Renin-angiotensin System In Man Research Articles

A pharmacodynamic study of SR 47436, a selective AT1 receptor antagonist, on blood pressure in conscious cynomolgus monkeys.

1. Conscious normotensive cynomolgus monkeys were chronically instrumented for the measurement of arterial blood pressure and heart rate to investigate the relationships between the plasma concentration, suppression of the pressor response to angiotensin II (AII), compensatory increase in plasma AII, and hypotensive effect obtained after a single oral dose of SR 47436, a potent and specific nonpeptide AT1 receptor antagonist. As blood sampling could influence the hypotensive effect of SR 47436 through activation of the renin angiotensin system (RAS), drug effects were studied in groups of animals with or without blood samplings. 2. SR 47436 at 10 mg kg-1 induced a hypotensive effect which was not greater following a second dose of 30 mg kg-1, indicating that a maximal hypotensive effect had already been obtained. 3. A single oral dose of SR 47436 (10 mg kg-1) caused a sustained hypotension and a marked inhibition of the AII-induced pressor response, lasting for up to 28 h. These effects of SR 47436 are consistent with good oral bioavailability and a slow elimination of the drug (t 1/2 approximately 20 h), and were accompanied by a sustained increase in plasma AII concentration. Taken together, both the hypotensive response and the compensatory increase in AII indicated that vascular and juxtaglomerular AII receptors were blocked. 4. Although a fair correlation between individual plasma drug concentrations and inhibition of AII-induced pressor response was observed, neither the hypotensive effect nor the compensatory increase in AII correlated with the plasma drug levels. 5. Basal arterial pressure and AII-induced pressor response were not affected by blood samplings. 6. These results suggest that SR 47436 is an effective and long lasting AT1 receptor antagonist with a potent hypotensive action in normotensive cynomolgus monkeys. It may be an efficacious blocker of the RAS in man and suitable for once-a-day dosing.

Characterization of angiotensin peptides in plasma of anephric man

Recent evidence suggests that a considerable proportion of plasma angiotensin is generated not in blood but in peripheral tissues. Through the measurement of angiotensin peptides and renin in the plasma of 11 anephric subjects, we have investigated whether kidney-derived renin, or some other tissue mechanism for angiotensin generation, is the major determinant of plasma angiotensin. Particular care was taken to prevent inadvertent activation of inactive renin and possible generation, conversion and metabolism of angiotensin peptides during processing of blood samples. Initial experiments revealed that plasma from anephric subjects contains high amounts of material which interferes in radioimmunoassays for angiotensin, even after high-performance liquid chromatography (HPLC). Therefore, in order to obtain an unambiguous identification of angiotensin peptides, a dual HPLC method was developed in which angiotensin peptides were first separated by HPLC, then acetylated and run again on HPLC before radioimmunoassay for angiotensin I and II (detection limits, 0.25 and 0.2 fmol/ml, respectively). The levels of angiotensin I and II were 1.2 +/- 1.6 and 0.7 +/- 0.5 fmol/ml (mean +/- s.d., n = 9-10), respectively, being 6% of levels in normal subjects, and were consistent with the active renin levels (1.8 +/- 1.7 muIU/ml, n = 11) which were 7% of levels in normal subjects. Artefactual activation of prorenin and angiotensin generation during sample processing were excluded as significant causes of the low levels of active renin and angiotensin I and II in anephric plasma. These data indicate that kidney-derived renin is the major determinant of angiotensin levels in normal human plasma. However, the present demonstration of low levels of active renin and angiotensin I and II in plasma of anephric subjects provides unequivocal evidence for a functional extrarenal renin-angiotensin system in man.

Angiotensin II induces the release of 19-hydroxyandrostenedione in man.

