Novel guanylyl cyclase inhibitor, ODQ reveals role of nitric oxide, but not of cyclic GMP in endothelin-1 secretion.
The role of nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cyclic GMP) in cellular regulation of endothelin-1 (ET-1) secretion was investigated in cultured porcine aortic endothelial cells. NO synthase was inhibited with NG-nitro-L-arginine (L-NNA) and guanylyl cyclase with the novel selective inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) (3 microM). Basal and phorbol ester (PMA)-stimulated ET-1 secretion were unaffected by ODQ, but stimulated secretion was increased by L-NNA. In the presence of the NO donors, spermine/NO, S-nitroso-glutathione (GSNO), and nitroprusside (NP) ET-1 secretion was reduced, but ODQ had no effect on this inhibition, although it effectively inhibited cyclic GMP production. NO release from donors, measured with a sensitive NO electrode, was greatest for spermine/NO, intermediate for GSNO, minimal for NP and paralleled inhibition of ET-1 secretion. The data suggest that in cultured endothelial cells, curtailment of ET-1 secretion is mediated by NO and independent of cyclic GMP.
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology*; D016232:Endothelins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine; D009599:Nitroprusside / Q000737:chemistry; D010069:Oxadiazoles / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D013552:Swine; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D016232:Endothelins; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D013729:Terpenes; D009599:Nitroprusside; D019335:Nitroarginine; D009569:Nitric Oxide; D019284:Thapsigargin; D001120:Arginine; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium