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 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.
Okumura
H
H
Pharmaceutical Research Laboratories, Sapporo Breweries, Ltd., Shizuoka, Japan.
Ashizawa
N
N
Asakura
R
R
Aotsuka
T
T
Kobayashi
F
F
Matsuura
A
A
D000758:Anesthesia; D000818:Animals; D016757:Death, Sudden, Cardiac; D004110:Diltiazem / Q000494:pharmacology; D004562:Electrocardiography; D019332:Endothelin-1; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D006020:Glycopeptides / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017202:Myocardial Ischemia / Q000139:chemically induced; D009206:Myocardium / Q000378:metabolism; D011188:Potassium / Q000097:blood; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D004110:Diltiazem; D011188:Potassium; C008890:phosphoramidon