Role of angiotensin II in the pressor response to cortisol in fetal sheep during late gestation

Glucocorticoids increase blood pressure in utero, but the mechanisms responsible are unclear. This study investigated the hypothesis that the hypertensive effects of cortisol depend upon a functional renin-angiotensin system (RAS). The study examined, in the sheep fetus, whether blockade of the Ang II type 1 (AT(1)) specific receptor prevented the cortisol-induced increase in blood pressure. From 124 +/- 1 days of gestation (term 145 +/- 2 days), 27 chronically catheterized sheep fetuses were infused i.v. for 5 days with one of the following: (1) saline (0.9% NaCl at 2.5 ml day(-1), n= 6); (2) cortisol (3-5 mg kg(-1) day(-1), n= 7); (3) AT(1) receptor antagonist (GR138950, 1-3 mg kg(-1) day(-1) in saline, GRS, n= 7); or (4) cortisol and GR138950 (GRC, n= 7). On all days of infusion, plasma cortisol was greater in both groups of cortisol-treated fetuses than in the respective control fetuses (P < 0.05), and GR138950 prevented the pressor response to exogenous Ang II. Over 5 days of infusion, blood pressure increased by a maximum of 7.6 +/- 1.4 mmHg (mean +/-s.e.m., P < 0.05) in the cortisol-, but not saline-infused, fetuses. Blockade of the AT(1) receptor caused significant reductions in blood pressure in both GRS- and GRC-treated groups (P < 0.05); in the GRS-treated fetuses, the fall in blood pressure was significant from the first day of infusion, while in GRC-treated fetuses the decrement was not significant until the second day (P < 0.05). Over the period of the infusion, decreases in arterial blood pH andP(a,O(2)), and an increase inP(a,CO(2)), were observed in the fetuses treated with the AT(1) receptor antagonist (P < 0.05). Therefore, in the sheep fetus, 5 days of AT(1) receptor antagonism suppresses the cortisol-induced rise in blood pressure. These results suggest that cortisol may increase blood pressure within 24 h of administration by a mechanism that is independent of the fetal RAS. Thereafter, Ang II, via the AT(1) receptor, may mediate, in part, the hypertensive effects of cortisol in utero.     

Failure of naloxone to reduce the clonidine induced reduction of blood pressure and plasma noradrenaline in patients with essential hypertension

Studies in animals and man indicate a functional interaction between the adrenergic and the opiate systems. In the present study the effect of the opiate receptor blocker naloxone on the reduction of blood pressure and plasma noradrenaline induced by the alpha 2-agonist clonidine was investigated in nine patients with essential hypertension. In a randomised manner the patients received a bolus dose of naloxone (10 micrograms/kg) or physiological saline followed by a slow infusion of naloxone (5 micrograms/kg/h) or saline, respectively. Fifteen minutes after the respective bolus dose, clonidine (3 micrograms/kg) was infused over 10 minutes. Naloxone had no effect on the clonidine induced hypotension and reduction of plasma noradrenaline. Accordingly, there is no evidence that the clonidine induced reduction of blood pressure and plasma noradrenaline involves opiate receptors that can be blocked by naloxone. Plasma adrenaline increased significantly during the early phase of naloxone infusion.     

Effect of angiotensin II on parotid saliva secretion in conscious sheep.

Intravenous infusion of angiotensin II over the dose range 3-20 microgram/h for 15 min caused a dose-dependent reduction in parotid saliva secretion and increase in arterial blood pressure in conscious sheep. The blood levels of angiotensin II contrived by these infusions were probably within the physiological range for sheep. Infusion of angiotensin II (3 microgram/h) into the carotid artery ipsilateral to the parotid gland under study caused greater reduction in saliva secretion rate than an equivalent infusion of angiotensin II into the contralateral carotid artery. This result suggests a direct effect of angiotensin II at the parotid, possibly by a constrictor action on its vasculature or by altering water and electrolyte transport by the gland. In sodium-deplete sheep, intravenous infusion of the angiotensin antagonist saralasin (1 mg/h for 1 h) caused transient increase of saliva flow for 20-30 min. It is suggested that angiotensin II may have a physiological role in regulating parotid saliva secretion during sodium depletion.     

