Carlos R. Ayers

THE ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN THE CONTROL OF ALDOSTERONE SECRETION

Within the last year, evidence (1-4) has accumulated to show that the kidney secretes a hormone which is a prime regulator of aldosterone secretion. The renal origin of an aldosteronestimulating hormone (ASH) has been demonstrated following acute blood loss (1-3), during chronic thoracic caval constriction (4), and during chronic Na depletion (4). Nephrectomizedhypophysectomized dogs failed to respond to acute hemorrhage with an increase in aldosterone secretion, and acute bilateral nephrectomy of hypophysectomized caval and hypophysectomized Nadepleted dogs resulted in a marked drop in aldosterone secretion. Furthermore, crude saline extracts of kidney produced a striking increase in aldosterone secretion (1-5). In malignant experimental renal hypertension, hyperaldosteronism was consistently present (6). These findings and the reports that renin preparations (6) and synthetic angiotensin II (6-8) increase the rate of aldosterone production suggest the possibility that ASH is renin. The present experiments were undertaken to determine the chemical nature of this ASH by fractionation of crude kidney extracts for aldosterone-stimulating and pressor activity. The renin content of kidneys from dogs with thoracic caval constriction and secondary hyperaldosteronism and from normal dogs has been compared. Since dogs with thoracic caval constriction and Na-depleted dogs do not have hypertension, the response in blood pressure to synthetic angiotensin

RENAL ORIGIN OF AN ALDOSTERONE-STIMULATING HORMONE IN DOGS WITH THORACIC CAVAL CONSTRICTION AND IN SODIUM-DEPLETED DOGS

Recent studies (1-5) indicate that the immediate stimulus to aldosterone production is humoral. Evidence for secretion of an aldosterone-stimulating hormone (ASH) by the kidney in response to acute blood loss was presented at the Laurentian Hormone Conference in 1960 (4). The present study is concerned with the locus of secretion of an ASH in two other experimental situations: 1) hyperaldosteronism secondary to chronic constriction of the thoracic inferior vena cava, and 2) chronic Na depletion. The present data provide evidence for extension of our knowledge of an ASH to clinical states with edema; the dog with thoracic caval constriction is very similar in regard to electrolyte and water metabolism and hyperaldosteronism to the patient with cirrhosis of the liver and ascites. Studies of the origin of secretion of an ASH during Na depletion were made because changes in electrolyte intake constitute one of the most important physiological mechanisms in the regulation of aldosterone secretion. Evidence for secretion of an ASHby the kidney in these two experimental situations was obtained by study of the effects of acute nephrectomy on aldosterone secretion.

THE EFFECTS OF CHRONIC HEPATIC VENOUS CONGESTION ON THE METABOLISM OF d,l-ALDOSTERONE AND d-ALDOSTERONE

In 1950 Deming and Luetscher demonstrated increased salt-retaining activity in urine from patients with congestive heart failure (1). In 1953 aldosterone was isolated (2), and subsequently the urinary excretion of this hormone was found to be elevated in nearly all the clinical states associated with edema. Two possible mechanisms could lead to an increase in the plasma level of aldosterone and thus to an increase in urinary aldosterone excretion: 1) hypersecretion of aldosterone, and 2) a decreased rate of metabolism of the hormone. In 1957, it was demonstrated that a sixfold increase in aldosterone secretion occurred in dogs with experimental right heart failure and in dogs with thoracic inferior vena caval constriction (3). The possibility of decreased metabolism of aldosterone was suggested by Yates, Urquhart and Herbst (4) who found a decrease in the 4,5-steroid reductase activity for inactivation of aldosterone by liver tissue from rats subjected to chronic passive venous congestion. They suggested that a decreased rate of reduction of ring A of aldosterone might increase the plasmal level of the hormone in these animals. The primary purpose of the present study was to evaluate the possibility of a decreased rate of metabolism of aldosterone by the congested liver. The disappearance of H3aldosterone from plasma was studied in dogs with chronic hepatic venous congestion secondary to thoracic inferior vena caval constriction and in normal animals. In addition, several aspects of the metabolism of dl-aldosterone were studied including the urinary and biliary excretion of

The renin response to diuretic therapyl A limitation of antihypertensive potential.

