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.

Abstract

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.

• Authors: S Shirakura, A Karasawa, K Kubo
• Journal: Arzneimittel-Forschung (Arzneimittelforschung) Vol. 41 Issue 12 Pg. 1242-5 (Dec 1991) ISSN: 0004-4172 [Print] Germany
• PMID: 1815523 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Benzimidazoles
• Benzoxepins
• Phenylacetates
• Platelet Aggregation Inhibitors
• Prostaglandin Endoperoxides, Synthetic
• Sulfonamides
• Thromboxanes
• Thromboxane A2
• sulotroban
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• Ticlopidine
• Aspirin
• daltroban
• KW 3635

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• Animals
• Aspirin (pharmacology)
• Benzimidazoles (pharmacology)
• Benzoxepins (pharmacology)
• Blood Pressure (drug effects)
• Death, Sudden (pathology)
• Dose-Response Relationship, Drug
• Guinea Pigs
• Male
• Phenylacetates (pharmacology)
• Platelet Aggregation Inhibitors (pharmacology)
• Platelet Count (drug effects)
• Prostaglandin Endoperoxides, Synthetic (antagonists & inhibitors, toxicity)
• Rats
• Rats, Inbred Strains
• Sulfonamides (pharmacology)
• Thromboxane A2 (antagonists & inhibitors)
• Thromboxanes (antagonists & inhibitors)
• Ticlopidine (pharmacology)