William S. Spielman

The Renin-Angiotensin System and Aldosterone Secretion during Sodium Depletion in the Rat

The role of the renin-angiotensin system in the control of aldosterone secretion was studied in the sodium-depleted rat. Administration of angiotensin II produced a significant increase in aldosterone secretion and arterial blood pressure in normal rats; simultaneous infusion of the angiotensin analogue. 1-sarcosine-8-alanine-angiotensin II, blocked both the pressor and the steroidogenic actions of angiotensin. Since the angiotensin II analogue was effective in blocking exogenous angiotensin II, an attempt was made to block endogenously formed angiotensin II in the sodium-depleted rat; infusions of large doses of the analogue produced a significant fall in arterial blood pressure, but aldosterone secretion failed to change. Bilateral nephrectomy also failed to decrease aldosterone secretion in the sodium-depleted rat even though arterial blood pressure fell. Since the secretion of corticosterone in these rats was high, it seemed likely that the failure of aldosterone secretion to fall resulted from an overriding influence of adrenocorticotropic hormone (ACTH). To test this hypothesis, the renin-angiotensin system was again blocked in sodium-depleted rats with three levels of anterior pituitary function. With high or intermediate rates of corticosterone secretion, a nonapeptide converting enzyme inhibitor (CEI) failed to influence aldosterone secretion. However, when the influence of ACTH was completely eliminated by hypophysectomy in sodium-depleted rats, the nonapeptide CEI produced a striking fall in aldosterone secretion. In contrast, arterial blood pressure was significantly reduced by CEI in rats with all three levels of anterior pituitary function. The data suggest a role for angiotensin II in the regulation of aldosterone secretion and the maintenance of arterial blood pressure in the sodium-depleted rat.

Brief Reviews: Agents Which Block the Action of the Renin-Angiotensin System

• The role of the renin-angiotensin system in the control of arterial blood pressure and aldosterone secretion has been studied extensively in homeostasis, hypertensive disease, and edematous states. For many years it has been realized that the availability of effective blocking agents for renin or for angiotensin II might help greatly in the study of this system and might have important value in the treatment of conditions such as renal hypertension and heart failure. During the past few years, an increasing number of blocking agents for the reninangiotensin system have been developed. These agents act at one of three sites: (1) they block the action of renin in plasma, (2) they prevent converting enzyme from forming angiotensin II from angiotensin I, or (3) they block the receptor sites for angiotensin II in arteriolar smooth muscle and adrenal cortex. In addition, adrenergic blocking agents such as propranolol decrease the release of renin from the renal juxtaglomerular cells. This review is concerned only with the agents which block the action of the renin-angiotensin system, not with those that decrease the release of renin. The new observations with blocking agents have helped solve several specific problems under investigation, and, in addition, new important functions of the renin-angiotensin system have been uncovered. For example, it is now recognized (1-5) that in low output states angiotensin II acts directly on the peripheral arterioles including the renal vasculature to increase peripheral resistance, decrease renal blood flow, and maintain arterial blood pressure. In this review, the recent findings have been collated to present this new knowledge on the physiology of angiotensin II, to evaluate the present state of our knowledge on such important problems as the pathogenesis of experimental renal hypertension, and to stimulate additional research on the physiology of the renin-angiotensin system.

Evidence that des-Asp1 angiotensin II mediates the renin-angiotensin response.

Studies were undertaken to compare and evaluate the influence of angiotensin II and its heptapeptide fragment, des-Asp1-angiotensin II, at various receptor sites for angiotensin in both dogs and rats. Receptor sites evaluated were those which are found in the glomerulosa, reticularis, and fasiculata of the adrenal cortex, in the renal arterioles and the juxtaglomerular cells of the kidney, and in the peripheral arterioles. Both peptides produced similar changes in the steroid secretion profiles for aldosterone, corticosterone, and cortisol in the dog. In the rat, both peptides similarly increased aldosterone and corticosterone secretion; however, a larger dose of the competitive antagonist Sar1,Ala8-angiotensin II was required to block the steroid response to the heptapeptide. This finding suggests that receptor affinity for des-Asp1-angiotensin II may be greater than its affinity for angiotensin II. Both peptides also decreased renin secretion and renal blood flow similarly in the dog. The pressor response to the heptapepide was only about one-half the pressor response to angiotensin II in both the rat and dog studies. Collectively, these observations in dogs and rats suggest that des-Asp1-angiotensin II may mediate the response to the renin-angiotensin system at both adrenal and renal receptors.

