Possible Involvement of Different Mechanisms in Sudden Death Induced by Endothelin-1 and Big Endothelin-1

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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 with 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 lethality, diltiazem only slightly prolonged the latency and did not reduce the mortality. Although diltiazem moderately inhibited the rise in plasma IR-ET-1 and potassium concentration in these mice, it did not affect the accumulation of IR-ET-1 in the heart, lung or kidney. Phosphoramidon (2 mg/kg, i. v.) decreased the lethality of big ET-1 with the decrement 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 rats, ET-1 (5 nmol/kg, i. v.) elevated ST-segment of electromyocardiograms, and diltiazem (2 mg/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. These findings suggest that accumulation of ET-1 in the heart, which may lead to lethal cardiac ischemia, is an important factor in the lethality of ET-1,while additional factors (such as hemoconcentration and bronchoconstriction) may be involved in big ET-1-induced lethality.
社団法人日本薬学会の論文
1995-01-15

Possible Involvement of Different Mechanisms in Sudden Death Induced by Endothelin-1 and Big Endothelin-1

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