Influence of the Pituitary and the Renin-Angiotensin System on the Secretion of Aldosterone, Cortisol, and Corticosterone

A B STRA CT Secretion of cortisol, corticosterone, and aldosterone was measured in vivo in normal and sodium-depleted hypophysectomized dogs.Biogenesis of steroids was then measured in vitro with outer slices of the adrenals of the same dogs. In some studies, metyrapone or puromycin was added.In vivo, sodium depletion stimulated the production of cortisol, corticosterone, and aldosterone. In vitro, tissues from sodium-depleted animals released more aldosterone, but less corticosterone than those from sodium-replete controls.The results are interpreted to indicate that (a) biosynthesis of aldosterone is regulated at at least two sites in the biosynthetic pathway. The final conversion, that of corticosterone to aldosterone, is stimulated by sodium depletion. This effect persists for at least 3 hr while slices from sodiumdepleted dogs are incubated in vitro. Stimulation at this site is thus relatively stable in vitro; its activation by sodium depletion is not inhibited by puromycin in the dog. Stimulation at this site can explain, at least in part, the increased effectiveness of adrenocorticotropin (ACTH) on aldosterone biogenesis during sodium depletion.(b) the earlier site at which sodium depletion stimulates the secretion of aldosterone is "above" the position of desoxycorticosterone in the pathway; it is probably at the conversion of cholesterol to pregnenolone. Stimulation at this site is quickly lost during incubation of adrenal slices. It is thus A preliminary report of some of these data has been published previously (1) .

Section: Resultssupporting

confidence: 91%

Sites of action of sodium depletion on aldosterone biosynthesis in the dog

Davis¹,

Burwell²,

Casper³

et al. 1968

“…In any event, the adrenal responses to potassium and angiotensin were clearly different from the responses to ACTH. The specificity of our responses in man differs from the results of certain experiments in dogs in which both sodium depletion and angiotensin appeared to stimulate the zona fasciculata (18,19).…”

Section: Res Ultscontrasting

confidence: 89%

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.

“…Thus far, the stimulation of cortisol synthesis by angiotensin has been reported in only two species (6)(7)(8)(9). It seems likely that the ability to synthesize cortisol in response to angiotensin is species specific since the human adrenal does not produce cortisol in response to angiotensin infusion (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…Angiotensin has been shown to induce aldosterone synthesis in man (3,4) and in sheep with adrenal transplants (5), and to stimulate cortisol as well as aldosterone synthesis in isolated bovine adrenals (6,7) and in the hypophysectomized dog (8,9). However, attempts to demonstrate an effect of angiotensin on adrenal adenylate cyclase activity (10,11) or cyclic AMP levels (12) have thus far been unsuccessful.…”

Section: Introductionmentioning

confidence: 99%

Comparative Effects of Angiotensin and ACTH on Cyclic AMP and Steroidogenesis in Isolated Bovine Adrenal Cells

Peytremann¹,

Nicholson²,

Brown³

et al. 1973

A B S T R A C T The comparative effects of angiotensin II and adrenocorticotropic hormone (ACTH) on cyclic AMP and steroidogenesis were investigated employing isolated bovine adrenal cells from the zona fasciculata. Like ACTH, angiotensin produced a prompt increase in cyclic AMP which preceded the increase in corticosteroid production. Although this increase in cyclic AMP was small when compared to that induced by ACTH, it correlated with the amount of steroidogenesis. This observation is consistent with the view that cyclic AMP is the intracellular mediator of the steroidogenic action of angiotensin.Angiotensin acted synergistically with ACTH on cyclic AMP levels. This synergism was not explained by inhibition of phosphodiesterase activity. Unlike ACTH, angiotensin failed to stimulate adenylate cyclase in broken cell preparations. The observations suggest that more than one mechanism may be involved in effects of ACTH and angiotensin on cyclic AMP levels. 'Abbreviations used in this paper: ACTH, adrenocorticotropic hormone; KRBG, Krebs-Ringer bicarbonate huffer; MIX, genesis through activation of the adenylate cyclase system (1, 2); however, relatively little attention has been focused on the mechanism of action of angiotensin on steroid biosynthesis. Angiotensin has been shown to induce aldosterone synthesis in man (3, 4) and in sheep with adrenal transplants (5), and to stimulate cortisol as well as aldosterone synthesis in isolated bovine adrenals (6, 7) and in the hypophysectomized dog (8, 9). However, attempts to demonstrate an effect of angiotensin on adrenal adenylate cyclase activity (10, 11) or cyclic AMP levels (12) have thus far been unsuccessful. INTRODUCTIONIn the present study, we have compared the effects of angiotensin and ACTH on adrenal cyclic AMP and steroidogenesis in vitro, utilizing isolated cells from the bovine zona fasciculata. Our results demonstrate that angiotensin increases cyclic AMP levels in cells from the zona fasciculata, and they are consistent with the view that the steroidogenic action of angiotensin in fasciculata cells is mediated through cyclic AMP. METHODS Materials. Lot H of the United States Pharmacopeiacorticotropin Reference Standard was used throughout this study. In order to express the doses of ACTH on a molar basis it was assumed that each ampule of the standard contained 1.5 i.v. U (13,14) and that each unit of activity was equivalent to 10 Ag of ACTH (2 X 10-9 mol) (15). Asparaginyl'-valyl' angiotensin II was purchased from Ciba Corp., Summit, N. J. 1 jug is equivalent to 10-' mol.Appropriate dilutions of angiotensin and ACTH were made in acid-albumin-saline (0.6 ml 12N HCl, 1 g bovine albumin, and 8.5 g NaCl/liter of water). Twice crystallized trypsin and bovine serum albumin (BSA) (Cohn fraction V) were obtained from Sigma Chemical Co., St. Louis, Mo. Lima bean trypsin inhibitor was from Worthington Biochemical Corp., Freehold, N. J. 1-Methyl-3-isobutylxanthine (SC 2964) was kindly provided by the G. Sayers, Swallow, and Giordano (17). Eight calf adrenals w...