POSSIBLE INVOLVEMENT OF DIFFERENT MECHANISMS IN SUDDEN-DEATH INDUCED BY ENDOTHELIN-1 AND BIG ENDOTHELIN-1

The effects of diltiazem and phosphoramidon on sudden death induced by endothelin (ET)-1 and by big ET-1 were compared in rodents. Diltiazem (2 mg/kg, i.v.) remarkably diminished the lethal toxicity of ET-1 wit h a reduction in the extent of the rise in plasma immunoreactive ET-1- like activity (IR-ET-1), tissue IR-ET-1 accumulation in the heart and the rise in plasma potassium concentration. In big ET-1-induced lethal ity, diltiazem only slightly prolonged the latency and did not reduce the mortality. Although diltiazem moderately inhibited the rise in pla sma IR-ET-1 and potassium concentration in these mice, it did not affe ct the accumulation of IR-ET-1 in the heart, lung or kidney. Phosphora midon (2mg/kg, i.v.) decreased the lethality of big ET-1 with the decr ement in elevation of IR-ET-1 in the heart, lung and plasma as well as with the decrease in plasma potassium concentration, but it failed to improve any parameters in ET-1-induced lethality. In anesthetized rat s, ET-1 (5 nmol/kg, i.v.) elevated ST-segment of electromyocardiograms , and diltiazem (2mg/kg, i.v.) significantly reversed this change. Big ET-1 (25 nmol/kg, i.v.) also induced the ST-segment elevation, which was significantly inhibited by phosphoramidon but not by diltiazem. Th ese findings suggest that accumulation of ET-1 in the heart, which may lead to lethal cardiac ischemia, is an important factor in the lethal ity of ET-1, while additional factors (such as hemoconcentration and b ronchoconstriction) may be involved in big ET-1-induced lethality.