We attempted to determine whether a diuretic-induced increase in renin secretion results in angiotensin II-mediated vasoconstriction which counteracts the antihypertensive action of diuretics. The angiotensui antagonist saralasin was administered to nine normal renin and five low renin essential hypertensives prior to and during stimulation of the renin-angiotendn system by 6 weeks of chronic diuretic therapy alone. Initial responses to saralasin infusion in all subjects on placebo varied, but were pressor overall. Following chronic polythiazide therapy, saralasin induced depressor responses of variable magnitude in seven of nine normal renin subjects. The combination of the diuretic and saralasin normalized blood pressure in four subjects. However, four normal renin subjects maintained a diastolic Mood pressure greater than 95 mm Hg despite simultaneous volume depletion and angiotensin blockade. One had a maximum antihypertensive effect with diuretic therapy alone. Pressor responses to saralasin persisted in four of five low renin subjects despite diuretic therapy. In general, the magnitude of the change hi plasma renin activity induced by diuretic therapy correlated with the difference in Mood pressure responses to saralasin. However, individual Mood pressure responses and absolute renin levels after diuretic therapy failed to predict consistently the ensuing responses to saralasin. Hence, in eight subjects (seven normal and one low renin), the compensatory increase in renin secretion hi response to diuretic-induced volume depletion limited diuretic antihypertensive efficacy. Yet diuretic-induced angiotensin dependency was not the sole mechanism supporting residual hypertension hi all subjects refractory to diuretic therapy.

Activity of [Des-Aspartyl1]-Angiotensin II and Angiotensin II in Man: DIFFERENCES IN BLOOD PRESSURE AND ADRENOCORTICAL RESPONSES DURING NORMAL AND LOW SODIUM INTAKE

This study was designed to compare the effect of [des-Aspartyl(1)]-angiotensin II ([des-Asp]-A II) and angiotensin II (A II) on blood pressure and aldosterone production in man under conditions of normal and low sodium (Na) intake. Seven normal male subjects in balance on constant normal Na intake (U(Na) V 160.3+/-5.0 meq/24 h) for 5 days received A II and [des-Asp]-A II infusions on two consecutive days; 1 mo later they were restudied after 5 days of low Na intake (U(Na) V 10.5+/-1.6 meq/24 h). Each dose was infused for 30 min, sequentially. During normal Na intake, [des-Asp]-A II from 2 to 18 pmol/kg per min increased mean blood pressure from 85.2+/-3 to 95.3+/-5 mm Hg and plasma aldosterone concentration from 5.2+/-1.1 to 14.3+/-1.9 ng/100 ml. During low Na intake, the same dose of [des-Asp]-A II increased mean blood pressure from 83.7+/-3 to 86.7+/-3 mm Hg and plasma aldosterone concentration from 34.4+/-6.0 to 51.0+/-8.2 ng/100 ml. In contrast, A II from 2 to 6 pmol/kg per min during normal Na intake increased mean blood pressure from 83.3+/-4 to 102.3+/-4 mm Hg and plasma aldosterone concentration from 7.0+/-2.2 to 26.8+/-2.0 ng/100 ml; during low Na intake, A II increased mean blood pressure from 83.0+/-3 to 96.0+/-4 mm Hg and plasma aldosterone concentration from 42.0+/-9.7 to 102.2+/-15.4 ng/100 ml. A II and [des-Asp]-A II were equally effective in suppressing renin release. Plasma cortisol and Na and K concentration did not change. The effects of two doses (2 and 6 pmol/kg per min) of each peptide on blood pressure and aldosterone production were evaluated. During normal Na intake, [des-Asp]-A II had 11-36% of the pressor activity and 15-30% of the steroidogenic activity of A II. Na deprivation attenuated the pressor response and sensitized the adrenal cortex to both peptides, but the increase in steroidogenesis was greater with [des-Asp]-A II than with A II. The dose-response curves for [des-Asp]-A II with respect to blood pressure and aldosterone production were not parallel, and although no maximum was established for A II, [des-Asp]-A II was less efficacious.In summary, (a) [des-Asp]-A II has biologic activity in man, (b) [des-Asp]-A II is less efficacious than A II in stimulating aldosterone production, (c) Na deprivation sensitizes the adrenal cortex more markedly to [des-Asp]-A II than A II, and (d) dose-response curves for the two peptides differ, suggesting the possibility that they act at different receptor sites in vascular smooth muscle and the adrenal cortex.

Relation of Renin and Angiotensin II to the Control of Aldosterone Secretion

1. Evidence is presented to show that the renin-angiotensin system leads to increased aldosterone secretion following acute blood loss, during experimental heart failure, during thoracic inferior vena cava constriction, during chronic sodium depletion and in malignant experimental renal hypertension. Since alterations in sodium intake constitute one of the most important factors in the daily regulation of aldosterone secretion, studies of sodium-depleted animals suggest that the renin-angiotensin system is important in the physiological regulation of aldosterone secretion. 2. Renin appears to be secreted by the juxtaglomerular cells of the kidney. Some hemodynamic alteration secondary to a decrease in pressure and flow through the kidney leads to release of renin by the juxtaglomerular cells. Available data indicate that angiotensin II acts on the zona glomerulosa of the adrenal cortex to promote aldosterone production.