Steroid secretion was studied in conscious dogs before and during 4 days of Na depletion. A threefold increase in aldosterone secretion occurred but corticosterone output was unchanged. Plasma renin was markedly elevated. Plasma Na and K concentrations were unchanged until the 4th day of Na depletion at which time plasma Na was decreased and plasma K was elevated. The Na content of the adrenal cortex expressed as fat-free tissue solids was decreased. It seems likely that the adrenocortical Na loss was extracellular; adrenocortical K content was unaltered. It is suggested that the normal rate of corticosterone secretion during Na depletion is maintained by a negative corticosteroid feedback mechanism, since corticosterone output was consistently increased in Na-depleted hypophysectomized dogs. Aldosterone secretion was three times as great in the presence as in the absence of the anterior pituitary during Na depletion. It is concluded that increased activity of the renin-angiotensin system is the primary mechanism leading to hyperaldosteronism during Na depletion and that the adenohypophysis plays an important supportive role.

Renal and peripheral venous plasma was prepared for assay of renin by the technique of Helmer and the formed angiotensin II was assayed for both pressor and steroidogenic activity. Both assays showed higher concentrations of renin in both renal and peripheral venous plasma from dogs with thoracic caval constriction than from normal dogs. The increase in aldosterone and corticosterone secretion by isolated adrenals in response to incubated plasma with its formed angiotensin II was qualitatively similar to that observed for synthetic angiotensin II. Thus, the steroid assay provided evidence that the final product formed for assay was angiotensin II. That the pressor activity in renal vein plasma was referable to a substance of renal origin is indicated by the lower level of activity in peripheral venous than in renal venous plasma and the fall in activity in peripheral venous plasma following nephrectomy. Further evidence for the validity of the assay for renin was obtained from studies of renin substrate. A large excess of renin substrate was found in normal dog plasma so that angiotensin II formed by incubation was not limited by substrate exhaustion. Also, the peripheral plasma level of renin substrate was essentially the same in dogs with thoracic caval constriction and in normal dogs.

Measurements of plasma renin were made in unilaterally nephrectomized dogs with renal artery stenosis and hypertension. Plasma renin was elevated throughout the course of the malignant renal hypertensive disease, and during the first three days only in chronic hypertension. Hypertension was produced by renal artery constriction in unilaterally nephrectomized dogs with prior thoracic caval constriction and in sodium-depleted, left nephrectomized animals. Plasma renin was high in both dogs with caval constriction and sodium depletion before hypertension was added. When the renal artery was constricted, two of the dogs with thoracic caval constriction developed malignant hypertension and a further striking increase in plasma renin occurred. In two other dogs with caval constriction, chronic hypertension developed but plasma renin increased further in only one of the two animals; this occurred during the first four days of hypertension after which plasma renin returned to the high control level. The sodium-depleted dogs developed chronic hypertension following renal artery constriction but no further elevation in plasma renin occurred. Sodium repletion and sodium depletion of chronic hypertensive dogs produced marked changes in plasma renin without alterations in arterial pressure. The present findings revealed a striking correlation between plasma renin and sodium balance but neither bore any relation to the level of arterial pressure.

In an earlier study (1), the rate of metabolism of aldosterone was found to be decreased in dogs with chronic passive congestion of the liver secondary to thoracic inferior vena caval constriction. After hepatectomy of these animals and of normal dogs, the metabolism of aldosterone was almost abolished. It was suggested that the decreased aldosterone metabolism during liver congestion might be secondary to decreased hepatic blood flow and associated hepatic anoxia. More recently, Tait and his colleagues (2, 3) have provided evidence that the rate of hepatic blood flow is one of the primary determinants of the rate of aldosterone metabolism.The present observations were undertaken to examine the metabolism of aldosterone in several experimental situations in which altered aldosterone secretion occurs and in which there are known or suspected alterations in liver blood flow. The primary objectives were twofold: 1) to define the distribution, metabolic clearance rate (MCR), and hepatic extraction of aldosterone, and 2) to determine the contribution of altered aldosterone metabolism to the peripheral plasma level of aldosterone. Aldosterone metabolism was studied following acute hemorrhage, in dogs depleted of sodium, and in dogs with chronic experimental heart failure. Observations were made in both low and high output failure because hepatic blood flow is reduced in the former and, presumably, normal or elevated in the latter situation. Since exercise greatly reduces the blood flow through the liver in patients with heart failure (4), observations were made before and during ex- hausting exercise in dogs with low output heart failure. The metabolism of aldosterone was also studied in hypophysectomized dogs; in this situation there is a low rather than a high rate of aldosterone secretion, and hepatic blood flow is probably reduced. Finally, the hepatic extraction of aldosterone was measured in several experimental situations. MethodsThe rate of metabolism of aldosterone was studied by observing the rate of disappearance of 1,2-H'-d-aldosterone from peripheral plasma; single iv injections of 12 X 10' cpm of 1,2-H3-d-aldosterone with a SA of 100 Acc per ug were made. The efficiency of the liquid scintillation spectrometer was approximately 25%b. Peripheral venous blood samples of 20 ml were drawn at 5, 10, 15,20, 30, 45, 60, 75, and 90 minutes, and plasma was analyzed for true H3-d-aldosterone. The dogs weighed from 17 to 22 kg.To study the effects of hemorrhage, 30 ml of arterial blood per kg body weight was removed over a 5-to 15-minute period in nine dogs anesthetized with Na pentobarbital. As soon as the arterial pressure had stabilized, tritiated aldosterone was injected, and peripheral venous blood samples were obtained. Arterial pressure was measured continuously throughout the experiment by means of a Statham strain gauge and a Sanborn recording system. As a control experiment, the disappearance of tritiated aldosterone was studied in a series of seven normal dogs anesthetized similarly.Sodium depletion was ...

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