endothelin-1 and dithiol

The effects of metal chelators on endothelin (ET)-converting enzyme (ECE) activity in vivo were examined. Three compounds, (2,3-dimercapto-1-propanol (DMP), toluene-3,4-dithiol (TDT) and 8-mercaptoquinoline (8-MQ)), which inhibited ECE in in vitro studies, exhibited inhibitory activity towards big ET-1-induced sudden death in mice, while EDTA did not. Similar results were obtained in big ET-1-induced hypertension. Big ET-1-induced hemoconcentration was inhibited by pretreatment with 8-MQ or EDTA but not with DMP or TDT. The elevation of immunoreactive ET-1 (IR-ET-1) in plasma after administration of big ET-1 was inhibited by pretreatment with the three compounds but not by EDTA. On the other hand, no chelator inhibited the elevation of IR-ET-1 in lung tissue after injection of big ET-1. Taking into consideration the in vitro results, more selective chelating activity of the compounds towards Zn2+ 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 characteristics from that involved in big ET-1-induced sudden death or hypertension.

Topics: Animals; Aorta, Thoracic; Aspartic Acid Endopeptidases; Blood Pressure; Chelating Agents; Death, Sudden; Dimercaprol; Edetic Acid; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Glycopeptides; Hematocrit; Lung; Male; Metalloendopeptidases; Mice; Mice, Inbred ICR; Muscle Contraction; Muscle, Smooth, Vascular; Protein Precursors; Quinolines; Rats; Rats, Sprague-Dawley; Toluene