Contractile activity of endothelins and their precursors in human umbilical artery and vein: identification of distinct endothelin-converting enzyme activities

A number of studies using endothelin (ET) precursors, commonly termed big ETs, have revealed the presence of endothelin-converting enzyme (ECE) activity in various vascular and nonvascular preparations. Since then, more than one ECE has been cloned. It has also been observed that big ET-1 and big ET-3 are not converted by the same enzyme. The ECE responsible for big ET-3 conversion is rarely present because big ET-3 does not induce a contractile response in most isolated preparations tested. In this study we characterized ECE activities present in two human preparations, the umbilical artery and vein, testing the contractile activities of the three human Big ETs in the presence or absence of phosphoramidon, a dual ECE/neutral endopeptidase inhibitor. The results show that human big ET-1(1-38) is 6.3-fold more potent than big ET-2(1-38) in the human umbilical artery (an ETA preparation), whereas big ET-1 is equipotent to big ET-2 in the vein (which contains ETA and ETB receptors). Human big ET-3(1-41) is inactive on both vessels. Furthermore, phosphoramidon attenuated human big ET-1-induced contractions only in the umbilical artery and not in the vein. Such observations, in terms of substrate selectivity and phosphoramidon sensitivity, suggest the presence of distinct ECE activities in human vein and arteries