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 H3-aldosterone 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 * Reported in preliminary form to the Endocrine Society, June, 1960, and at the Laurentian Hormone Conference, Sept., 1960. total tritium radioactivity, the disappearance of total methylene chloride-extractable radioactivity from the plasma, the effect of hepatectomy on the biological half-life (ti) of aldosterone, and binding of H3-aldosterone to plasma protein. At the time these studies were performed tritiated d-aldosterone was not available; recently, d-aldosterone has been tritiated and additional observations have been made with the natural hormone. METHODSStudies with d,l-aldosterone. The disappearance of H3-d,l-aldosterone from peripheral plasma was determined in 9 normal dogs before and after constriction of the thoracic inferior vena cava, and in one additional dog after caval constriction. Ten or 20 ,sc (7 to 21 pug) of the d,l-form of randomly ring-labeled H3-aldosterone, with a specific activity ranging from 1.0 to 3.0 MAc per 1ug was injected intravenously; the efficiency of the liquid scintillation spectrometer was approximately 25 per cent. The concentration of true H3-aldosterone in peripheral plasma was measured at intervals of 5, 10,15,20, 30, 45, 60, and 90 minutes. In the dogs with thoracic inferior vena caval constriction, large volumes of ascitic fluid formed and sodium retention was almost complete. In a preliminary experiment it was found that equilibration of H3-aldosterone between ascitic fluid and plasma was v...

Previous reports (1-9) have delegated a secondary role to anterior pituitary hormones in the control of aldosterone secretion.' Although hypophysectomy resulted in decreased aldosterone secretion (3) or reduced urinary aldosterone output (2), hyperaldosteronuria, marked sodium (Na) retention and ascites occurred in the absence of the adenohypophysis in dogs with thoracic inferior vena cava constriction (2). Also, in patients with hypopituitarism, Luetscher and Axelrad (6) and Hernando and associates (7) found that urinary aldosterone output was within normal limits in some patients on an unselected diet or a normal salt intake, and Liddle, Duncan 'and Bartter (8) reported hyperaldosteronuria in one patient with hypopituitarism on a low Na diet.However, no conclusive evidence of hypersecretion 1 of aldosterone in the absence of anterior pituitary hormones has been reported. The critical pertinent data on the rate of aldosterone secretion during stimulation which produces hypersecretion in normal animals have not been reported for hypophysectomized dogs or patients. It is important that studies in man be conducted on hypophysectomized patients since patients with so-called panhypopituitarism may not have loss of all anterior pituitary function. Furthermore, our knowledge is incomplete on the importance of specific anterior pituitary hormones. Several studies (3,7,(8)(9)(10) have demonstrated an increase in aldosterone secretion or urinary aldo-* This investigation was aided in part by Grant A-1944 from the National Institutes of Health, Bethesda, Md.1 The phrases "aldosterone secretion" or "hypersecretion of aldosterone" have been used to refer to actual measurements of the rate of secretion by the adrenal gland into the effluent plasma and are to be distinguished from urinary aldosterone excretion. sterone excretion following administration of various corticotropin preparations, but the data are inadequate to establish the role of ACTH in secondary hyperaldosteronism.2The question of the role of the anterior pituitary in the control of aldosterone secretion was reopened by the finding of a 76 to 97 per cent fall in adrenal vein aldosterone output following hypophysectomy of dogs with experimental secondary hyperaldosteronism ( 11). In the present report, data are presented on the efficacy of ACTH 3 in preventing this fall in aldosterone secretion which follows hypophysectomy. Large doses of cortisone have been administered to inhibit ACTH secretion in dogs with hyperaldosteronism secondary to caval constriction; the resultant effects on aldosterone and corticosterone production were observed. Subsequently, the effects of hypophysectomy and ACTH were studied in these animals. Also, the effects of synthetic a-melanophore-stimulating hormone (MSH) and of highly purified preparations of natural a-and ,B-MSH have been studied. Attempts have been made to stimulate hypersecretion of aldosterone in simple hypophysectomized dogs by 1) a low Na diet and 2) acute constriction of the thoracic inferior vena cava.2 In this pap...

"Low Km" cAMP phosphodiesterase and cGMP-stimulated cyclic nucleotide phosphodiesterase activities were partially purified from calf liver supernatant by chromatography on DEAE-cellulose and DEAE-Sepharose and ammonium sulfate precipitation. The low Km phosphodiesterase was not retained on N6-H2N(CH2)2-cAMP-agarose and could be separated from the cGMP-stimulated phosphodiesterase which was absorbed by this matrix. From the proteins that did not bind, two distinct low Km cAMP phosphodiesterases were separated on Ultrogel AcA 34. One form (fraction C) hydrolyzed cAMP with an apparent Km of approximately 0.5 microM and was very sensitive to inhibition by cGMP. Lineweaver-Burk plots of cAMP hydrolysis by a second form (fraction B) were nonlinear, with an apparent low Km component of approximately 2 microM. This form was rather insensitive to inhibition by cGMP. With both fractions, hydrolysis of cAMP relative to cGMP was much greater at low (approximately 1 microM) than at high (approximately 100 microM) substrate concentrations. Maximal velocities for cAMP and cGMP were similar. From sedimentation equilibrium, the apparent weight-average molecular weight of fraction B was estimated as 174000, and that of fraction C was 85000. Another fraction (A) of cAMP phosphodiesterase eluted at the void volume of the AcA 34 column. On the basis of the relative affinities for cAMP and cGMP and inhibition by cGMP, fraction A is most likely an aggregated form of fraction B. No apparent interconversion of fractions A, B, or C was observed on high-performance liquid chromatography.(ABSTRACT TRUNCATED AT 250 WORDS)

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