The Signal Perceived by the Macula Densa during Changes in Renin Release

Renin secretion was studied in acute experiments in dogs during occlusion of the ureter alone (experiment 1), ureteral occlusion with a superimposed intrarenal infusion of papaverine (experiment 2), or ureteral occlusion with a superimposed intravenous ethacrynic acid injection (experiment 3) and following release of the ureteral occlusion (all three experiments). In all three experiments, ureteral occlusion increased renin secretion four- to fivefold. In experiment 2, papaverine, an inhibitor of smooth muscle contractility, was infused intrarenally during the last 20 minutes of ureteral occlusion, but renin secretion was unchanged by the infusion. Renin secretion decreased rapidly and was at the control level 5, 12½, and 27½ minutes after release of the occlusion, but urinary sodium concentration and excretion rate increased markedly during this period. In experiment 3, a superimposed injection of ethacrynic acid failed to alter renin secretion during ureteral occlusion. After release of the ureter, renin secretion remained unchanged for the first 5 minutes. Although renin secretion had decreased 12½ and 27½ minutes after release of the occlusion, it was still elevated twofold above the control level. Again, sodium excretion increased markedly and urinary sodium concentration was high after ureteral release. These findings support the hypothesis that the rate of renin release is inversely related to the rate of sodium transport by the macula densa cells.

Arterial Pressure Regulation during Hemorrhage: Homeostatic Role of Angiotensin II:

Summary The role of the renin-angio-tensin system in the maintenance of arterial pressure following hemorrhage was studied in conscious dogs. Hemorrhage (20 ml/kg body wt) decreased the mean arterial pressure, but compensatory mechanisms partially restored the arterial pressure toward normal. Plasma renin activity increased more than twofold following hemorrhage. To evaluate the role of endogenous angiotensin II in this compensatory response, a specific competitive antagonist of angiotensin II, l-sarcosine-8-alanine-angiotensin II, was infused intravenously at 6.0 μgAg min-1 for 30 min; the mean posthemorrhage arterial pressure decreased from 102 ± 7 mmHg to 80 ± 6 mmHg after 15 and 30 min of analog infusion (P < 0.01 for both values). After a recovery period of 60 min, arterial pressure returned to pre-infusion levels. These results suggest that angiotensin II plays an important role in the short-term maintenance of arterial pressure following hemorrhage in the conscious animal.

Des-Asp-1-Angiotensin II: Possible Role in Mediating the Renin-Angiotensin Response in the Rat

Summary Angiotensin II and its heptapeptide fragment, Des-Asp-1-angiotensin II, produced a striking increase in aldosterone secretion in rats pretreated with dexamethasone and morphine to reduce ACTH release. l-Sar-8-Ala-angiotensin II (10 μg/kg min−1) given simultaneously with angiotensin II (1 μg/min) blocked the aldosterone response to angiotensin II in rats pretreated to reduce ACTH release. In contrast, 1-Sar-8-Ala-angiotensin II at the same dose failed to block the steroid response to Des-Asp-1-angiotensin II (1 μg/min) but a larger dose of 50 μg/kg min−1 of the angiotensin II antagonist blocked completely both the aldosterone and the corticosterone responses to 1 μg/min of Des-Asp-1-angiotensin II. From these data it is suggested that the heptapeptide has a higher affinity for zona glomerulosa receptors than the octapeptide and that Des-Asp-1-angiotensin II mediates, at least in part, the steroidogenic response to the renin-angiotensin system in the rat. The pressor response to Des-Asp-1-angiotensin II was approximately 50% of that produced by the octapeptide in the rat, and 1-Sar-8-Ala-angiotensin II was as effective in partially blocking the pressor response to the octapeptide as in inhibiting the heptapeptide. The present observations indicate a dissociation of adrenal cortex and peripheral arteriolar receptors in their affinity for angiotensin.

Metabolism of aldosterone in dogs with renovascular hypertension

Summary The rate of metabolism of aldo-sterone was measured in seven normal dogs, 4 dogs with chronic renal hypertension and five dogs with malignant renal hypertension. Tritiated aldosterone was injected intravenously and the rate of disappearance of authentic aldosterone was determined. The disappearance curves were resolved into two exponential components and the plasma half-life was measured from the slow component which reflects the rate of metabolism of aldosterone. The half-life of aldosterone was essentially the same for the three groups of dogs. It is concluded, therefore, that the rate of aldosterone metabolism is normal in dogs with experimental renal hypertension.

Hypersecretion of Renin in Dogs with a Chronic Aortic–Caval Fistula and High-Output Heart Failure

Summary The rate of renin secretion was measured in six dogs with large aortic—caval fistulas and evidence of cardiac failure. At the time of the study, the dogs showed a decrease in mean femoral arterial pressure, increased mean right atrial pressure, marked sodium retention, edema and ascites. Renin secretion was measured by determining renal blood flow with an electromagnetic flowmeter and the renal venous–arterial difference in plasma renin activity. Renin secretion was elevated to 1978 ng angiotensin/min in the six dogs with an aortic—caval fistula and cardiac failure in comparison with a value of 607 ng angiotensin/min for seven normal dogs studied similarly (p < 0.01).