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.