 ml of 0.15 M-sodium chloride. Intravenous infusion of 500 ml of 0.15 M-sodium chloride to the ewe produced no changes in fetal plasma sodium, potassium or plasma renin activity and had no effect on fetal renal function. After I.V. infusion of mannitol to the ewe, fetal urinary flow rate fell from control levels of 0.69 +/- 0.12 ml/min to 0.32 +/- 0.04 ml/min (S.E. of mean, P less than 0.006). This fall in urinary flow rate was due to increased water reabsorption because there was no change in glomerular filtration rate and osmolar clearance. Fetal urinary sodium excretion increased from 16.2 +/- 2.0 mumol/min, to 34.2 +/- 6.9 mumol/min (S.E. of mean, P less than 0.04). This increase in fetal urinary sodium excretion was due to a fall in the fractional reabsorption of sodium which was related to this rise in fetal plasma sodium levels that occurred following infusion of mannitol to the ewe. The increases in fetal plasma sodium levels were also associated with reductions in fetal plasma renin activity.
Publisher: Wiley
Date: 07-1985
DOI: 10.1113/JPHYSIOL.1985.SP015745
Abstract: If fetal drinking activity is prevented and it is assumed that in the latter third of gestation the fetus is capable of maintaining itself in fluid balance, then the net amount of fluid gained across the placenta by the fetus is equal to the amount of fluid lost from the fetus, by routes other than the placenta, plus fluid deposited in growing tissues minus the amount of water produced as a result of oxidative metabolism. Net transplacental transfer of fluid to the fetus over a 3 h period was measured in eight chronically catheterized fetal sheep in which drinking activity was prevented by ligating the oesophagus. Urine and lung liquid flow rates were measured. In the latter third of gestation, these are the only significant sources of fluid loss from these fetuses during the 3 h experimental period. Water produced as a result of oxidative metabolism was calculated, as was the amount of fluid deposited in growing tissues during the course of the experiment. The weight of the fetus at the beginning of the experiment and the change in weight that occurred during the experiment was calculated by measuring the weight of the fetus at death (within 30 h) and applying an equation which describes the body weight-gestation age relationship for merino sheep. Net transplacental fluid transfer was 0.40 +/- 0.09 ml min-1 kg-1 (range 0.30-0.54 ml min-1 kg-1). Fetal urine flow rate averaged 0.30 +/- 0.11 ml min-1 kg-1. It was 72.8 +/- 10.0% of the volumes used to calculate net transplacental fluid transfer to the fetus. Lung liquid flow rate was 0.079 +/- 0.039 ml min-1 kg-1. It was 20.2 +/- 9.2% of the volumes used to calculate net fluid intake. The amount of fluid deposited as a result of tissue growth was 0.023 +/- 0.001 ml min-1 kg-1 it was 5.94 +/- 1.1% of the volumes used in the equation, while the production of water as a result of metabolism was 3.9 X 10(-3) ml min-1 kg-1 (Conrad & Faber, 1977) and constituted 1.01 +/- 0.22% of the volumes used in the equation. This method of measuring net transplacental fluid transfer to the fetus can be used to measure fetal fluid intake over relatively short periods of time. It also means that the effects of disturbances in maternal fluid and electrolyte balance on fluid transfer to the fetus can be studied and quantitated.
Publisher: Wiley
Date: 05-1972
DOI: 10.1111/J.1445-5994.1972.TB03929.X
Abstract: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. The Barcelona Clinic Liver Cancer (BCLC) classification has been endorsed as the optimal staging system and treatment algorithm for HCC by the European Association for the Study of Liver Disease and the American Association for the Study of Liver Disease. However, in real life, the majority of patients who are not considered ideal candidates based on the BCLC guideline still were performed hepatic resection nowadays, which means many hepatic surgeons all around the world do not follow the BCLC guidelines. The accuracy and application of the BCLC classification has constantly been challenged by many clinicians. From the surgeons' perspectives, we herein put forward some comments on the BCLC classification concerning subjectivity of the assessment criteria, comprehensiveness of the staging definition and accuracy of the therapeutic recommendations. We hope to further discuss with peers and colleagues with the aim to make the BCLC classification more applicable to clinical practice in the future.
Publisher: Wiley
Date: 1992
DOI: 10.1113/JPHYSIOL.1992.SP018940
Abstract: 1. Nine chronically catheterized pregnant ewes were monitored before, during and after 1 week in which fetal urine was drained continuously, to determine whether they could compensate for the resulting loss of salt and water and increase net supply across the placenta to the fetus. 2. Fetal growth and urine and lung liquid production were not affected by loss of all fetal fluids. 3. When fetal urine was drained, the increase (P less than 0.05) in maternal drinking was greater than the extra amount of fluid lost. Thus, maternal plasma osmolality fell (P less than 0.01). When fetal urine again flowed into the amniotic and allantoic cavities, maternal drinking did not fall significantly and plasma osmolality remained low. Maternal urine flow rate increased (P less than 0.05) and its osmolality fell (P less than 0.02). 4. Maternal food intake increased (P less than 0.005) during fetal urine drainage. 5. Maternal plasma renin activity increased (P less than 0.05), her urinary sodium excretion fell (P less than 0.005) and the Na(+)-K+ ratio in both her urine and faeces decreased (P less than 0.01 and P less than 0.05 respectively) when fetal urine was drained. Maternal urinary and faecal sodium conservation continued after drainage ceased because of continued loss of sodium in lung liquid. 6. It is concluded that the ewe can compensate for inappropriate loss of salt and water from the conceptus.
Publisher: Wiley
Date: 02-1978
DOI: 10.1038/ICB.1978.2
Abstract: In acute experiments on the in utero foetal lamb, angiotensin II was a more potent pressor agent that either noradrenaline or adrenaline, and the response to angiotensin II was not consistently modified by the combined administration of alpha and beta-adrenergic blocking agents. A significant reduction in the pressor response of the foetus to angiotensin II and noradrenaline occurred with infusion of these compounds to the foetus by the umbilical artery when compared with the response obtained with infusions of the same doses of these drugs by the umbilical vein. Moreover, the concentration of angiotensin II (pg. ml-1) present in the foetal circulation was less following umbilical arterial infusions compared with umbilical vein infusions of the same doses. A similar reduction in the pressor activity of adrenaline and the cardio-stimulant effect of isoprenaline occurred when these drugs were infused by the umbilical artery. It is concluded that the foetus, like the adult animal, is more sensitive to angiotensin II than to catecholamines and that the biological activities of noradrenaline, angiotensin II, adrenaline and isoprenaline are reduced by perfusion through the foetal placenta.
