phosphoramidon and Death--Sudden

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

The lethal activity of big endothelin-1 (bET-1) was examined in mice and compared with endothelin-1 (ET-1). Like ET-1, intravenous administration of bET-1 produced sudden death with an approximate LD50 value at 21.0 nmol/kg, higher than that of ET-1 (3.8 nmol/kg). At doses above the respective LD90 value, the latency to death was much longer in bET-1-treated mice with sustained elevation of plasma immunoreactive ET-1 (IR-ET-1). A metalloproteinase inhibitor, phosphoramidon, although failing to inhibit sudden death induced by ET-1, suppressed bET-1-induced lethality and elevation of plasma IR-ET-1 probably due to an inhibition of the enzymatic conversion of bET-1 to ET-1.

Topics: Animals; Chromatography, High Pressure Liquid; Death, Sudden; Drug Antagonism; Endothelin-1; Endothelins; Glycopeptides; Immunoenzyme Techniques; Male; Metalloendopeptidases; Mice; Mice, Inbred ICR; Protein Precursors