Some Studies on the Biosynthesis of Aldosterone and Other Adrenal Steroids

169

Angiotensin II has been shown to increase the excretion (1) and secretion (2) of aldosterone by normal human subjects, and the secretion of aldosterone by hypophysectomized, nephrectomized dogs (3)(4)(5). In the latter preparation (3), renin, which leads to the liberation of angiotensin in the circulation (6), has been shown to stimulate aldosterone secretion. The present studies were done to determine whether angiotensin and renin can act directly on the adrenal cortex. The slices were minced with scissors and weighed. Specimens weighing about 500 mg were placed in 5 ml of Krebs-Ringer bicarbonate medium containing glucose in a concentration of 200 mg per 100 ml. At least 4 vessels were incubated and analyzed separately for each portion of each experiment. Thus, there were at least 4 control vessels and at least 4 with each precursor or stimulating agent studied in each experiment. The tissues were kept chilled until incubation, which was started between 3 and 5 hours after the death of the cattle. Tissues were preincubated for 1 hour at 37°C under 5 per cent CO2-95 per cent 02 on the Dubnoff metabolic shaker. The preincubation medium was removed, and 5 ml of fresh medium was used to transfer the slices to vessels to which the appropriate precursor had been added with or without ACTH, renin, or angiotensin II. Incubation was for 2 hours.The control values for synthesis of aldosterone by the adrenals in vitro showed wide variations from experiment to experiment. The higher the control value, the less was the effect of any given stimulus. Thus, when production of aldosterone by the control beef slices was greater than 2 gsg per g of tissue per hour, experimental procedures produced little or no increase of synthesis. Therefore, only preparations with control values below 2 ,lg per g per hour are included. Factors which may have affected the control level of aldosterone production were water and salt deprivation. Control values were above 4 ,ug per g per hour only during the winter months when the ground was frozen and the cattle had no access to water for at least 24 to 48 hours before slaughter and limited access to water and salt for a longer period. A stimulatory effect of water deprivation on synthesis of aldosterone in vivo (7) and of salt depletion on synthesis in vitro (8) has been observed. Other factors may have led to this seasonal variation, a problem noted by others studying corticosteroid synthesis in vitro (9).The capacity of the tissue to respond to any given stimulus was found to decrease with the passage of time, so this was kept relatively constant in all experiments.Rat adrenal sections. The technique of Saffran and Schally (10) was closely followed. A quarter of one adrenal gland from each of eight 150-to 200-g SpragueDawley male rats was included in each of four vessels 715

Section: Discussionmentioning

confidence: 99%

“…Angiotensin had no effect on the synthesis of aldosterone in the presence of progesterone and corticosterone. Figure 8 shows in abbreviated form biosynthetic pathways by which aldosterone and cortisol have been shown to be formed from acetate (17,18). A number of alternate pathways have been suggested.…”

Section: Effect Of Precursor Alonementioning

confidence: 99%

The Effect of Acth, Renin, Angiotensin Ii, and Various Precursors on Biosynthesis of Aldosterone by Adrenal Slices

Kaplan¹,

Barter²

1962

169

“…Ayres and associates (34) have proposed that corticosterone is the immediate precursor to aldosterone in the major pathway of aldosterone synthesis; under certain experimental circumstances 50 to 92 per cent of aldosterone produced in vitro was derived from corticosterone. In the present study, there was a striking similarity in the changes in aldosterone secretion and corticosterone secretion following hypophysectomy and during ACTH administration to hypophysectomized dogs with caval constriction.…”

Section: Discussionmentioning

confidence: 99%

The Role of the Anterior Pituitary in the Control of Aldosterone Secretion in Experimental Secondary Hyperaldosteronism*

Davis¹,

Yankopoulos²,

Lieberman³

et al. 1960

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...

“…It has been established (6)(7)(8)(9)(10)(11) that aldosterone is synthesized by a series of reactions that involve cholesterol, pregnenolone,1 progesterone, deoxycorticosterone (DOC), corticosterone, and probably 18-hydroxycorticosterone. In the present investigation, we have taken advantage of the availability of methods for "isolating" in vivo the early part of the aldosterone pathway (before the formation of DOC) and the availability of a new method (12) for measuring plasma DOC in order to determine whether angiotensin and potassium act early in the pathway so as to stimulate the biogenesis of aldosterone precursors.…”

Section: Introductionmentioning

confidence: 99%

Site of stimulation of aldosterone biosynthesis by angiotensin and potassium

Brown¹,

Strott²,

Liddle³

1972

A B S T R A C T Studies were undertaken to determine what part of the aldosterone biosynthetic pathway is stimulated by angiotensin and potassium. The availability of a method for isolating the early portion of the aldosterone pathway and a new method for measuring plasma deoxycorticosterone permitted the design of experiments to determine whether angiotensin and potassium stimulate the pathway before deoxycorticosterone. To eliminate ACTH-dependent steroid synthesis, the experiments were performed in subjects receiving constant dosage of dexamethasone. To minimize the intra-adrenal conversion of deoxycorticosterone to corticosterone, all subjects also received constant dosage of metyrapone. Plasma deoxycortisol was measured as an index of the activity of the zona fasciculata. In the absence of changes in plasma deoxycortisol, one may infer that changes in plasma deoxycorticosterone represent changes in function of zona glomerulosa, the site of aldosterone formation. Under these conditions, human subjects responded both to angiotensin and to potassium with significant increases in plasma deoxycorticosterone but without significant increases in plasma deoxycortisol. In contrast, small doses of ACTH given under similar conditions never induced increases in plasma deoxycorticosterone without simultaneously inducing large increases in plasma deoxycortisol. It is concluded that the aldosterone-stimnulating effects of angiotensin and potassium are, at least in part, consequences of stimulation of the biosynthetic pathway at some point before the formation of deoxycorticosterone so as to increase the availability of aldosterone precursors.