Publisher: Public Library of Science (PLoS)
Date: 27-03-2014
Publisher: Elsevier BV
Date: 09-2007
Publisher: Bioscientifica
Date: 05-2016
DOI: 10.1530/EC-15-0112
Abstract: Endometrial cancer (EC) is the most common gynaecological malignancy and its incidence is increasing. Dysregulation of the endometrial renin–angiotensin system (RAS) could predispose to EC therefore, we studied the prevalence of RAS single nucleotide polymorphisms (SNPs) in Australian women with EC. SNPs assessed were AGT M235T (rs699) AGTR1 A1166C (rs5186) ACE A240T and T93C (rs4291, rs4292) and ATP6AP2 (rs2968915). They were identified using TaqMan SNP Genotyping Assays. The C allele of the AGTR1 SNP (rs5186) was more prevalent in women with EC (odds ratio (OR) 1.7, 95% confidence interval (CI) (1.2–2.3), P =0.002). The CC genotype of this SNP is associated with upregulation of the angiotensin II type 1 receptor (AGTR1). The G allele of AGT rs699, which is associated with higher angiotensinogen (AGT) levels, was less prevalent in women with EC (OR 0.54, 95% CI (0.39–0.74), P .001) compared with controls. AGT and AGT formed by removal of angiotensin I (des(Ang I)AGT) are both anti-angiogenic. In women with EC who had had hormone replacement therapy (HRT), the prevalence of the AGTR1 SNP (rs5186) and the ACE SNPs (rs4291 and rs4292) was greater than in women who had no record of HRT SNP rs4291 is associated with increased plasma ACE activity. These data suggest there is an interaction between genotype, oestrogen replacement therapy and EC. In conclusion, the prevalence of two SNPs that enhance RAS activity was different in women with EC compared with healthy controls. These genetic factors may interact with obesity and hyperoestrogenism, predisposing ageing, obese women to EC.
Publisher: Wiley
Date: 28-01-2016
Abstract: Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. This study examined and compared the prevalence of single nucleotide polymorphisms (SNPs) in genes of the renin-angiotensin system (RAS) in a desert community of Indigenous Australians and in non-Indigenous Australians. The polymorphisms were angiotensinogen, AGT G-217A (rs5049) AGT G+174A (rs4762) Angiotensin II type 1 receptor, AGTR1 A+1166C (rs5186) angiotensin converting enzyme, ACE A-240T (rs4291), ACE T-93C (rs4292) renin, REN T+1142C (rs5706). They were measured using allelic discrimination assays. The prevalence of REN T+1142C SNP was similar in the two populations 99% were homozygous for the T allele. All other SNPs were differently distributed between the two populations (P < 0.0001). In non-Indigenous Australians, the A allele at position 204 of ACE rs4291 was prevalent (61.8%) whereas in the Indigenous Australians the A allele was less prevalent (28%). For rs4292, the C allele had a prevalence of 37.9% in non-Indigenous Australians but in Indigenous Australians the prevalence was only 1%. No Indigenous in iduals were homozygous for the C allele of AGTR1 (rs5186). Thus the prevalence of RAS SNPs in this Indigenous Australian desert community was different from non-Indigenous Australians as was the prevalence of cytokine SNPs (as shown in a previous study). These differences may affect susceptibility to chronic renal and cardiovascular disease and may alter the efficacy of drugs used to inhibit the RAS. These studies highlight the need to study the pharmacogenetics of drug absorption, distribution, metabolism and excretion in Indigenous Australians for safe prescribing guidelines.
Publisher: MDPI AG
Date: 09-02-2021
DOI: 10.3390/NU13020569
Abstract: Suboptimal nutrition during pregnancy is recognised as a significant modifiable determinant in the development of chronic disease in offspring in later life. The current study aimed: (i) to assess the dietary intakes of pregnant Indigenous Australian women against national recommendations and (ii) to investigate the associations between maternal nutrition during pregnancy and the growth of the offspring, including kidney development in late gestation in the Gomeroi gaaynggal cohort (n = 103). Maternal dietary intake in the third trimester was assessed using the Australian Eating Survey Food Frequency Questionnaire. Estimated fetal weight (EFW) and kidney size were obtained by ultrasound. Birth weight was retrieved from hospital birth records. Of the five key nutrients for optimal reproductive health (folate, iron, calcium, zinc and fibre), the nutrients with the highest percentage of pregnant women achieving the nutrient reference values (NRVs) were zinc (75.7%) and folate (57.3%), whereas iron was the lowest. Only four people achieved all NRVs (folate, iron, calcium, zinc and fibre) important in pregnancy. Sodium and saturated fat intake exceeded recommended levels and diet quality was low, with a median score of 28 out of 73 points. After adjusting for smoking and pre-pregnancy body mass index, only maternal intake of retinol equivalents and the proportion of energy from nutrient-dense or energy-dense, nutrient-poor (EDNP) foods were associated with fetal growth. EFW decreased by 0.13 g and birth weight decreased by 0.24 g for every µg increase in maternal dietary retinol intake. Interestingly, EFW, but not actual birth weight, was positively associated with percentage energy from nutrient dense foods and negatively associated with percentage energy from EDNP foods. Dietary supplement usage was associated with increased birthweight, most significantly iron and folate supplementation. Current dietary intakes of pregnant Australian women from this cohort do not align with national guidelines. Furthermore, current findings show that maternal retinol intake and diet composition during pregnancy can influence fetal growth, but not fetal kidney growth in late gestation. Strategies that aim to support and optimise nutrient intakes of Indigenous pregnant women are urgently needed. Future studies with long-term follow-up of the children in the current cohort to assess renal damage and blood pressure are imperative.
Publisher: Wiley
Date: 10-2015
DOI: 10.14814/PHY2.12586
Publisher: Elsevier BV
Date: 08-1999
DOI: 10.1016/S0014-2999(99)00454-9
Abstract: This study was performed to investigate the roles of angiotensin receptors (AT1 and AT2) in the contractility of uterine arteries during normal pregnancy and after angiotensin II levels have been elevated. Pregnant ewes were given intravenous infusions of saline for 24 h (control) or angiotensin II (30 ng kg(-1) min(-1)) for 2 or 24 h. The contractile responses of uterine arterial rings to angiotensin II (4 microM) and antagonists were then examined in vitro. Most uterine arteries were relatively insensitive to the vasoconstrictor effects of angiotensin II. In rings from control ewes an angiotensin AT2 antagonist enhanced (P < 0.05) the contractile responses to angiotensin II, suggesting that angiotensin AT2 receptors inhibited the angiotensin AT1 receptor mediated contractions. Uterine arterial rings from ewes given intravenous infusions of angiotensin II displayed greater (P < 0.05) contractile responses to angiotensin II in vitro compared to rings from control ewes. This was in part due to down regulation of angiotensin AT2 receptors. Surprisingly, while performing these experiments a small number of ewes had uterine arteries which were "hyperreactive" to angiotensin II (contractile responses 6-fold greater). These ewes also had abnormal renin angiotensin systems and had some features which are characteristic of those seen in preecl sia. The "hyperreactivity" of these arteries could only in part be explained by down regulation of angiotensin AT2 receptors. It is concluded that in normal pregnancy angiotensin AT2 receptors play a role in maintaining an adequate uterine blood flow for the fetus. When angiotensin II levels are elevated for a prolonged period this protective effect is lost partly because angiotensin AT1 receptors are down regulated.