Development of cardiovascular function in the horse fetus

In mammals, the mechanisms regulating an increase in fetal arterial blood pressure with advancing gestational age remain unidentified. In all species studied to date, the prepartum increase in fetal plasma cortisol has an important role in the maturation of physiological systems essential for neonatal survival. In the horse, the prepartum elevation in fetal cortisol and arterial blood pressure are delayed relative to other species. Hence, the mechanisms governing the ontogenic increase in arterial blood pressure in the horse fetus may mature much closer to term than in other fetal animals. In the chronically instrumented pony mare and fetus, this study investigated how changes in fetal peripheral vascular resistance, in plasma concentrations of noradrenaline, adrenaline and vasopressin, and in the maternal-to-fetal plasma concentration gradient of oxygen and glucose relate to the ontogenic changes in fetal arterial blood pressure and fetal plasma cortisol concentration as term approaches. The data show that, towards term in the horse fetus, the increase in arterial blood pressure occurs together with reductions in metatarsal vascular resistance, elevations in plasma concentrations of cortisol, vasopressin, adrenaline and noradrenaline, and falls in the fetal : maternal ratio of blood   P _a,O2  and glucose concentration. Correlation analysis revealed that arterial blood pressure was positively related with plasma concentrations of vasopressin and noradrenaline, but not adrenaline in the fetus, and inversely related to the fetal : maternal ratio of blood   P _a,O2  , but not glucose, concentration. This suggests that increasing vasopressinergic and noradrenergic influences as well as changes in oxygen availability to the fetus and uteroplacental tissues may contribute to the ontogenic increase in fetal arterial blood pressure towards term in the horse.     

Effect of adrenal arterial infusion of P-113 on aldosterone secretion in Na-deficient sheep.

To examine the role of the renin-angiotensin system in aldosterone regulation, P-113 ([Sar1,Ala8]angiotensin II) was infused into the arterial blood supply of the transplanted adrenal gland in conscious sheep. Effects on the aldosterone response to infused angiotensin II and III in sodium-replete sheep were compared with effects of P-113 on aldosterone secretion in sodium deficiency. P-113 infusion up to 1,000 microgram/h for 1-2 h did not consistently alter aldosterone secretion in sodium-deficient sheep. However, in sodium-replete sheep P-113 infusion for 20 min at 10 microgram/h or more abolished aldosterone responses to high blood levels of angiotensin II and III produced by systemic intravenous or adrenal intra-arterial infusion. P-113 infusions alone had minor agonist activity on aldosterone secretion in sodium-replete sheep. These results indicate that the increased secretion of aldosterone in Na-depleted sheep is not simply and commensurately determined by increase of angiotensin II and III concentration in the arterial blood perfusing the adrenal gland.     

Effects of angiotensin II on blood flow in rat submandibular gland

The effect of angiotensin II (Ang II) was studied on blood flow in the submandibular gland and tongue in male rats. Blood flow changes were determined with laser Doppler flowmetry and Ang II was infused into the common carotid artery before and after i.v. doses (18 nmol kg-1) of the angiotensin II antagonist saralasin. Angiotensin II (10-60 pmol min-1) dose-dependently increased blood pressure and tongue blood flow, whereas glandular blood flow decreased at all of the doses used. After saralasin administration the angiotensin II effects on blood pressure, tongue and glandular blood flow were significantly diminished (glandular blood flow reduction was diminished from 29%-3%, P less than 0.005, n = 9). However, the responsiveness of these 3 parameters to local infusions with noradrenaline (0.75-3.0 pmol min-1) was unaffected by saralasin. The dose of saralasin used in the present study did not affect any of the parameters on it's own. Our results show that vascular receptors sensitive to angiotensin II operate in the submandibular gland but not in the tongue.     

Angiotensin II and bradykinin: interactions between two centrally active peptides

Two neuropeptides, bradykinin (BK) and angiotensin II (ANG II), produce an increase in blood pressure when injected into the brain ventricles. This study is an example of central peptide-peptide interaction and was carried out to determine if BK and ANG II share a common mechanism in the brain to control blood pressure and drinking in rats. Prior injection of saralasin [10 micrograms intraventricularly (ivt)] was found to enhance the pressor response to ivt BK (5 micrograms) by 44%. The same dose of saralasin attenuated the pressor response to ivt ANG II (200 ng) by 55%. 50 ng ANG II and 5 micrograms BK given together ivt did not significantly alter blood pressure or urine conductance compared to 50 ng ANG II alone. Drinking to ivt infusions of ANG II (14 ng/min) was significantly attenuated when combined with BK (0.7 micrograms or 2.8 micrograms/min). Pretreatment with 10 micrograms indomethacin ivt diminished the pressor response to 5 micrograms ivt BK. Prostaglandin E2 (1.4 micrograms/min), but not prostaglandin A2, inhibited drinking to 14 ng/min ivt infusions of ANG II. The results suggest that ANG II and BK share an interrelationship with respect to their central actions: ANG II inhibits the BK pressor response and BK acts to inhibit drinking induced by ANG II. Prostaglandins of the E series may mediate these central actions of bradykinins.     

