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 microM) inhibited aldosterone release of a cell suspension of porcine adrenocortical cells, potency order: doxazosin > prazosin > trimazosin. Phenoxybenzamine also inhibited the aldosterone release at a concentration of 100 microM. Alpha1-adrenoceptor antagonists from other chemical classes had no measurable effect on the aldosterone output from adrenocortical cells in vitro. Agonists selective for either alpha1- or beta-adrenoceptors did not affect the aldosterone release. The inhibition of the aldosterone release induced by quinazolines was similar with different substrates. The small differences between the drug-induced inhibitions could be ranked as corticosterone = progesterone > pregnenolone = deoxycorticosterone. The doxazosin (10 microM)-induced changes in the release of nine steroids indicated that quinazoline-type alpha1-antagonists interfere with enzymes of the aldosterone biogenesis pathway involved in C18-oxidation and C21beta-hydroxylation, reducing the release of both aldosterone and corticosterone. At higher concentrations (100 microM), the C21beta-hydroxylation in the cortisol biogenesis pathway is also affected, decreasing the output of cortisol and deoxycortisol, but increasing the output of progesterone and OH-progesterone. Simultaneously, the C17-oxidation and side-chain cleavage is also inhibited, decreasing the output of androstenedione. The rank order of phenoxybenzamine (100 microM)-induced inhibition of the aldosterone release with different substrates is pregnenolone > corticosterone = progesterone > deoxycorticosterone. With pregnenolone as substrate, the output of aldosterone, corticosterone, and cortisol was reduced to the same extent. The dehydroepiandrosterone, androstenedione, and progesterone release was enhanced. It seems that phenoxybenzamine is a rather selective inhibitor of the mitochondrial P450(11beta/18) enzymes.