Plasma concentrations of 19-hydroxyandrostenedione [19-hydroxy-4-androstene-3,17-dione (19-OH-A-dione)], which we reported to be an amplifier of the action of aldosterone on the basis of results obtained in bioassays using adrenalectomized rats, were measured in man using a specific and sensitive RIA. Plasma 19-OH-A-dione concentrations (mean +/- SE) in normal subjects were 56 +/- 4 pg/ml in men and 51 +/- 4 pg/ml in women. Plasma 19-OH-A-dione rose significantly during ACTH stimulation and declined significantly during dexamethasone suppression. Plasma 19-OH-A-dione levels in the adrenal vein were an order of magnitude higher than those in the inferior vena cava. These results demonstrate that 19-OH-A-dione is directly secreted by the adrenal cortex and that its secretion is under the control of ACTH. As the action of 19-OH-A-dione may be closely related to that of aldosterone, the response of 19-OH-A-dione to angiotensin II infusion was evaluated and compared with that of aldosterone. During the infusion of graded doses (0.5-4.0 ng/kg . min) of angiotensin II, plasma 19-OH-A-dione increased significantly after the infusion of angiotension II at rates of 1.0 and 2.0 ng/kg . min. It then declined after the infusion of angiotensin II at a rate of 4.0 ng/kg . min. In contrast, plasma aldosterone did not increase significantly until the infusion rate reached 4.0 ng/kg . min. These results indicate that the secretion of 19-OH-A-dione is under the control of angiotensin II. Similar changes in 19-OH-A-dione and aldosterone were found during postural changes. In those subjects who had a small increase in plasma aldosterone when they were upright, 19-OH-A-dione significantly increased. In contrast, in those subjects who had a large increase in plasma aldosterone when upright, 19-OH-A-dione significantly declined. These results suggest that a small elevation of endogenous angiotensin II induces an elevation of plasma 19-OH-A-dione, and a sharp increase in endogenous angiotensin II induces an increase in plasma aldosterone and a decline in plasma 19-OH-A-dione. As angiotensin II stimulated the release of 19-OH-A-dione when the secretion of ACTH was suppressed, angiotensin II acted directly on the adrenal cortex. 19-OH-A-dione is a newly recognized biologically active adrenal C19 steroid which is regulated by both ACTH and the renin-angiotensin system in man.

Interaction of signals influencing renin release.

The various physiological mechanisms that individually modulate the release of renin from the kidney have been reviewed by a number of investigators (18, 27, 68). It is apparent that the juxtaglomerular cells that release renin are influenced by a variety of both stimulatory and inhibitory input signals. The final control mechanisms that govern renin release must process these signals and produce an integrated response. However, the approach to the study of renin release has frequently involved the examination of only a single stimulus, for example renal perfusion pressure, adrenergic activity, or tubular sodium concentration. Moreover, much of this work has been performed with anesthe­ sized animals, immediately following surgery-when the physiologic state is markedly altered-or in isolated tissue lacking many of the control inputs. Although such experiments provide valuable information, we will primarily review how some of the stimuli for renin secretion interact in homeostatic adjustments in the chronic, unanesthetized dog, in order to elucidate the response of the renin-angiotensin system in man in health and disease. In fact, it was the well-known relationship between renal and cardiac diseases and the possible endocrine role of the kidney that motivated Tigerstedt & Bergman (65) in their discovery of renin.

Endogenous prostacyclin synthesis is decreased during activation of the renin-angiotensin system in man.

Prostacyclin has been implicated as a mediator of renin release, whereas angiotensin II evokes prostaglandin I2 (PGI2) release from both vascular and nonvascular tissues in vitro. The physiological significance of these observations was assessed by measurement of an index of endogenous prostacyclin biosynthesis in human volunteers during varied activation of the renin-angiotensin system secondary to manipulation of dietary sodium. Excretion of the major urinary metabolite of prostacyclin in man, 2,3-dinor-6-keto-PGF1 alpha (PGI-M), fell from 295 +/- 51 to 176 +/- 35 (+/- SEM) ng g creatinine-1 (P less than 0.01) in 10 normal subjects when sodium intake was decreased from 150 to 10 meq/day. In five patients with primary hyperaldosteronism, PGI-M fell from 199 +/- 34 ng g creatinine-1 preoperatively to 120 +/- 26 pg/mg creatinine-1 after removal of the adenoma. In such patients, the reduction in PGI-M was associated with a significant increase in PRA. Thus, in both normal subjects and patients with hyperaldosteronism, PGI-M excretion fell rather than increased with activation of the renin-angiotensin system. This suggests that systemic biosynthesis of PGI2 is unrelated to renin release and that angiotensin II is unlikely to stimulate endogenous prostacyclin biosynthesis under these conditions in man.

19-Hydroxyandrostenedione and 6β-hydroxyandrostenedione: New steroids regulated by the renin-angiotensin system in man

The changes of plasma 19-hydroxyandrostenedione (19-OH-A-dione) and 6β-hydroxyandrostenedione (6β-OH-A-dione) during the infusion of angiotensin II were evaluated and were compared with those of plasma aldosterone in man. Angiotensin II was infused into 5 normal subjects with an infusion pump at rates of 0.5, 1.0, 2.0 and 4.0 ng/kg per min. Each dose was infused for 20 min. Plasma 19-OH-A-dione rose significantly following the infusion of angiotensin II at a rate of 0.5 ng/kg per min and plasma 6β-OH-A-dione rose significantly following the infusion of angiotensin II at a rate of 1.0 ng/kg per min. In contrast, plasma aldosterone did not change significantly until the infusion rate reached 4.0 ng/kg per min. These results indicate that the secretion of 19-OH-A-dione and 6β-OH-A-dione is under the control of angiotensin II and the release of 19-OH-A-dione and 6β-OH-A-dione is induced earlier by the smaller doses of angiotensin II prior to the secretion of aldosterone. As 19-OH-A-dione and 6β-OH-A-dione amplify the action of aldosterone in bioassays using adrenalectomized rats and work as sodium-retaining and hypertensinogenic agents in intact rats, they are newly recognized biologically active steroids which are regulated by the renin-angiotensin system in man.

