Selective inhibition of aldosterone synthesis by 11-hydroxylated spirolactone in rat adrenals.

Abstract

The effect of the spirolactone SC5233 [3′-(3-oxo-17β-hydroxy-4-androstene-17α-yl)propionic acid-γ-lactone] and of the 11β-hydroxylated SC5233 on the synthesis of corticosteroids was examined in rat adrenal tissue. SC5233 markedly inhibited the production of both corticosterone and aldosterone. 11β-Hydroxy-SC5233 also inhibited markedly the production of aldosterone but only slightly that of corticosterone. 50% inhibition of aldosterone production by 11β-Hydroxy-SC5233 was obtained at a concentration of 7×10−5 M when the synthesis of corticosteroids was stimulated by dibutyryl cyclic AMP, while 50% inhibition of corticosterone production was obtained only at 4×10−4 M. In incorporation experiments a highly significant inhibition by SC5233 of the incorporation of 14C-progesterone into corticosterone, 18-hydroxycorticosterone and aldosterone was detectable in connexion with an accumulation of labelled deoxycorticosterone. In experiments with 11β-Hydroxy-SC5233 a significant inhibition of the incorporation of 14C-progesterone was shown for only 18-hydroxycorticosterone and aldosterone with a moderate accumulation of labelled deoxycorticosterone. Incorporation of 14C-progesterone into corticosterone was not affected by 11β-Hydroxy-SC5233. The results show that 11β-hydroxylated SC5233 induced a largely selective inhibition of aldosterone production; in contrast, SC5233 had an unselective inhibitory effect on the synthesis of both corticosteroids, aldosterone and corticosterone.