The effect of intravenous prostaglandin E1 on ischaemic pain and on leg blood-flow in subjects with peripheral artery disease: a double-blind controlled study

The effect of intravenous PGE1 (15 micrograms/h for 72 h) and saline (placebo) on ischaemic resting pains and the macro- and microcirculation was studied in 16 patients with peripheral artery disease. No significant difference in pain relief was observed between PGE1 and placebo. The calf blood-flow was unchanged during both infusions. Skin temperature in the arteriosclerotic foot, however, increased significantly during PGE1 infusion but not during saline infusion. No significant effects were seen on blood-pressure, fluorescein angiography or vital capillary microscopy of the big toe 1 week or 1 month after the PGE1 and placebo infusions.     

The cardiovascular and renal effects of acute and chronic inhibition of nitric oxide production in fetal sheep

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.     

A study of the action of angiotensin II on perfusion through the cortex and papilla of the rat kidney.

The effect of angiotensin II on blood pressure and perfusion of blood through the cortex and papilla regions of the kidney was determined in pentobarbitone-anaesthetized rats which were subjected to laser-Doppler flowmetry to estimate regional renal haemodynamics. Angiotensin II was infused at 10, 45 and 150 ng (kg body weight-1 min-1) which caused dose-related increases in blood pressure of 3, 12 and 24%, respectively, and decreases in cortical perfusion of 9, 15 and 24%, respectively. Papillary perfusion did not change at any dose of angiotensin II. This pattern and magnitude of responses to angiotensin II in blood pressure, cortical and papillary perfusions was essentially unaffected (a) following blockade of cyclo-oxygenase activity with indomethacin (1.3 mg kg-1 plus 2 mg kg-1 h-1), (b) during infusion of a bradykinin antagonist, at 1.3 micrograms min-1, (c) when renal perfusion pressure was regulated at control levels and (d) following Methylene Blue administration to inhibit potential endothelial-derived relaxing factor production. By contrast, infusion of phenylephrine at 5, 10 and 20 micrograms kg-1 min-1 caused dose-related increases in blood pressure and decreases in both cortical and papillary perfusions reaching some 28, 7 and 17% respectively at the highest dose of phenylephrine used. These results showed that both cortex and papilla were sensitive to vasoconstrictor agents. They are compatible with the suggestion that angiotensin II regulates cortical but not papillary perfusion in the kidney, and that these responses do not depend on prostaglandin, bradykinin, renal perfusion pressure or endothelium-derived relaxing factor.     

Application of a new technique--blood pressure clamping--for analysis of prostaglandin interference with sympathetic neurotransmission in man

To circumvent baroreceptor reflexes following drug-induced interference sympathetic neurotransmission, a new technique - blood pressure clamping--has developed. This implies that the sympathetic activity in an awake human is 'clamped' at a supranormal level by infusion of a vasodilator. In 11 healthy volunteers nitroprusside or saline was randomly infused in two consecutive 2-h periods. Plasma and urinary catecholamine levels were analysed by liquid chromatography. The experiments were repeated after random administration of the prostaglandin synthesis inhibitor, ibuprofen, or placebo. In the basal state (no ibuprofen, saline infusion) the mean arterial blood pressure was 81.4 +/- 2.3 mmHg, the heart rate was 60.9 +/- 0.3 beats min-1 and the plasma level of noradrenaline was 1.12 +/- 0.15 nM. Infusion of nitroprusside at a dose lowering the mean blood pressure by 11.6 +/- 1.6 mmHg and increasing the heart rate to 74.6 +/- 2.9 beats min-1 elevated plasma noradrenaline to 2.86 +/- 0.39 nM. After pretreatment with ibuprofen (saline infusion), the systemic blood pressure, the heart rate, and the plasma and urinary levels of noradrenaline were unaffected in comparison to before drug (80.1 +/- 2.3 mmHg, 58.4 +/- 0.3 beats min-1 and 1.13 +/- 0.12 nM respectively). Infusion of nitroprusside at a rate lowering the blood pressure by 11.2 +/- 2.4 mmHg and increasing the heart rate to 74.4 +/- 0.5 beats min-1, elevated the plasma level of noradrenaline to 2.46 +/- 0.38 ng ml-1, which is not different from before ibuprofen. The amount of nitroprusside required to lower the blood pressure was not different in the presence and absence of ibuprofen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of angiotensin ll on blood flow in rat submandibular gland

