Peripheral serum corticosteroid concentrations in relation to the rat adrenal cortical circadian rhythm in androgen-induced hypertension.

Abstract

Adrenal function was assessed in control rats and in rats treated for 2 and 4 weeks with 17 alpha-methylandrostenediol (MAD; 17 alpha-methyl-5-androstene-3 beta-diol), a synthetic androgen known to produce hypertensive cardiovascular disease. In both groups and at both time periods, a circadian rhythm of blood corticosteroid concentrations was observed. The high point for serum corticosterone (B), 18-hydroxy-11-deoxycorticosterone (18-hydroxy-DOC), and 11-deoxycorticosterone (DOC) concentrations occurred at the beginning of the dark period (1800 hours), and the low point occurred at the onset of the light period (0600 hours). Serum concentrations of DOC were always found to be higher in MAD-treated rats as compared with controls. The serum concentrations of B and 18-hydroxy-DOC were lower than control values at 1800 hours but higher than control concentrations at 0600 hours. The in vitro 11 beta- and 18-hydroxylation of DOC was markedly reduced with MAD treatment. In contrast, cholesterol side-chain cleavage activity was higher in animals treated with MAD. These in vitro findings correlated with spectral studies that showed a decreased binding of DOC to cytochrome P450(11) beta and increased binding of cholesterol to cytochrome P450scc. These studies suggest that MAD treatment selectively decreases 11 beta- and 18-hydroxylation in adrenal mitochondria, and this results in an increased serum concentration of DOC, a hypertensinogenic steroid. This effect of MAD on peripheral serum DOC concentration is most readily observed in quiescent animals at the high point of the circadian rhythm.