Endothelins stimulate aldosterone secretion from dispersed rat adrenal zona glomerulosa cells, acting through ETB receptors coupled with the phospholipase C-dependent signaling pathway

Compelling evidence indicates that endothelins (ETs) stimulates aldosterone secretion from rat zona glomerulosa (ZG) cells, acting. through the ETB re ceptor subtype. We have investigated the mechanisms transducing the: aldost erone secretagogue signal elicited by the pure activation of ETB receptors. Aldosterone response of dispersed rat ZG cells to the selective ETB-recept or agonist BQ-3020 was not affected by inhibitors of adenylate cyclase/prot ein kinase (PK)A, tyrosine kinase-, mitogen-activated PK-, cyclooxygenase- and lipoxygenase-dependent pathways. in contrast, the inhibitor of phosphol ipase C (PLC) U-73122 abrogated, and the inhibitors of PKC, phosphatidylino sitol trisphosphate (IP3)-kinase and calmodulin (calphostin-C, wortmannin a nd W-7, respectively) partially prevented aldosterone response to BQ-3020. When added together, calphostin-C and wortmannin or W-7 abolished the secre tagogue effect of BQ-3020. BQ-3020 elicited a mal ked increase in the intra cellular Ca2+ concentration ([Ca2+](i)) in dispersed rat ZG cells, and the effect was abolished by the Ca2+-release inhibitor dantrolene. The Ca2+ cha nnel blocker nifedipine affected neither aldosterone nor Ca2+ response to B Q-3020. Collectively, our findings suggest that (1) ETs stimulate aldostero ne secretion from rat ZG cells through the activation of PLC-coupled ETB re ceptors; (2) PLC stimulation leads to the activation of PKC and to the rise in [Ca2+]i with the ensuing activation of calmodulin; and (3) the increase in [Ca2+] is exclusively dependent on the stimulation of IP3-dependent Ca2 + release from intracellular stores. (C) 2001 Elsevier Science Inc. All rig hts reserved.