The effect of angiotensin II (Ang II) was studied on blood flow in the submandibular gland and tongue in male rats. Blood flow changes were determined with laser Doppler flowmetry and Ang II was infused into the common carotid artery before and after i.v. doses (18 nmol kg^-l) of the angiotensin II antagonist saralasin. Angiotensin II (10–60 pmol min^-l) dose-dependently increased blood pressure and tongue blood flow, whereas glandular blood flow decreased at all of the doses used. After saralasin administration the angiotensin II effects on blood pressure, tongue and glandular blood flow were significantly diminished (glandular blood flow reduction was diminished from 29%-3%, P < 0.005, n = 9). However, the responsiveness of these 3 parameters to local infusions with noradrenaline (0.75–3.0 pmol min^-1) was unaffected by saralasin. The dose of saralasin used in the present study did not affect any of the parameters on it's own. Our results show that vascular receptors sensitive to angiotensin II operate in the submandibular gland but not in the tongue.     

Plasma angiotensins and human forearm circulation: effects of sympatho-adrenal activation

Complex interactions appear to exist between the renin–angiotensin system and sympathetic neurotransmission, and sympathetic activity may influence local angiotensin II formation. Arterial and forearm venous plasma levels of angiotensin I and II were therefore studied in 11 healthy males at rest, during sympathetic activation elicited by mental stress, and during adrenaline induced vasodilation. Specific assays for angiotensin-(1–8) octapeptide and for angiotensin-(1–10) decapeptide (i.e. angiotensin II and I, respectively), were used. Special precautions to minimize ex vivo formation and/or degradation of angiotensins were employed. Mental stress increased regional noradrenaline overflow three-fold, with a concomitant three-fold increase in forearm blood flow, whereas intravenous adrenaline infusion increased forearm blood flow two-fold and noradrenaline overflow four-fold. There was a constant positive veno-arterial concentration difference for angiotensin I under all conditions tested, compatible with local angiotensin I formation. We found no veno-arterial concentration difference for angiotensin II or regional net angiotensin II overflow under the conditions tested. These results in the forearm circulation support previous animal experimental evidence in skeletal muscle and provide no evidence in favour of a de novo formation of angiotensin II in skeletal muscle in vivo during basal conditions. Furthermore, sympathetic nerve stimulation does not seem to enhance angiotensin II generation importantly in this vascular bed.     

Angiotensin causes vasoconstriction during hemorrhage in baroreceptor-denervated dogs

The participation of angiotensin II (ANG II) in the maintenance of arterial blood pressure during hypotensive hemorrhage was examined in unanesthetized, baroreceptor-denervated dogs. When mean aortic blood pressure was reduced to 69.0 +/- 2.2 mmHg, plasma renin activity increased from 0.6 +/- 0.3 ng ANG I X ml-1 X h-1 during the prehemorrhage control period to 4.5 +/- 1.6. Twenty minutes after the hemorrhage, mean aortic blood pressure rose to 78.9 +/- 3.1 mmHg. Subsequent infusion of the angiotensin II antagonist saralasin (5.2-14.0 micrograms X kg-1 X min-1) decreased mean aortic pressure to 59.6 +/- 3.3 mmHg. When 5% dextrose was infused in place of saralasin, mean aortic pressure was 79.3 +/- 4.3 mmHg. The lower aortic blood pressure caused by saralasin infusion was the result of a significant decrease in total peripheral resistance. Resistance was 10.3 +/- 3.2 mmHg X l-1 X min lower during saralasin infusion than during dextrose infusion. We conclude that baroreceptor reflexes are not essential for the elevation of plasma renin activity during hemorrhage. In baroreceptor-denervated dogs subjected to hypotensive hemorrhage, the increased formation of ANG II has a vasoconstrictor action that contributes to the maintenance of arterial blood pressure.     