Publisher: Wiley
Date: 11-1997
DOI: 10.1111/J.1440-1681.1997.TB02706.X
Abstract: 1. The placental vascular bed is normally fully dilated. Therefore, changes in vascular resistance elsewhere in the body can affect uteroplacental blood flow (UBF). For ex le, antihypertensive drugs, such as diazoxide, hydralazine and the angiotensin-converting enzyme inhibitor captopril, cause falls in arterial pressure and, hence, in UBF. 2. Angiotensin II (AngII), prostacyclin and nitric oxide (NO) all influence uteroplacental vascular tone. Angiotensin II in a pharmacological dose (62.5 micrograms/h) had a biphasic effect on UBF in the sheep. Initially, there was a rise in UBF as pressure rose however, by 16-24 h, UBF had fallen. The AngII-induced fall in UBF caused severe foetal hypoxia and hypercapnia. 3. Prostacyclin may protect the uteroplacental circulation from vasoconstrictors such as AngII, as the vasoconstrictor effect of AngII in the uteroplacental circulation is enhanced following indomethacin. 4. Oestrogen-induced uterine artery vasodilation is nitrergic dependent. As well, nitrergic nerves alter the responsiveness of pregnant uterine arteries to noradrenaline. 5. Thus, both systemic and local factors are important in the control of UBF and in promoting foetal health and growth.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2005
Publisher: Canadian Science Publishing
Date: 06-1988
DOI: 10.1139/Y88-111
Abstract: Renal function was studied in unanaesthetized fetal sheep aged 112–120 and 126–132 days and in adult nonpregnant ewes. The clearance of lithium was used to measure proximal and distal fractional sodium reabsorption. In five nonpregnant adult sheep, 80.6 ± 1.7% (SE) of the filtered sodium load was reabsorbed proximaily and 18.2 ± 1.53% distally. This was different from all groups of fetal sheep (p 0.001). In younger fetuses, proximal fractional sodium reabsorption was less (51.3 ± 2.3% (SE), p 0.05) and distal fractional sodium reabsorption greater (42.4 ± 2.3% (SE), p 0.05) than older fetuses (126–132 days old) in which 61.4 ± 2.4% (SE) was reabsorbed proximaily and 33.6 ± 2.5% (SE) distally. In another group of fetuses aged 125–137 days, in which proximal tubular sodium reabsorption was measured after distal tubular blockade, proximal fractional sodium reabsorption was 57.8 ± 2.95% (SE) and distal fractional sodium reabsorption, 38.7 ± 2.64% (SE). In adult sheep there was no relationship between distal tubular sodium reabsorption and glomerular filtration rate, i.e., proximal tubular function was responsible for glomerulotubular balance. However, in the fetuses, both proximal and distal tubular sodium reabsorption contributed to glomerulotubular balance. Thus in fetal life, the proximal tubule participates to a lesser extent in reabsorbing the filtered sodium load possibly because its function is suppressed by its relatively "volume-expanded" state or because it is functionally immature. Therefore, a greater proportion is reabsorbed distally and the distal nephron participates under physiological conditions in glomerulotubular balance.
Publisher: Bioscientifica
Date: 07-02-2013
DOI: 10.1530/JME-12-0211
Abstract: Correct timing of parturition requires inflammatory gene activation in the gestational tissues at term and repression during pregnancy. Promoter methylation at CpG dinucleotides represses gene activity therefore, we examined the possibility that DNA methylation is involved in the regulation of labour-associated genes in human pregnancy. Amnion and decidua were collected at 11–17 weeks of gestation and at term following elective Caesarean delivery or spontaneous labour. Methylation of the inflammatory genes PTGS2 , BMP2 , NAMPT and CXCL2 was analysed using the Methyl-Profiler PCR System and bisulphite sequencing. Methylation of the glucocorticoid, progesterone and oestrogen receptor genes, involved in the hormonal regulation of gestational tissue function, and the expression of the DNA methyltransferases DNMT1 , -3A and -3B were also determined. Variable proportions of inflammatory and steroid receptor gene copies, to a maximum of 50.9%, were densely methylated in both tissues consistent with repression. Densely methylated copy proportions were significantly different between genes showing no relationship with varying expression during pregnancy, between tissues and in in iduals. Methylated copy proportions of all genes in amnion and most genes in decidua were highly correlated in in iduals. DNMT1 and -3A were expressed in both tissues with significantly higher levels in the amnion at 11–17 weeks than at term. We conclude that the unmethylated portion of gene copies is responsible for the full range of regulated expression in the amnion and decidua during normal pregnancy. Dense methylation of in idually variable gene copy proportions happens in the first trimester amnion influenced by sequence context and affected strongly by in idual circumstances.
Publisher: American Physiological Society
Date: 03-2009
DOI: 10.1152/AJPENDO.90497.2008
Abstract: Intrafetal insulin-like growth factor (IGF)-I promotes cardiac hypertrophy in the late-gestation fetal sheep whether these effects are sustained is unknown. IGF-I was infused for 4 days at 80 μg/h from 121 to 125 days of gestation, and its effects at 128 days, 3 days after the infusion stopped, were determined by comparison with untreated fetal sheep. After IGF-I treatment, fetal weights were similar to those in control fetuses but kidney weights were bigger ( P 0.05), as were spleen weights of male fetuses ( P 0.05). Cardiac myocytes were larger in female than male fetal sheep ( P 0.001). IGF-I increased male ( P 0.001) but not female myocyte volumes. IGF-I did not alter the proportions of uni- or binucleated right or left ventricular myocytes. Female fetal sheep had a greater proportion of binucleated cardiac myocytes than males ( P 0.05). IGF-I-treated fetuses had a slightly greater proportion of right ventricular nuclei in cell cycle phase G 2 /M and a reduced proportion of G 0 /G 1 phase nuclei ( P 0.1). Therefore, evidence for IGF-I-stimulated cardiac cell hyperplasia in fetal sheep in late gestation was limited. In conclusion, the greater sizes and larger proportion of binucleated cardiac myocytes in female fetal sheep suggest that myocyte maturation may occur earlier in females than in males. This may explain in part the male sex-specific responsiveness of cardiac hypertrophy to IGF-I in late gestation. If IGF-I-stimulated cardiomyocyte growth is accompanied by maturation of contractile function, IGF-I may be a potential therapeutic agent for maintaining cardiac output in preterm males.