Evidence that 19-hydroxyandrostenedione is secreted by the adrenal cortex and is under the control of ACTH and the renin-angiotensin system in man

Plasma 19-hydroxyandrostenedione (19-OH-A-dione) concentrations in man were evaluated using a specific and sensitive radioimmunoassay. Plasma 19-OH-A-dione concentrations (mean ± SE) in normal subjects are 151 ± 14 pg/ml (n=13) in males and 141 ± 9 pg/ml (n=14) in females. Plasma 19-OH-A-dione (mean ± SE) rises significantly during ACTH stimulation (116 ± 25 pg/ml vs 288 ± 38 pg/ml; P<0.01; n=5), declines significantly during dexamethasone suppression (180 ± 30 pg/ml vs 36 ± 14 pg/ml; P<0.01; n=4) and rises significantly during angiotensin II infusion (89 ± 10 pg/ml vs 159 ± 27 pg/ml; P<0.05; n=5). Plasma 19-OH-A-dione in the adrenal vein is much higher than that in the inferior vena cava (2076–3076 pg/ml vs 115–184 pg/ml; n=2). These results demonstrate that 19-OH-A-dione is directly secreted by the adrenal cortex and is under the control of ACTH and the renin-angiotensin system.

The effect of sodium restriction and prostaglandin inhibition on the renin-angiotensin system in man.

To investigate the possible interrelationship between the renin-angiotensin and prostaglandin systems, two groups of normal men were evaluated under conditions of varied sodium intake and after indomethacin, an inhibitor of prostaglandin synthesis. Eight subjects were placed on a 200 mEq Na diet and given 45 min infusions of prostaglandin A1 (PGA1) at 0.075 microng/kg/min and angiotensin II at 10 ng/kg/min on separate mornings. PGA1 produced a significant rise in both plasma renin activity (PRA) and aldosterone. Angiotensin II caused a similar rise in aldosterone. The patients were then placed on a 10-20 mEq Na diet and the infusions repeated. PGA1 again induced a further increase in both PRA and aldosterone. Angiotensin II produced the expected increase in aldosterone while PRA decreased. Body weight and 24 h sodium excretion were not different from control days on either diet. When indomethacin was administered to patients on the low sodium diet, PRA fell significantly and there was an increased pressor responsiveness to angiotensin. In a separate group of 4 patients on a low salt intake, basal PRA fell significantly during a 4 day period of indomethacin administration and returned to control values within 48 h after discontinuing the drug. These studies suggest that PGA1 infusions stimulate renin release independently of sodium balance. Inhibition of prostaglandin synthesis lowers PRA and increases pressor responsiveness to angiotensin. The data provide further evidence that vasodepressor prostaglandins may play a role in renin release and blood pressure homeostasis.

The effect of angiotensin II and indomethacin on immunoreactive prostaglandin “A” levels in man

The effect of angiotensin II on peripheral levels of immunoreactive prostaglandin A 2 (IR-PGA) was determined in 17 normal male volunteers. IR-PGA rose from 338 ± 65 (SE) pg/ml to 635 ± 142 in response to pressor infusions of angiotensin II ( p <0.05 on paired analysis). This increase was not observed when indomethacin, 75 mg p.o., was given to 8 patients two hours prior to a repeat infusion. Five patients of the original group were placed on a low sodium diet (10–20 mEq). The response to angiotensin was now exaggerated (278 ±52 pg/ml to 916 ± 284). These five patients were kept on a low sodium intake and given indomethacin 50 mg p.o. q 6 hourly for 4 days. There was no significant rise with angiotensin infusion (106 ± 31 pg/ml to 120 ± 70). Pressor infusions of angiotensin II raise peripheral levels of IR-PGA, and this response is exaggerated by a low sodium diet and blocked by either acute or chronic indomethacin administration. This data supports the concept that vasodilatory prostaglandins may be released by endogenous angiotensin and thus provide a dynamic antagonism to the renin angiotensin system in man.

The John Phillips Memorial Award Lecture: Normal and Altered Function of the Renin-Angiotensin-Aldosterone System in Man. Application in Clinical and Research Medicine.

Excerpt Improved methods now make it possible to assess the activity of the renin-angiotensin system in man by measuring renin activity in peripheral plasma. Angiotensin II, the active octapeptide ...