Effects of α1-antagonists on production and release of aldosterone and other steroid hormones by porcine adrenocortical cells in vitro

Abstract

Quinazoline type alpha1-adrenoceptor antagonists (range 10–100 µM) inhibited aldosterone release of a cellsuspension of porcine adrenocortical cells, potency order: doxazosin > prazosin > trimazosin. Phenoxybenzamine alsoinhibited the aldosterone release at a concentration of 100 µM. alpha1-Adrenoceptor antagonists from other chemicalclasses had no measurable effect on the aldosterone output from adrenocortical cells in vitro. Agonists selective foreither alpha1- or beta-adrenoceptors did not affect the aldosterone release. The inhibition of the aldosterone release induced byquinazolines was similar with different substrates. The small differences between the drug-induced inhibitions could beranked as corticosterone = progesterone > pregnenolone = deoxycorticosterone. The doxazosin (10 µM)-inducedchanges in the release of nine steroids indicated that quinazoline-type alpha1-antagonists interfere with enzymes of thealdosterone biogenesis pathway involved in C18-oxidation and C21beta-hydroxylation, reducing the release of bothaldosterone and corticosterone. At higher concentrations (100 µM), the C21beta-hydroxylation in the cortisol biogenesispathway is also affected, decreasing the output of cortisol and deoxycortisol, but increasing the output of progesteroneand OH-progesterone. Simultaneously, the C17-oxidation and side-chain cleavage is also inhibited, decreasing theoutput of androstenedione. The rank order of phenoxybenzamine (100 µM)-induced inhibition of the aldosteronerelease with different substrates is pregnenolone > corticosterone = progesterone > deoxycorticosterone. Withpregnenolone as substrate, the output of aldosterone, corticosterone, and cortisol was reduced to the same extent. Thedehydroepiandrosterone, androstenedione, and progesterone release was enhanced. It seems that phenoxybenzamine is arather selective inhibitor of the mitochondrial P45011 beta/18 enzymes.Key words: piperazinyl quinazolines, steroid hormones, porcine adrenocortical cells in vitro, carbadox, prazosin, doxazosin, trimazosin, phenoxybenzamine.