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 synt hase was inhibited with N-G-nitro-L-arginine (L-NNA) and guanylyl cycl ase with the novel selective inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3, -a]quinoxalin-1-one) (3 mu M). Basal and phorbol ester (PMA)-stimulate d 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-n itroso-glutathione (GSNO), and nitroprusside (NP) ET-1 secretion,vas r educed, but ODQ had no effect on this inhibition, although it effectiv ely inhibited cyclic GMP production. NO release from donors, measured with a sensitive NO electrode, was greatest for spermine/NO, intermedi ate for GSNO, minimal for NP and paralleled inhibition of ET-1 secreti on. The data suggest that in cultured endothelial cells, curtailment o f ET-1 secretion is mediated by NO and independent of cyclic GMP.