Influence of forebrain lesions and isoflurane anaesthesia,respectively, on responses to the intracarotid infusion of angiotensin II in sheep

In conscious sheep, lesions involving the anterior wall of the third cerebral ventricle extinguished the dipsogenic and cortisol releasing effects of 10 min intracarotid (i. c.) infusions of angiotensin II (Ang II) (20 pmol kg^-1 min^-1). The sustained hypertension obtained in response to i. c. Ang II in the intact animal was not significantly changed by the forebrain lesions. Pronounced, but short-lasting tachycardia immediately developed in response to i. c. Ang II in control animals. After a 1 min return to initial values the heart rate (HR) rose to about 20 beats min^-1 above pre-infusion level during the remaining infusion period. After a brief post-infusion fall, HR retook that level. It then gradually declined but did not return to initial level until about 25 min later. During isoflurane anaesthesia in the latter animals carotid blood pressure (cBP) was reduced by ? 30% while the HR was more than doubled. The cBP rise in response to i. c. Ang II infusion was < 50% of that seen in awake animals and the pressure returned to initial level within ? 5 min after the end of the infusion. The infusion did not influence the HR. This study provides support for the idea that blood borne Ang II, bound at cerebral sites posterior to the hypothalamic reion, continues to have cardiovascular effects for ? 20 min after the concentration in the blood has returned to pre-infusion level.     

Activities of hypothalamic angiotensin II-sensitive neurons are greately enhanced even in prehypertensive spontaneously hypertensive rats

We have previously demonstrated that some neurons in the anterior hypothalamic area (AHA) of rats are tonically activated by endogenous angiotensins and that reactivities of these neurons to angiotensin II are enhanced in 15- to 16-week-old spontaneously hypertensive rats (SHR). To investigate whether the enhanced reactivity of SHR AHA neurons to angiotensin II is secondary to raised blood pressure, we examined whether the enhanced reactivity to angiotensin II also occurs in prehypertensive SHR. We also examined whether reactivities of AHA angiotensin II-sensitive neurons to intracerebroventricular hypertonic saline are enhanced in prehypertensive SHR, since intracerebroventricular injection of hypertonic saline increases the firing rate of AHA neurons via release of angiotensins at AHA neuron levels. Male 4-week-old SHR and age-matched Wistar Kyoto rats (WKY) were used in this study. There was no difference in systolic blood pressure between both rats. They were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Pressure application of angiotensin II onto some AHA neurons increased their firing rate. The basal firing rate of angiotensin II-sensitive neurons was increased in SHR as compared with WKY. The increase of unit firing by angiotenisn II was enhanced in SHR as compared with WKY. Intracerebroventricular injection of hypertonic saline increased the firing rate of AHA angiotensin II-sensitive neurons. The average threshold sodium concentration for the saline-induced increase of neural firing was lower in SHR than in WKY. These findings demonstrate that basal activities and responsiveness to angiotensin II in AHA angiotensin II-sensitive neurons are enhanced in prehypertensive SHR as compared with age-matched WKY. In addition, these findings indicate that central saline-induced activation of AHA angiotensin II-sensitive neurons is also enhanced in SHR. It appears that the enhanced reactivity of SHR AHA neurons to angiotensin II occurs primarily in nature but not secondarily to raised blood pressure in SHR.     

Adrenoreceptor blockade in angiotensin-induced hypertension: effect on rat coronary arteries and myocardium

Adrenoreceptor blockade has been used to separate the actions of elevated blood pressure, angiotensin II, and catecholamines on the coronary vasculature and myocardium of rats. Twenty-two male Wistar-Kyoto rats received phentolamine (an alpha-receptor blocker, 10 mg/kg body weight) and/or propranolol (a beta-receptor blocker, 1 mg/kg body weight) followed by an infusion for 2 hours of angiotensin amide (1.7 micrograms/min/kg) or saline. Sections of left ventricle were examined by light and electron microscopy. Blood pressure was elevated only in animals receiving angiotensin II with or without propranolol. Epicardial arteries were devoid of lesions in all animals. Small intramural arteries and arterioles in the hypertensive animals exhibited vasoconstriction, endothelial cell vacuolization with bleb formation, and medial smooth muscle cell fragmentation and necrosis. Foci of irreversible ischemic or anoxic myocardial injury consisting of contraction zones and bands and translocated mitochondria with granular matrix densities were seen in angiotensin-infused animals. Similar but less severe myocardial changes were found in the animals pretreated with propranolol. Vascular lesions were also seen in animals receiving phentolamine, propranolol, and angiotensin II; but myocardial alterations consisted solely of areas with contraction zones. Vascular but not myocardial lesions were observed in animals that received angiotensin II and phentolamine. It is concluded that angiotensin II can produce vascular injury in the absence of elevated systemic blood pressure or catecholamine effects. In contrast, irreversible myocardial injury seems to depend upon the increased pressure and/or coronary artery vasoconstriction associated with angiotensin administration.     

