Mechanism of the protective action of Bay-u-3405, a new specific thromboxane receptor antagonist, in arachidonate-induced sudden death.
Injection of sodium arachidonate (NaAr) intravenously at a dose of 2 mg/kg is uniformly lethal in rabbits within 3 min. This sudden death is characterized by a precipitous drop in mean blood pressure within 2 min after injection of NaAr, a marked decrease in the circulating platelet count, a significant increase in intratracheal pressure and in plasma thromboxane A2 (TxA2) concentration as measured by radioimmunoassay of its stable breakdown product, TxB2. Pretreatment with Bay-u-3405, a new specific thromboxane receptor antagonist, at a dose of 1 or 10 mg/kg dramatically protected rabbits against sudden death induced by injection of NaAr. All of the rabbits treated with either of these two doses of Bay-u-3405 survived, and their thrombocytopenia, elevated plasma TxB2 concentration and bronchoconstriction were significantly attenuated. However, administration of 0.1 mg/kg Bay-u-3405 exerted no protective effect in this lethal model. Bay-u-3405 was shown to be a potent and specific inhibitor of thromboxane-mimetic induced platelet aggregation in vitro. Our data clearly show that Bay-u-3405 is a very effective protective agent against NaAr-induced sudden death in rabbits, blocking all of the known deleterious effects of TxA2.
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Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA.
Karasawa
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Lefer
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D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D001980:Bronchi / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D003645:Death, Sudden; D004562:Electrocardiography; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011817:Rabbits; D011863:Radioimmunoassay; D013449:Sulfonamides / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000633:toxicity; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D002227:Carbazoles; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D013931:Thromboxanes; D016718:Arachidonic Acid; D013928:Thromboxane A2; C063119:ramatroban