Publisher: Wiley
Date: 03-1979
DOI: 10.1113/JPHYSIOL.1979.SP012708
Abstract: 1. In conscious non‐pregnant and pregnant ewes and in chronic fetal lamb preparations, the beat by beat relationship between pulse interval and systolic pressure was studied during acute elevations in arterial pressure induced by phenylephrine. Baroreflex sensitivity, which was defined as the slope of the pressure‐pulse interval relationship when phenylephrine was used to raise pressure, was abolished by atropine and increased by propranolol. Baroreflex sensitivity was less in pregnant ewes and in foetal lambs compared with non‐pregnant ewes. 2. These findings suggest that the vagus nerve is responsible for the reflex bradycardia that occurs in the foetus and the ewe when arterial pressure is increased. 3. In both fetal and adult sheep, actue hypertension due to I.V. injection of angiotensin II was not associated with a consistent and progressive bradycardia, such as was seen with acute hypertension caused by phenylephrine. Angiotensin II has no direct chronotropic effect on heart rate in either the adult or the fetus. 4. No linear relationship between arterial pressure and pulse interval was seen when angiotensin II was used to raise pressure in sheep which were treated with propranolol. Therefore the lack of cardiac slowing with pressor doses of angiotensin II was not due to concomitant activation of the sympathoadrenal system. 5. It is concluded that in both fetal and adult sheep angiotensin II reduces the increase in vagal tone which is responsible for slowing of heart rate in response to acute rises in arterial pressure.
Publisher: Wiley
Date: 2001
DOI: 10.1113/EPH8602075
Abstract: Previous studies in fetal sheep have concluded that (a) the vascular AT(1) angiotensin II (Ang II) receptor subtype is present in the external umbilical artery, but not in other systemic blood vessels, and (b) carotid arterial rings contract in vitro in response to Ang II. These contractions are blocked by the AT(1) specific receptor antagonist losartan. The aim of the present study was to resolve the apparent contradiction of these earlier conclusions, by examining the distribution of Ang II receptor subtypes in different regions of the ovine fetal cardiovascular system, and to find out at what stage in development AT(1) receptors first appear. We measured AT(1) and AT(2) receptors in hearts, carotid arteries, aortae and umbilical vessels from fetal sheep aged 65-144 days (term approximately 150 days), and in hearts and aortae from lambs, and adult pregnant and non-pregnant ewes. Both AT(1) and AT(2) receptors were present in aortae of fetuses > 118 days gestation, and carotid arteries of fetuses > 121 days gestation, while in younger fetuses only AT(2) receptors were found. The proportion of carotid artery and aortic AT(1) receptors increased with age, while the proportion of AT(2) receptors decreased. The internal umbilical artery contained both subtypes, but there was no relationship between receptor density and gestational age. The external umbilical artery had only AT(1) receptors. The highest density of Ang II receptors was found in the fetal heart where the AT(2) subtype predominated. The density of fetal cardiac Ang II receptors declined with age (r = -0.44, P < 0.02) due to the decrease in the AT(2) subtype. The density in late gestation fetal hearts was greater than in lamb or adult hearts (P < 0.001). Our study shows that fetal systemic blood vessels contain AT(1) receptors, and we have documented for the first time that the appearance of AT(1) receptors is both different in different regions of the fetal cardiovascular system and is developmentally regulated. Together with the in vitro contractile studies, this suggests that Ang II can play an important role in fetal blood pressure regulation via AT(1) receptors in the fetal systemic vasculature, as well in the umbilicoplacental vessels. Experimental Physiology (2001) 86.1, 71-82.
Publisher: Portland Press Ltd.
Date: 07-1999
DOI: 10.1042/CS19980356
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.MCE.2022.111609
Abstract: Placental renin-angiotensin system (RAS) components prorenin, angiotensinogen, and angiotensin (Ang) II type 1 receptor (AT
Publisher: Canadian Science Publishing
Date: 02-1995
DOI: 10.1139/Y95-029
Abstract: To determine the effects on the fetus of high maternal levels of noradrenaline, experiments were carried out in 17 pregnant ewes (123–137 days gestation). Intravenous infusion of 40 mg/min of norepinephrine to the ewe for 1.5 h increased maternal arterial pressure and significantly decreased maternal placental blood flow (p 0.05). Fetal arterial pressure did not change, but fetal arterial [Formula: see text] fell (p 0.01) and [Formula: see text] rose (p 0.01). Fetal urine flow fell and osmolality rose (p 0.01), fetal lung liquid flow and osmolar excretion fell (p 0.01, p 0.05, respectively), and the lung sodium:potassium ratio changed. These effects of high levels of maternal noradrenaline were transient, i.e., 2.5 h after the infusion of noradrenaline had finished, fetal urine flow and lung liquid flow had both returned to control values and fetal [Formula: see text] was significantly depressed relative to control values (p 0.01). It is concluded that high levels of maternal catecholamines reduce placental blood flow and cause small changes in fetal oxygenation. These changes are sufficient to transiently affect fetal water excretion and to reduce lung liquid flow.Key words: maternal noradrenaline, uterine blood flow, fetal oxygen, lung liquid, blood volume, fetal, renal.
Publisher: American Physiological Society
Date: 15-01-2014
DOI: 10.1152/AJPREGU.00034.2013
Abstract: This review describes the changes that occur in circulating renin-angiotensin-aldosterone system (RAAS) components in human pregnancy. These changes depend on endocrine secretions from the ovary and possibly the placenta and decidua. Not only do these hormonal secretions directly contribute to the increase in RAAS levels, they also cause physiological changes within the cardiovascular system and the kidney, which, in turn, induce reflex release of renal renin. High levels of ANG II play a critical role in maintaining circulating blood volume, blood pressure, and uteroplacental blood flow through interactions with the ANG II type I receptor and through increased production of downstream peptides acting on a changing ANG receptor phenotype. The increase in ANG II early in gestation is driven by estrogen-induced increments in angiotensinogen (AGT) levels, so there cannot be negative feedback leading to reduced ANG II production. AGT can exist in various forms in terms of redox state or complexed with other proteins as polymers these affect the ability of renin to cleave ANG I from AGT. Thus, during pregnancy the rate of ANG I production varies not only because levels of renin change in response to homeostatic demand but also because AGT changes not only in concentration but in form. Activation of the circulating and intrarenal RAASs is essential for normal pregnancy outcome subserving the increased demand for salt and, hence, water during pregnancy. Thus, the complex integration of the secretions and actions of the circulating maternal renin-angiotensin system in pregnancy plays a key role in pregnancy outcome.
