Endothelin-1 [1-31] acts as a selective ETA-receptor agonist in the rat adrenal cortex

Endothelin-1 (ET-1) is a 21-amino acid residue (ET-1[1-21]) hypertensive pe ptide, which together with its receptor subtypes A and B (ETA and ETB) is e xpressed in the rat adrenal cortex, where it stimulates steroid-hormone (al dosterone and corticosterone) secretion through the ETB receptor and the gr owth (proliferative activity) of the zona glomerulosa (ZG) through the ETA receptor. ET-1[1-21] is generated from bigET-1 by the endothelin-converting enzyme (ECE-1). However, recent evidence indicates the existence of an alt ernative chymase-mediated biosynthetic pathway leading to the production of an ET-1[1-31] peptide, which was found to reproduce the ETA receptor-media ted vascular effects of ET-1[1-21]. We found that ET-1[1-21], but not ET-1[ 1-31], concentration-dependently raised steroid secretion from dispersed ra t adrenocortical cells, its effect being blocked by the ETB-receptor select ive antagonist BQ-788. Both ET-1s concentration-dependently increased the n umber of "S-phase" cells (as detected by the 5-bromo-2'-deoxyuridine immuno cytochemical method) in capsule-ZG strips within a 240 min incubation. The ZG proliferogenic action of both ET-1s was blocked by the ETA-receptor anta gonist BQ-123, and ET-1[1-31] was found to be significantly more potent tha n ET-1[1-21]. Autoradiography showed that in the rat adrenal ET-1[1-21] dis placed the binding of selective ligands to both ETA ([I-125]PD-151242) and ETB receptors ([I-125]BQ- 3020), while ET-1[1-31] eliminates only the bindi ng to ETA receptors. Collectively, our findings provide strong evidence tha t ET-1[1-31] acts in the rat adrenal glands as a selective ETA-receptor ago nist, mainly involved in the stimulation of ZG proliferative activity.