P-117: Effects of endothelin-1[1-31] on human adrenal cortex

Endothelin-1 (ET-1), a potent 21 aminoacid residue vasoconstrictor peptide, is expressed in the human and rat adrenal cortex together with its receptor subtypes A and B (ETA and ETB), and stimulates steroids secretion. Although ET-1[1-21] is generated from big-ET-1 by an endothelin converting enzyme (ECE)-1, recent evidence indicates the existence of an alternative chymase-mediated biosynthetic pathway leading to the production of an ET-1[1-31] peptide. Since the role of the latter in adrenal pathophysiology is largely unknown, we investigated a) whether chymase is expressed at the gene and protein level in the human adrenal cortex; b) the secretagogue effect of ET-1[1-31], as compared to that of ET-1[1-21] on human adrenocortical cells. We found both ET-1[1-21] and ET-1[1-31] peptide concentration-dependently elicited a clear-cut secretory response by dispersed human adrenocortical cells, ET-1[1-31] being significantly less potent than ET-1[1-21]. The secretagogue effect of ET-1[1-31] was unaffected by high concentrations of phosphoramidone and thus did not require its conversion to ET-1[1-21] by ECE-1. The secretory response of adrenocortical cells to ET-1[1-31] was abolished by the ETA receptor antagonist BQ-123 and unaffected by the ETB receptor antagonist BQ-788. Since in humans the adrenocortical secretory response to ET-1[1-21] seems to occur via both ETA and ETB receptors, the weaker secretagogue action of ET-1[1-31] may be ascribed to a selective activation of ETA receptors. This contention is supported by findings that 1) that ET-1[1-31] displaced [125I]ET-1[1-21] autoradiographic binding to ETA, but not ETB receptors; and 2) that ET-1[1-31] was more effective than ET-1[1-21] in stimulating ETA-mediated cell proliferation. Collectively, these results raise the possibility that in human adrenals alternative cleavage of big-ET-1 by ECE-1 or chymase may lead to the production of either ET-1[1-21] mainly exerting secretagogue effects via both ETA and ETB receptors, or ET-1[1-31], mainly promoting growth via ETA receptors.