CONVERSION OF BIG ENDOTHELIN-1 AND CHARACTERIZATION OF ITS CONTRACTILE EFFECTS ON ISOLATED HUMAN PLACENTAL ARTERIES

Objectives: To study the conversion of human big endothelin-1 (bigET-1 ) to endothelin-1 (ET-1) and to characterize contractile ET-1 receptor s in human placental arteries. Methods: BigET-1 was incubated with art ery membranes and the formation of ET-1 was investigated. ET-1 and big ET-1-induced contractile responses were studied in the absence or pres ence of the metalloprotease inhibitor phosphoramidon, the ETA-receptor antagonist BQ 123, or the ETB-receptor antagonists IRL 1038 and RES 7 01-1. Results: The artery membranes hydrolysed bigET-1 to ET-1 through a partly phosphoramidon-sensitive pathway. The contractile responses to ET-1 and bigET-1 were similar, with pEC(50%) values of 8.1 +/- 0.2 and 7.8 +/- 0.1, respectively (NS; n = 17). Phosphoramidon decreased P EC50% for bigET-1-evoked contractions (p < 0.05; n = 8), without affec ting the response to ET-1. A Schild plot of BQ 123 effects on ET-1 and bigET-1-induced contractions resulted in identical pA(2) values and a slope of 0.56 +/- 0.2 and 0.47 +/- 0.01, respectively. IRL 1038 and R ES 701-1 did not affect the contractile responses. Conclusion: BigET-1 -evoked contractions in isolated human placental arteries depend on a rapid and metalloprotease-dependent hydrolytic conversion to ET-1, whi ch in turn causes a, mainly ETA-receptor-mediated, contraction.