Publisher: American Physiological Society
Date: 08-1986
DOI: 10.1152/AJPRENAL.1986.251.2.F226
Abstract: Renal excretion of acid and reabsorption of bicarbonate was studied in 17 chronically catheterized fetal sheep aged 121-143 days. The rates of excretion of titratable acid (0.16-6.2 mumol/min) and ammonium (1.2-9.7 mumol/min) were variable. Urinary phosphate excretion was significantly greater (P less than 0.001) than the excretion of titratable acid. Of the filtered bicarbonate load 80-100% was reabsorbed. In 9 of the 17 fetuses net acid excretion was positive. Bicarbonate, sodium, and chloride reabsorption were related to glomerular filtration rate (GFR) (P less than 0.0005). The increase of GFR results in an increase in the excretion of titratable acid (P less than 0.001), phosphate (P less than 0.0005), and ammonium (P less than 0.001). These relationships could account for the age-dependent increase in renal excretion of acid (P less than 0.0005), ammonium (P less than 0.025), and bicarbonate reabsorption (P less than 0.0005). Arterial pH affected the rates of excretion of titratable acid (P less than 0.005), ammonium ions (P less than 0.05), and net acid (P less than 0.025). It is concluded that the fetal kidneys can excrete protons and generate bicarbonate. This ability increases with age due mainly to the concomitant increase in GFR.
Publisher: Springer Science and Business Media LLC
Date: 06-2015
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.PLACENTA.2015.11.011
Abstract: During the first trimester, normal placental development occurs in a low oxygen environment that is known to stimulate angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Expression of the placental renin-angiotensin system (RAS) is highest in early pregnancy. While the RAS and oxygen both stimulate angiogenesis, how they interact within the placenta is unknown. We postulated that low oxygen increases expression of the proangiogenic RAS pathway and that this is associated with increased VEGF in a first trimester human trophoblast cell line (HTR-8/SVneo). HTR-8/SVneo cells were cultured in one of three oxygen tensions (1%, 5% and 20%). RAS and VEGF mRNA expression were determined by qPCR. Prorenin, angiotensin converting enzyme (ACE) and VEGF protein levels in the supernatant, as well as prorenin and ACE in cell lysates, were measured using ELISAs. Low oxygen significantly increased the expression of both angiotensin II type 1 receptor (AGTR1) and VEGF (both P < 0.05). There was a positive correlation between AGTR1 and VEGF expression at low oxygen (r = 0.64, P < 0.005). Corresponding increases in VEGF protein were observed with low oxygen (P < 0.05). Despite no change in ACE1 mRNA expression, ACE levels in the supernatant increased with low oxygen (1% and 5%, P < 0.05). Expression of other RAS components did not change. Low oxygen increased AGTR1 and VEGF expression, as well as ACE and VEGF protein levels, suggesting that the proangiogenic RAS pathway is activated. This highlights a potential role for the placental RAS in mediating the proangiogenic effects of low oxygen in placental development.
Publisher: Wiley
Date: 02-07-2018
DOI: 10.1113/JP275583
Publisher: Wiley
Date: 04-1990
DOI: 10.1111/J.1440-1681.1990.TB01327.X
Abstract: 1. Angiotensin II (AII, 0.22 microgram/min) infused for 7-14 days, into adult unanaesthetized wethers, caused a rise in blood pressure of 7 +/- 3/7 +/- 3 mmHg (mean +/- s.e.m.) from control values of 90 +/- 5/54 +/- 3 mmHg (P less than 0.05, n = 11). Cardiac output and pulse interval were not affected. A high salt intake had no effect on blood pressure, cardiac output and pulse interval, nor did it potentiate the action of AII. 2. Ethinyl oestradiol (EE, 20 mg/week) caused a small fall in systolic and diastolic pressure of 6 +/- 3/6 +/- 5 mmHg (n = 7, P less than 0.1, P less than 0.05). When AII (0.22 microgram/min) was given with EE, it still caused a significant rise in blood pressure (P less than 0.01). The synthetic progestin (1 mg of norethisterone [NE] for 8-18 days) plus a high salt diet had no effect on arterial pressure and cardiac output but pulse interval rose significantly (P less than 0.05). 3. Therefore the reduction in vascular reactivity to angiotensin seen in human pregnancy is probably not related to high levels of oestrogen. Further, NE combined with a high salt diet does not cause hypertension in sheep.
Publisher: American Physiological Society
Date: 07-2001
DOI: 10.1152/AJPREGU.2001.281.1.R318
Abstract: In the adult, insulin-like growth factor I (IGF-I) increases glomerular filtration rate (GFR) and renal blood flow (RBF) during both acute and chronic treatment. To study its effects on the developing kidney, chronically catheterized fetal sheep (120 ± 1 days gestation) were infused intravenously for up to 10 days with 80 μg/h IGF-I ( n = 5) or vehicle (0.1% BSA in saline, n = 6). In contrast to previous acute studies in adult rats and humans, after 4 h of IGF-I fetal GFR and RBF were unchanged. Fractional sodium reabsorption increased ( P 0.05). However, by 4 days, GFR per kilogram had risen by 35 ± 13% ( P 0.05), whereas RBF remained unchanged. Tubular growth and maturation may have occurred, as proximal tubular sodium reabsorption increased by ∼35% ( P 0.005). Therefore, despite a marked increase in filtered sodium (∼30%, P 0.05), fractional sodium reabsorption did not change. Although the effects of IGF-I on renal function were delayed, plasma renin activity and concentration were both elevated after 4 h and remained high at 4 days ( P 0.05). Despite this, arterial pressure and heart rate did not change. Kidneys of IGF-I-infused fetuses weighed ∼30% more ( P = 0.05) and contained ∼75% more renin than control fetuses ( P 0.005). Thus, in the fetus, the renal effects of long-term IGF-I infusion are very different from the adult, possibly because IGF-I stimulated kidney growth.
