Okumura H, Ashizawa N, Asakura R, Aotsuka T, Kobayashi F, Matsuura A
Pharmaceutical Research Laboratories, Sapporo Breweries, Ltd., Shizuoka, Japan.
Biol Pharm Bull. 1995 Jan;18(1):18-23. doi: 10.1248/bpb.18.18.
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.
在啮齿动物中比较了地尔硫䓬和磷酰胺对内皮素（ET）-1及大内皮素-1所致猝死的影响。地尔硫䓬（2毫克/千克，静脉注射）显著降低了ET-1的致死毒性，同时血浆免疫反应性ET-1样活性（IR-ET-1）升高幅度减小、心脏组织IR-ET-1蓄积减少以及血浆钾浓度升高幅度降低。在大内皮素-1诱导的致死性方面，地尔硫䓬仅略微延长了潜伏期，并未降低死亡率。尽管地尔硫䓬适度抑制了这些小鼠血浆IR-ET-1和钾浓度的升高，但它并未影响心脏、肺或肾脏中IR-ET-1的蓄积。磷酰胺（2毫克/千克，静脉注射）降低了大内皮素-1的致死性，同时心脏、肺和血浆中IR-ET-1升高幅度减小以及血浆钾浓度降低，但它未能改善ET-1诱导的致死性中的任何参数。在麻醉大鼠中，ET-1（5纳摩尔/千克，静脉注射）使心电图ST段抬高，而地尔硫䓬（2毫克/千克，静脉注射）显著逆转了这一变化。大内皮素-1（25纳摩尔/千克，静脉注射）也诱导了ST段抬高，这被磷酰胺显著抑制，但未被地尔硫䓬抑制。这些发现表明，心脏中ET-1的蓄积可能导致致命性心肌缺血，这是ET-1致死性的一个重要因素，而其他因素（如血液浓缩和支气管收缩）可能参与大内皮素-1诱导的致死性。
