Protective effects of the novel thromboxane A2 receptor antagonist sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)-ethylidene]-6,11- dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate against 9,11-dideoxy- 9 alpha, 11 alpha-epoxymethano-prostaglandin F2 alpha-induced sudden death in guinea-pigs and rats.
Injection of U-46619 (9,11-dideoxy-9 alpha, 11 alpha-epoxymethano- prostaglandinF2 alpha; 130 micrograms/kg i.v.) produced sudden death in anesthetized guinea-pigs and rats within 10-15 min. This sudden death is typified by a precipitous drop in mean arterial blood pressure (MABP) and a dramatic decrease in the circulating platelet counts. In guinea-pigs, KW-3635 (sodium(E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11- dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate, CAS 127166-41-0) at doses of 0.1 mg/kg or greater dramatically protected animals against sudden death induced by injection of U-46619. Pretreatment with KW-3635 (0.3, 1.0 mg/kg i.v.) inhibited the decrease in circulating platelet counts and the decline in blood pressure associated with the i.v. injection of U-46619. Oral administration of KW-3635 (10, 30 mg/kg) also protected the animals from the U-46619-induced sudden death. The effect of KW-3635 was almost the same as that of daltroban, and was more potent than that of sulotroban. In rats, intravenous administration of KW-3635 at doses of 0.3 mg/kg or greater protected against sudden death. In contrast, acetylsalicylic acid a cyclooxygenase inhibitor, did not protect against sudden death induced by U-46619, indicating that the formation of endogenous thromboxane does not play a major role in the lethal effect of U-46619, and that the blockade of the lethal effects of U-46619 is specific for thromboxane receptor antagonists. Our data show that KW-3635 protects guinea-pigs and rats against U-46619-induced sudden death. Therefore, KW-3635 may be useful for the investigation of diseases where thromboxane is involved.
Shirakura
S
S
Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Karasawa
A
A
Kubo
K
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001584:Benzoxepins / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003645:Death, Sudden / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D010648:Phenylacetates / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010976:Platelet Count / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D013988:Ticlopidine / Q000494:pharmacology
D001562:Benzimidazoles; D001584:Benzoxepins; D010648:Phenylacetates; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D013449:Sulfonamides; D013931:Thromboxanes; D013928:Thromboxane A2; C040624:sulotroban; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013988:Ticlopidine; D001241:Aspirin; C051762:daltroban; C065729:KW 3635