Publisher: Wiley
Date: 08-1998
DOI: 10.1111/J.1440-1681.1998.TB02255.X
Abstract: 1. Experiments were carried out in 30 chronically catheterized foetal sheep (128‐144 days term 150 days) and in seven of these foetuses before, during and after acute hypoxaemia. The extent to which changes in sympathoadrenal activity and cardiac vagal activity affected the foetal cardiac response to hypoxaemia was measured. Three measurements were used: foetal heart rate (FHR), heart rate variability (HRV measured as the coefficient of variation in pulse interval) and power spectral density (PSD measured over the frequency ranges of 0.04‐1.3 Hz). Cardiac vagal activity was blocked by atropine, β‐adrenoceptor activity was blocked by propranolol. 2. Under normoxaemic conditions, cardiac vagal blockade caused a rise in mean arterial pressure (MAP P .001), an increase in FHR ( P .001), a decrease in HRV ( P .001) and a decrease in PSD ( P .001). β‐Adrenoceptor blockade caused a rise in MAP ( P .001), a fall in FHR ( P .01), a decrease in HRV ( P .001) but no change in PSD. 3. During mild hypoxaemia ( Po 2 = 12‐14.5 mmHg) and moderate hypoxaemia ( Po 2 = 10‐11.9 mmHg), foetal MAP ( P .001, P .001), HRV ( P .01, P .001) and PSD in the frequency range 0.04‐0.45 Hz increased ( P .05‐ P .001). Foetal heart rate decreased when foetuses became moderately hypoxaemic ( P .001). 4. After cardiac vagal blockade, hypoxaemia was associated with an increase in FHR compared with non‐blocked hypoxaemic foetuses ( P .01, P .001). The increase in HRV was abolished ( P .001, P .001) as was the increase in PSD ( P .01‐ P .001). 5. After β‐adrenoceptor blockade, the bradycardia that occurred during hypoxaemia was enhanced ( P .01, P .05), the increase in HRV was not affected and neither was the increase in PSD. 6. As FHR and HRV of normoxaemic foetal sheep were affected both by atropine and propranolol, it would seem that both cardiac vagal and sympathoadrenal activity modulate the foetal heart under resting conditions. The lack of any effect of β‐adrenoceptor blockade on PSD under these conditions suggests that power spectral analysis (PSA) is not as sensitive as the other two methods in detecting sympathetically mediated modulation of the heart. 7. Because the hypoxaemia induced bradycardia and increase in HRV and in PSD were abolished by atropine ( P .01‐ P .001), it is concluded that during hypoxaemia foetal HRV is mainly modulated by changes in cardiac vagal tone. Propranolol had no effect on foetal HRV, although it reduced it under normoxaemic conditions therefore, it is concluded that cardiac sympathetic neural activity was not increased in acute hypoxaemia uncomplicated by acidosis. However, there was strong evidence of increased sympathoadrenal tone on the foetal heart in hypoxaemia, that is, there was a rise in FHR in hypoxaemic atropinized foetuses and a greater fall in FHR in β‐adrenoceptor blocked hypoxaemic foetuses. Therefore, this increased sympathetic influence on the foetal heart during hypoxaemia must be predominantly the result of increased adrenomedullary secretion of catecholamines. 8. Maintenance of foetal cardiac output depends on the chronotropic and ionotropic effects of catecholamines. Therefore, this adrenomedullary influence on the foetal heart during hypoxaemia is important to offset the opposing effects of increased cardiac vagal tone.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.PLACENTA.2018.12.001
Abstract: Placental development occurs in a low oxygen environment, which stimulates angiogenesis by upregulating vascular endothelial growth factor A (VEGFA), plasminogen activator inhibitor-1 (SERPINE1) and the angiopoietin-2/-1 ratio (ANGPT2/1). At this time, Angiotensin II type 1 receptor (AT HTR-8/SVneo cells were cultured in 1%, 5% or 20% O Culture in low oxygen (1%) increased angiogenic VEGFA, SERPINE1 and placental growth factor (PGF) mRNA and VEGFA and SERPINE1 protein levels, and reduced anti-angiogenic ANGPT1, endoglin (ENG) and soluble fms-like tyrosine kinase-e15a (sFlt-e15a) mRNA (all P = 0.0001). At 1% oxygen, losartan significantly reduced intracellular VEGFA and SERPINE1 levels and secreted VEGF levels (P = 0.008, 0.0001 and 0.0001). HUVEC tube formation was increased in cells grown in HTR-8/SVneo conditioned medium from 1 to 5% cultures (all P = 0.0001). HUVECs cultured in medium from losartan treated HTR-8/SVneo cells had a reduced number of meshes, branching points and total branching length (P = 0.004, 0.003 and 0.0002). At 1% oxygen, losartan partially inhibited the oxygen-induced increase in cell viability (P = 0.0001). Thus, AT
Publisher: Wiley
Date: 09-1984
DOI: 10.1113/JPHYSIOL.1984.SP015392
Abstract: In unanaesthetized sheep, the sensitivity of the baroreceptor-cardio-inhibitory reflex was greater when intravenous vasopressin was used to raise blood pressure, than when intravenous phenylephrine was used to raise blood pressure. This difference was still evident in animals in which beta-adrenergic blockade had been carried out using propranolol. In the presence of combined beta-adrenergic and muscarinic blockade, a direct negative chronotropic effect of intravenous vasopressin could not be demonstrated. It was concluded, therefore, that intravenous vasopressin enhanced cardiac vagal tone. This effect of vasopressin on efferent cardiac vagal tone was confirmed directly in anaesthetized dogs by recording from single cardiac vagal efferent fibres. Furthermore, recordings from single carotid sinus baroreceptor fibres did not demonstrate a direct action of vasopressin on the sensitivity of the baroreceptors. However, the pressor effect of vasopressin is associated with a greater increase in efferent cardiac vagal discharge than that seen when equipressor doses of phenylephrine are given, or when blood pressure is raised by a similar amount by inflation of an intra-aortic balloon. Studies in isolated guinea-pig atrial preparations and in anaesthetized rabbits and dogs, revealed no consistent peripheral action of vasopressin on the action of the vagus at the heart.
Publisher: Hindawi Limited
Date: 11-08-2010
Abstract: Prorenin stimulates decidual prostaglandin (PG) production in vitro, the (pro)renin receptor ((P)RR) may mediate this action. The role of prorenin in amnion PG synthesis has not been examined, despite this being the key site of PG synthesis. To determine if (P)RR, prorenin and PGHS-2 are co-localized in gestational tissues and if expression is altered by labour, term amnion, chorion, decidua and placenta were collected during elective caesarean section or after spontaneous labour. Prorenin, (P)RR and PGHS-2 mRNA abundance was determined by real-time RT-PCR. (P)RR protein was examined by immunohistochemistry. The effect of recombinant human (rh) prorenin on PGHS-2 mRNA abundance in amnion explants was determined. Prorenin and (P)RR mRNA were highest in decidua and placenta, respectively. Decidual prorenin, (P)RR and placental (P)RR mRNA abundance decreased with labour. (P)RR protein was present in all gestational tissues. After labour, decidual prorenin was positively correlated with amnion PGHS-2 mRNA and rh-prorenin significantly increased PGHS-2 mRNA abundance in amnion explants. We conclude that the decidua is the principal source of prorenin and is downregulated with labour. All gestational tissues are targets for prorenin. Decidual prorenin may be involved in the labour-associated increase in amnion PGHS-2 abundance via the (P)RR.
