Endothelin-1 [1-311 acts as a selective ETA-receptor agonist in the rat adrenal cortex

Abstract

Endothelin-1 (ET-1) is a 21-amino acid residue (ET-1[1-211) hypertensive peptide, which together with its receptor subtypes A and B (ETA and ETB) is expressed in the rat adrenal cortex, where it stimulates steroid-hormone (aldosterone and corticosterone) secretion through the ETB receptor and the growth (proliferative activity) of the zona glomerulosa (ZG) through the ETA receptor. ET-1[1-211 is generated from bigET-1 by the endothelin-converting enzyme (ECE-1). However, recent evidence indicates the existence of an alternative chymase-mediated biosynthetic pathway leading to the production of an ET- 1[1-311 peptide, which was found to reproduce the ETA receptor-mediated vascular effects of ET-l[l-211. We found that ET-1[1-211, but not ET-1[1-311, concentration-dependently raised steroid secretion from dispersed rat adrenocortical cells, its effect being blocked by the ETB-receptor selective antagonist BQ- 788. Both ET-1s concentration-dependently increased the number of "S-phase" cells (as detected by the 5- bromo-2'-deoxyuridine immunocytochemical method) in capsule-ZG strips within a 240 min incubation. The ZG proliferogenic action of both ET-1s was blocked by the ETA-receptor antagonist BQ-123, and ET-l[l-311 was found to be significantly more potent than ET-1[1- 211. Autoradiography showed that in the rat adrenal ET- 1[1-211 displaced the binding of selective ligands to both ETA ([125I]PD-151242) and ETB receptors ([125I]BQ-3020), while ET-l[l-311 eliminates only the binding to ETA receptors. Collectively, our findings provide strong evidence that ET-1[1-311 acts in the rat adrenal glands as a selective ETA-receptor agonist, mainly involved in the stimulation of ZG proliferative activity.