Abstract
Evidence has been provided that the 21-amino acid hypertensive peptide endothelin (ET)-1 exerts a potent secretagogue effect on human adrenocortical zona glomerulosa (ZG), acting through two receptor subtypes, called ETA and ETB, the signaling mechanism(s) of which has (have) not yet been investigated. Collagenase dispersed human ZG cells were obtained from normal adrenals of patients undergoing nephrectomy/adrenalectomy for renal cancer. The selective ETA- and ETB-receptor activation was obtained by exposing dispersed cells to ET-1 plus the ETB-receptor antagonist BQ-788 and to the ETB-receptor agonist BQ-3020, respectively. The phospholipase (PL) C inhibitor U-73122 abolished ETA receptor-mediated secretory response, but only partially prevented the ETB receptor-mediated one. The phosphatidylinositol 3-kinase inhibitor wortmannin, the calmodulin inhibitor W-7 and the protein kinase (PK) C inhibitor calphostin-C significantly blunted the secretory responses ensuing from the activation of both receptor subtypes. When added together, calphostin-C and wortmannin or W-7 abolished ETA-mediated secretory response, but only decreased ETB-mediated one. The ETB receptor-, but not the ETA receptor-mediated aldosterone response was partially reversed by the cyclooxygenase (COX) inhibitor indomethacin, which when added together with U-73122 abolished it. ETA-receptor activation raised inositol triphosphate (IP3) production from dispersed ZG cells, while ETB-receptor stimulation enhanced both IP3 and prostaglandin-E2 production. Collectively, our findings indicate that ETs stimulate aldosterone secretion from human ZG cells, acting through ETA receptors exclusively coupled to PLC/PKC-dependent pathway and ETB receptors coupled to both PLC/PKC- and COX-dependent cascades.
Published Version
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