INHIBITORY ACTIVITIES OF METAL CHELATORS ON ENDOTHELIN-CONVERTING ENZYME .2. IN-VIVO STUDIES

The effects of metal chelators on endothelin (ET)-converting enzyme (E CE) activity in vivo were examined. Three compounds, (2,3-dimercapto-1 -propanol (DMP), toluene-3,4-dithiol (TDT) and and 8-mercaptoquinoline (8-MQ)), which inhibited ECE in in vitro studies, exhibited inhibitor y activity towards big ET-1-induced sudden death in mice, while EDTA d id not. Similar results were obtained in big ET-1-induced hypertension . Big ET-1-induced hemoconcentration was inhibited by pretreatment wit h 8-MQ or EDTA but not with DMP or TDT. The elevation of immunoreactiv e ET-1 (IR-ET-1) in plasma after administration of big ET-1 was inhibi ted by pretreatment with the three compounds but not by EDTA. On the o ther hand, no chelator inhibited the elevation of IR-ET-1 in lung tiss ue after injection of big ET-1. Taking into consideration the in vitro results, more selective chelating activity of the compounds towards Z n2+ rather than Ca2+ and Mg2+ may contribute to the inhibition of big ET-1-induced responses in vivo. The ET-1 formation involved in big ET- 1-induced hemoconcentration may have different physiological character istics from that involved in big ET-1-induced sudden death or hyperten sion.