MECHANISM OF INDUCTION OF PROSTAGLANDIN E(2) PRODUCTION BY ENDOTHELIN-1 IN CULTURED RAT MESANGIAL CELLS

The phospholipase A(2) inhibitors mepacrine, ONO-RS-082, and AACOCF(3) completely inhibited prostaglandin E(2) production induced by endothe lin 1 in cultured rat mesangial cells, suggesting that phospholipase A (2) is a critical enzyme in this process. TMB-8, an inhibitor of calci um mobilization from intracellular stores, abolished its production, w hile neither nicardipine nor chelation of extracellular calcium by EGT A did. The protein kinase C inhibitors, H-7 and staurosporine, and dow nregulation of protein kinase C could not inhibit prostaglandin E(2) p roduction, while W-7, a calmodulin inhibitor, abolished it. Pertussis toxin never influenced its production. Thus, endothelin 1 evokes prost aglandin E(2) production in mesangial cells mainly through the activat ion of phospholipase A(2), dependent on intracellular calcium and calm odulin and independent of extracellular calcium, protein kinase C, and pertussis toxin sensitive guanosine 5'-triphosphate binding proteins.