Publisher: Wiley
Date: 10-1993
DOI: 10.1111/J.1476-5381.1993.TB13886.X
Abstract: 1. Renal function was studied in chronically catheterized fetal sheep (119-128 days gestation), before and during treatment of the ewe with the angiotensin converting enzyme (ACE) inhibitor, captopril, which crosses the placenta and blocks the fetal renin angiotensin system. 2. An i.v. dose of 15 mg (about 319 micrograms kg-1) of captopril to salt-replete ewes followed by an infusion to the ewe of 6 mg h-1 (about 128 micrograms kg-1 h-1) caused a fall in fetal arterial pressure (P < 0.01), and a rise in fetal renal blood flow (RBF) from 67.9 +/- 5.6 to 84.9 +/- 8.3 ml min-1 (mean +/- s.e. mean) (P < 0.05). Renal vascular resistance and glomerular filtration rate (GFR) fell (P < 0.01) fetal urine flow (P < 0.01) fetal urine flow (P < 0.01) and sodium excretion declined (P < 0.05). 3. Ewes were treated for the next 2 days with 15 mg captopril twice daily. On the 4th day, 15 mg was given to the ewe and fetal renal function studied for 2 h during the infusion of captopril (6 mg h-1) to the ewe. Of the 9 surviving fetuses, 3 were anuric and 3 had low urine flow rates. When 6 micrograms kg-1 h-1 of angiotensin II was infused directly into the fetus RBF fell from 69 +/- 10.1 ml min-1 to 31 +/- 13.9 ml min-1, GFR rose (P < 0.05) and urine flow (P < 0.01) and sodium excretion increased in all fetuses. 4. It is concluded that the small fall in fetal arterial pressure partly contributed to the fall in fetal GFR but in addition, efferent arteriolar tone fell so that the filtration pressure fell further. Thus maintenance of fetal renal function depends on the integrity of the fetal renin angiotensin system. These findings explain why use of ACE inhibitors in human pregnancy is associated with neonatal anuria.
Publisher: Wiley
Date: 10-1970
DOI: 10.1038/ICB.1970.49
Abstract: Behavioral disturbances following chemotherapy with cisplatin are rare. Here, we report a patient with temporary loss of moral behavior in the setting of cisplatin-based chemotherapy for treatment of tonsillar cancer. A 66-year-old Caucasian male with no psychiatric or violent history was started on chemotherapy with cisplatin for treatment of tonsillar cancer. During the following weeks, the patient developed profound personality changes involving volatile emotions and impulsive aggression with verbal and physical assaults on others. Admitted to the hospital, the patient lacked any awareness that his behavior was wrong. Chemotherapy was discontinued and the patient was prescribed risperidone. Aside from mild cognitive impairment, comprehensive neuropsychological, neuroradiological and lab testing were unremarkable. Three weeks following cessation of chemotherapy, the patient had recovered to his original mental state and he was completely aware of his wrongdoing and social misconduct. Since neurotoxic effects of chemotherapeutics on the brain are not yet sufficiently elucidated, our case emphasizes that early signs of behavioral abnormalities in patients receiving chemotherapy should trigger comprehensive psychiatric evaluation and ongoing monitoring of the patients' mental state.
Publisher: Wiley
Date: 05-2002
DOI: 10.1046/J.1440-1681.2002.03678.X
Abstract: 1. In adult unanaesthetized sheep, there is a V‐shaped relationship between mean arterial pressure (MAP) and heart rate variability (HRV), measured in both time and frequency domains. In contrast, in fetal sheep, there is only a positive direct relationship between MAP and HRV, which is determined by the cardiac vagus. We postulated that by the time lambs were 8–10 days old, the ‘adult like’ V‐shaped relationship between MAP and HRV would be present and it may appear at or after birth. To test these hypotheses, experiments were performed in six chronically catheterized fetal sheep (aged 132–138 days gestation), 10 newborn sheep (within 10 h of birth) and 10 lambs (aged 8–10 days). The relationships between MAP and HRV (in both time and frequency domains) were studied before and during β ‐adrenoreceptor blockade with propranolol and before and during cardiac vagal blockade with atropine. 2. In 8–10‐day‐old lambs, V‐shaped relationships between MAP and HRV (measured in both time and frequency domain) were obtained. The negative limb of this V‐shaped relationship between MAP and HRV was present after cardiac vagal blockade. The positive slope of the V was present after β ‐adrenoreceptor blockade. 3. In 4‐h‐old newborn sheep, there was no relationship between MAP and HRV (measured in the time domain), but between 7 and 10 h of age a negative relationship was found during treatment with atropine and a positive relationship was found during β ‐adrenoreceptor blockade, when HRV was measured in both time and frequency domains. 4. As described previously, there was only a positive relationship between MAP and HRV in fetal sheep, which was abolished by atropine but not affected by β ‐adrenoreceptor blockade. 5. Thus, until relatively late in fetal life, baroreceptor‐ modulated changes in efferent cardiac sympathetic tone, determined by measuring the effects of autonomic blockade on HRV, could not be elicited, although reflex vagal pathways were active. By 7–10 h after birth, baroreceptor‐modulated changes in efferent cardiac sympathetic tone were present. It was possible using measurements of HRV made in the time domain to show that these baroreceptor‐modulated cardiac sympathetic effects became stronger over the first 10 days of life ( P 0.01). These studies are the first to show that the influence of baroreceptor‐mediated changes in cardiac sympathetic tone on HRV increases in early life. This is probably because maturation of sympathetic innervation of the fetal sheep heart is occurring at this age.
