INHIBITORY ACTIVITIES OF METAL CHELATORS ON ENDOTHELIN-CONVERTING ENZYME .1. IN-VITRO STUDIES

The effects of various metal chelators on endothelin (ET)-converting e nzyme (ECE) activity were examined in vitro. Three chelators, 2,3-dime rcapto-1-propanol (DMP), toluene-3,4-dithiol (TDT) and 8-mercaptoquino line (8-MQ), were found to dose-dependently inhibit ECE activity, but this inhibition was much weaker compared with EDTA. In the presence of Zn2+, the inhibitory activity of all these compounds, including EDTA, was abolished. The addition of Ca2+ and Mg2+ markedly attenuated the inhibitory activity of EDTA, but the other three chelators were still able to inhibit ECE. ECE, once inactivated by EDTA or 8-MQ, was reacti vated by the addition of divalent cations such as Zn2+ and Mn2+. These compounds also inhibited angiotensin-converting enzyme activity in a manner similar to the inhibition exhibited towards ECE. Chelate-titrat ion indicated that DMP, TDT and 8-MQ chelate Zn2+ but not Ca2+ and Mg2 +. These results suggest that the ECE inhibition exhibited by these co mpounds is mainly attributable to their chelating activities. The meta l-selective chelating activity by DMP, TDT and 8-MQ may contribute to the retention of ECE inhibition in the presence of Ca2+ and Mg2+.