ENDOTHELIN-1 (ET-1) AND CYCLOSPORINE-A (CSA) STIMULATE STEROID-SECRETION FROM RAT ADRENAL-CORTEX - EVIDENCE THAT BOTH ET-1 AND CSA SECRETAGOGUE EFFECTS ARE MEDIATED BY THE B-SUBTYPE OF ET-1 RECEPTORS

The effects of endothelin-l (ET-I) and cyclosporine-A (CSA) on adrenal steroidogenesis were investigated in vitro, using rat capsule-zona glomerulosa (ZG) and zona fasciculata (ZF) preparations. ET-1 concentration-dependently raised aldosterone (ALDO) and corticosterone (B) outputs by capsule-ZG and ZF preparations, respectively. Maximal effective concentrations was 10(-8) M. Two specific antagonists of subtypes A and B of ET-I receptors (BQ-123 and BQ-788, respectively) were employed. BQ-788 impaired the secretory response of our adrenal preparations to 10(-8) M ET-I, while BQ-123 was ineffective. The maximal effective concentration of BQ-788 was 10(-7) M. CSA (10(-8) M) elicited marked ALDO and B secretagogue effects, which were of the same order of magnitude of those evoked by 10(-8) M ET-1 and were abolished by 10(-7) M BQ-788. Autoradiography showed I-125-ET-1 binding in both ZG and ZF. BQ-788 decreased labeling in the ZG and virtually eliminated it in the ZF; CSA effects were analogous to those of BQ-788, as also demonstrated by quantitative densitometry. In light of these findings, the following conclusions can be drawn: 1) ET-1 stimulates in the rat not only the secretion of ALDO from ZG, but also that of B from ZF; 2) the adrenocortical secretagogue effect of ET-1 is exclusively mediated by the B subtype of ET-I receptors; and 3) CSA, at relatively low concentrations, exerts a stimulatory action on adrenal steroidogenesis, probably acting as an agonist of ET-1 receptors of type B.