A dissociated effect of Amino-Glutethimide on the mineralocorticoid secretion in man

Effect of Aminoglutethimide on Blood Pressure and Steroid Secretion in Patients with Low Renin Essential Hypertension

“…In contrast, whereas secretion of cortisol and related steroids by the adrenal zona fasciculata is decreased by amiiinoglutethimide, the eff'ect is not sustained becauise the initial f'all in plasma cortisol concentration leads to a compensatory increase in ACTH release (26)(27)(28). ACTH, in turn, stimulates the adrenal formation of A5-preginenolone f'rom cholesterol, the major step in steroid biosynthesis that is inhibited bv amiiinoglutethiimiide (27).…”

“…In contrast, whereas secretion of cortisol and related steroids by the adrenal zona fasciculata is decreased by amiiinoglutethimide, the eff'ect is not sustained becauise the initial f'all in plasma cortisol concentration leads to a compensatory increase in ACTH release (26)(27)(28). ACTH, in turn, stimulates the adrenal formation of A5-preginenolone f'rom cholesterol, the major step in steroid biosynthesis that is inhibited bv amiiinoglutethiimiide (27). The increases in plasmiia Woncentrations of progesterone, 17 a-hydroxyprogesterone, li-deoxycortisol, and 18-OH DOC observed in our 7 patients after 4 days of' aminoglutethimi(le treatment and in 2 of'these patients after 21 days of'tlherapy probably reflects such a compensatory increase in ACTH because concentrations of plasma cortisol were maintained in spite of' clroniic administratioin of' amiinogluitethimide.…”

“…2). Mean values for the 10 plasma cortisol samples (5 determinations each in the 2 patients) during the control period were not significantly dif- FIGuRE 2 Plasma concentrations of selected steroids in two patients with low renin essential hypertension before (control) and again 4 (26,27). The gradual lowering of' blood pressure an(d body weight during aminoglutethimide therapy in our low renin patients is also conisistent with the view that the antihypertenisive eff'ect of' the drug is mediated through a reduction in extracellular fluid volume, probably secondary to the sustained suppression of' aldosterone production (Table I).…”

“…Maintenance of blood pressure, however, depends not only upon aldosterone-regulated changes in blood volume but also upon the direct vasoconstriction produced by angiotensin 11 (33). Thus, administration of aminoglutethimide to patients with normal renin essential hypertension decreases their aldosterone production, and presumably their blood volume (8,27), but the rapid rise in renin and angiotensin II concentrations would be expected to lead to vasoconstriction, thereby compensating in part for the tendency towards reduced blood pressure secondary to the decrease in blood volume. In contrast, patients with low renin essential hypertension have low plasma concentrations of angiotensin 11 (34,35), and may be more dependent upon blood volume for maintenance of blood pressure.…”

Effect of metyrapone and aminoglutethimide on the murine sarcoma (MuSV‐M) and breast adenocarcinoma (C3HBA)

“…Aminoglutethimide [a(p-aminopheny1)-aethylglutarimide] , which was originally introduced as an anticonvulsant, is a specific competitive inhibitor of cholesterol desmolase [Kahnt and Neher, 1966;Cohen, 19681. It blocks the enzymatic conversion of cholesterol to pregnenolone [Camacho et al, 1967;Dexter et al, 1967;Fishman et al, 1967;Cohen, 19681 , a step required for the biosynthesis of adrenal and extra-adrenal steroid hormones Schteingart, Cash and Conn, 1967;Horky et al, 1969;Steinetz et al, 197.51, The block at this level of the biosynthetic pathway reduces not only the production of sex steroids, but also that of gluco-and mineralocorticoids Horky et al, 1969;Touitou, Legrand and Desgrez, 1973;Borrell and Borrell, 1974;Carballeira et al, 19741 , although zonal differences in the response or adjustment of the adrenal cortex to AG-effect are reported [Mancheno-Rico et al, 1973;Kiichel et al, 1970;Touitou et al, 19751 . A single injection of AG in rats causes marked lowering of glucocorticoids and ACTH-dependent mineralocorticoids in six to eight hours, which return to the normal range in less than 24 hours [Gaunt et al, 1970;Mancheno-Rico et al, 19731 .…”