CHARACTERIZATION OF BIG ENDOTHELIN-1-INDUCED CONTRACTION IN RABBIT SAPHENOUS ARTERY

We have characterized the endothelin-converting enzyme (ECE)-like acti vity involved in big endothelin (ET)-1-induced contraction in rabbit s aphenous artery (RSA). Big ET-1 30 nM caused a contraction that was in dependent of the vascular endothelium. Phosphoramidon and the neutral endopeptidase (NEP) inhibitors thiorphan and candoxatrilat blocked the vasoconstriction caused by big ET-1 in endothelium-denuded RSA. Cando xatrilat (IC50 17 nM) and thiorphan (IC50 2.5 nM), were 5- to 30-fold more potent than phosphoramidon (IC50 83 nM). Other protease inhibitor s were inactive. In cultured endothelial cells the ET-1 release was in hibited only by phosphoramidon (IC50 16 mu M) but at a concentration 2 00-fold that required an endothelium-denuded RSA. In conclusion, we ca n speculate that the big ET-1 contraction in RSA is mediated by an ECE , probably present on smooth muscle cells, which is susceptible to NEP inhibitors and is different from the ECE on endothelial cells.