Publisher: American Physiological Society
Date: 11-1990
DOI: 10.1152/AJPREGU.1990.259.5.R1004
Abstract: Uterine blood flow (UBF) was reduced for 1 h by partially occluding the maternal aorta below the renal arteries in seven pregnant ewes (gestation age 126-134 days). Fetuses became hypoxic, acidemic, and hypercapnic. They developed hypertension (P less than 0.005) and a bradycardia (P less than 0.05). During restricted UBF, fetal hematocrit (Hct) rose (P less than 0.005) and blood volume fell in five of seven fetuses. After release of constriction, fetal Hct fell, and blood volume rose by 7.5 +/- 3.26% (P less than 0.05) relative to control. During reduced UBF, lung liquid and urine flow rates fell (P less than 0.025 and P less than 0.05, respectively). After the occluder was released, Na excretion (which did not fall significantly during reduced UBF) increased (P less than 0.05), and fractional reabsorption of Na fell (P less than 0.05). Changes in fetal blood volume (FBV) were directly related to changes in maternal lower body flow (r = 0.47, P = 0.01, n = 33), and changes in fetal Hct were inversely related to maternal flow (r = -0.635, P = 0.001). Fetal urinary Na excretion per kilogram body weight was directly related to FBV per kilogram (r = 0.44, P = 0.005, n = 40), whereas fractional reabsorption of Na was inversely related to FBV per kilogram body wt (r = 0.48, P less than 0.002, n = 39). It is concluded that reductions in UBF cause fetal hypoxemia and acidemia, which lead to changes in fetal cardiovascular function and in FBV.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Canadian Science Publishing
Date: 1996
Publisher: IMR Press
Date: 30-05-2022
Publisher: Wiley
Date: 27-10-2013
Abstract: The renin-angiotensin system (RAS) plays a critical role in placentation and nephrogenesis. Failure to thrive during intrauterine life, possibly related to placental dysfunction and impaired expression of the renal RAS, as well as prematurity, results in smaller kidneys at birth and reduced nephron number. The remaining nephrons are therefore hyperfiltering from birth. Hyperfiltration, infections and Type 2 diabetes cause glomerular and tubular fibrosis, leading to further reductions in nephron number. The intrarenal RAS plays a key role in promoting tubulointerstitial fibrosis. Low birth weight and a high incidence of preterm birth program Indigenous children for early onset renal disease in adult life. Indigenous Australians have 404 000 fewer nephrons than non-Indigenous Australians. This, coupled with the high incidence of infectious diseases (particularly acute post-streptococcal glomerulonephritis) and the increasing prevalence of Type 2 diabetes, explains why end-stage renal disease is of epidemic proportions in Indigenous Australians. The existence of RAS gene polymorphisms and inflammatory cytokines may further potentiate susceptibility to renal disease in Indigenous Australians.
Publisher: Wiley
Date: 28-01-2008
DOI: 10.1002/AR.20651
Abstract: We have shown that fetuses whose mothers underwent subtotal nephrectomy (STNx) before pregnancy had high urine flow rates and sodium excretions, but lower hematocrits, plasma chloride, and plasma renin levels compared with controls. To see if these functional differences in utero persist after birth and are the result of altered renal development, we studied 8 lambs born to STNx mothers (STNxL) and 10 controls (ConL) in the second week of life. These lambs were of similar body weights, nose-rump lengths and abdominal girths. Their kidney weights were not different (ConL 36.1 +/- 1.9 vs. STNxL 39.8 +/- 3.3 g), nor were kidney dimensions or glomerular number (ConL 423,520 +/- 22,194 vs. STNxL 429,530 +/- 27,471 glomeruli). However, STNxL had 30% larger glomerular volumes (both mean and total, P < 0.01) and there was a positive relationship between total glomerular volume and urinary protein excretion (P < 0.05) in STNxL. Despite this change in glomerular morphology, glomerular filtration rate, tubular function, urine flow, and sodium excretion rates were not different between STNxL and ConL, nor were plasma electrolytes, osmolality, and plasma renin levels. Thus while many of the functional differences seen in late gestation were not present at 1-2 weeks after birth, the alteration in glomerular size and its relationship to protein excretion suggests that exposure to this altered intrauterine environment may predispose offspring of mothers with renal dysfunction to renal disease in adult life.
Publisher: Wiley
Date: 07-04-2017
DOI: 10.1111/AJO.12618
Abstract: Pregnancy can be a stressful time for many women. There is le evidence of numerous physical and mental health inequities for Indigenous Australians. For those Indigenous women who are pregnant, it is established that there is a higher incidence of poor physical perinatal outcomes when compared with non-Indigenous Australians. However, little evidence exists that examines stressful events and post-traumatic stress disorder (PTSD) symptoms in pregnant women who are members of this community. To quantify the rates of stressful events and PTSD symptoms in pregnant Indigenous women. One hundred and fifty rural and remote Indigenous women were invited to complete a survey during each trimester of their pregnancy. The survey measures were the stressful life events and the Impact of Events Scale. Extremely high rates of PTSD symptoms were reported by participants. Approximately 40% of this group exhibited PTSD symptoms during their pregnancy with mean score 33.38 (SD = 14.37) significantly higher than a study of European victims of crisis, including terrorism attacks (20.6, SD = 18.5). The extreme levels of PTSD symptoms found in the women participating in this study are likely to result in negative implications for both mother and infant. An urgent response must be mounted at government, health, community development and research levels to address these findings. Immediate attention needs to focus on the development of interventions to address the high levels of PTSD symptoms that pregnant Australian Indigenous women experience.
Publisher: Frontiers Media SA
Date: 10-03-2015
Publisher: Frontiers Media SA
Date: 30-09-2020
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.PREGHY.2018.04.009
Abstract: The intrarenal renin-angiotensin system (iRAS) is implicated in the pathogenesis of hypertension, chronic kidney disease and diabetic nephropathy. Urinary angiotensinogen (uAGT) levels reflect the activity of the iRAS and are altered in women with preecl sia. Since Indigenous Australians suffer high rates and early onset of renal disease, we hypothesised that Indigenous Australian pregnant women, like non-Indigenous women with pregnancy complications, would have altered uAGT levels. The excretion of RAS proteins was measured in non-Indigenous and Indigenous Australian women with uncomplicated or complicated pregnancies (preecl sia, diabetes/gestational diabetes, proteinuria/albuminuria, hypertension, small/large for gestational age, preterm birth), and in non-pregnant non-Indigenous women. Non-Indigenous pregnant women with uncomplicated pregnancies, had higher uAGT/creatinine levels than non-Indigenous non-pregnant women (P < 0.01), and levels increased as pregnancy progressed (P < 0.001). In non-Indigenous pregnant women with pregnancy complications, uAGT/creatinine was suppressed in the third trimester (P < 0.01). In Indigenous pregnant women with uncomplicated pregnancies, there was no change in uAGT/creatinine with gestational age and uAGT/creatinine was lower in the 2nd and 3rd trimesters than in non-Indigenous pregnant women with uncomplicated pregnancies (P < 0.03, P < 0.007, respectively). The uAGT/creatinine ratios of Indigenous women with uncomplicated or complicated pregnancies were the same. A decrease in uAGT/creatinine with advancing gestational age was associated with increased urinary albumin/creatinine, as is seen in preecl sia, but it was not specific for this disorder. The reduced uAGT/creatinine in Indigenous pregnant women may reflect subclinical renal dysfunction which limits the ability of the kidney to maintain sodium balance and could indicate an increased risk of pregnancy complications and/or future renal disease.
Publisher: Wiley
Date: 04-2015
DOI: 10.14814/PHY2.12313
No related grants have been discovered for Eugenie Lumbers.