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

Prenatal exposure to elevated maternal glucocorticoids (dexamethasone (DEX) or cortisol (CORT)) for 2 days early in pregnancy can 'programme' alterations in adult offspring of sheep, including elevated arterial pressure. DEX treatment also results in greater angiotensin II type 1 (AT₁) receptor expression in the medulla oblongata in late gestation fetuses than in saline (SAL)- or CORT-exposed animals. We hypothesized that this would result in functional changes in brainstem angiotensinergic control of cardiovascular function in DEX- but not CORT-exposed animals. To test this hypothesis, cardiovascular responses to intracerebroventricular ( i.c.v. ) angiotensin II were examined in adult male offspring exposed to DEX (0.48 mg h⁻¹; n = 7), CORT (5 mg h⁻¹, n = 6) or SAL ( n = 9) from 26 to 28 days of gestation. Increases in mean arterial pressure during i.c.v. infusion of angiotensin II (1 or 10 μg h⁻¹) were significantly greater in the DEX group (10 ± 1 mmHg at 1 μg h⁻¹) compared with SAL (6 ± 1 mmHg) or CORT (6 ± 1 mmHg) animals ( P < 0.05). i.c.v. infusion of the AT₁ antagonist losartan significantly decreased cardiac output and heart rate in DEX animals, but not in SAL or CORT animals. Thus, increased expression of brainstem AT₁ receptor mRNA after prenatal DEX is associated with increased responsiveness of cardiovascular control to activation of brain AT receptors by exogenous and endogenous angiotensin II. The altered role of the brain RAS in sheep exposed prenatally to DEX was not observed in sheep exposed prenatally to cortisol, suggesting these two glucocorticoids have distinct programming actions.     

Developmental regulation of hepatic and renal gluconeogenic enzymes by thyroid hormones in fetal sheep during late gestation

Tissue glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) activities were investigated in sheep fetuses after experimental manipulation of thyroid hormone status. Increments in hepatic and renal G6P and PEPCK activities seen between 127–130 and 140–145 days of gestation (term, 145 ± 2 days) were abolished when the normal prepartum rise in plasma triiodothyronine (T₃), but not cortisol, was prevented by fetal thyroidectomy (TX). At 127–130 days, hepatic and renal G6P, and renal PEPCK, activities were similar in intact and TX fetuses; however, hepatic PEPCK was increased by TX. At 140–145 days, tissue G6P and PEPCK activities in TX fetuses were lower than in intact fetuses. In immature fetuses infused with cortisol (2–3 mg (kg body wt) ⁻¹ day ⁻¹) for five days, hepatic and renal enzyme activities were increased to those seen in mature fetuses near term. After five days of T₃ infusion (8–12 μg (kg body wt) ⁻¹ day ⁻¹), G6P and PEPCK activities in the liver and kidney were greater than in saline-infused fetuses, but only renal G6P and PEPCK increased to the level seen close to term. Therefore, in fetal sheep, thyroid hormones are important for the prepartum rises in G6P and PEPCK activities in the liver and kidney and may mediate, in part, the maturational effects of cortisol.     

Effect of prolonged low-dose infusions of ile5-angiotensin II on blood pressure,aldosterone and electrolyte excretion in sodium replete man

Summary Two healthy young males on a constant normal sodium diet (135 mM/day) were infused for 132 h with 3 ng/kg/min of angiotensin II. Plasma angiotensin II levels were thereby raised to the range of moderate sodium depletion. Plasma aldosterone and the urinary excretion rate of aldosterone-18-glucuronide were markedly increased during the whole infusion period and returned to control levels after the infusion was stopped. A slight tendency of aldosterone secretion to decrease towards the end of infusion was probably due to sodium retention (appr. 200 mM and 350 mM respectively) and to a fall in plasma potassium by approximately 0.5 mM/l. Plasma aldosterone during infusion, maintained circadian variations similar to those of cortisol. Plasma cortisol patterns were unaffected by angiotensin II. Blood pressure increased gradually during angiotensin II infusion, reflecting changes in sodium balance. The results, differing from those of studies in dog and sheep, support the assumption that angiotensin II is an important regulator of aldosterone secretion in man rather than a merely permissive factor.Presented in part to the 22nd symposium of the Deutsche Gesellschaft für Endokrinologie, Travemünde, 1977