Cellular mechanism of endothelin-induced nitric oxide synthesis by cultured bovine endothelial cells.
Endothelins (ETs) cause initial and transient vasodilation via an endothelium-dependent mechanism. We studied the cellular mechanism by which ETs stimulate synthesis and release of endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) in cultured bovine endothelial cells (EC). ET-1 and ET-3 rapidly (within 1 min) and dose-dependently (10(-10) to 10(-7) M) stimulated production of nitrate/nitrite (NOx) in bovine EC; ET-3 was more potent than ET-1 at generating endothelial NOx. The ET-3-stimulated NOx production was completely abolished by a NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), the effect of which was reversed by coadministration of excess L-arginine. NOx production stimulated by ET-3 was blocked by an intracellular Ca2+ chelator but not by an extracellular Ca2+ chelator. A selective calmodulin inhibitor W-7 dose-dependently inhibited the ET-3-stimulated NOx production, whereas a nonselective calmodulin inhibitor W-5 failed to affect NOx production. These data suggest that ETs stimulate receptor-mediated EDRF/NO synthesis via a Ca2+/calmodulin-dependent pathway in vascular endothelial cells.
Hirata
Y
Y
Department of Medicine II, Tokyo Medical Dental University, Japan.
Emori
T
T
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002417:Cattle; D002478:Cells, Cultured; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013449:Sulfonamides / Q000494:pharmacology; D019323:omega-N-Methylarginine
D002147:Calmodulin; D016232:Endothelins; D013449:Sulfonamides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D004533:Egtazic Acid; C017967:W 7; D001120:Arginine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium