Effect of the thromboxane receptor antagonist, BM 13.505, on the sequelae of endotoxemia in the conscious rat.
The purpose of this study was to examine the effects of the thromboxane receptor antagonist, BM 13.505, on the responses to endotoxemia in the conscious rat. The pharmacodynamics of BM 13.505 (30 mg/kg, i.v.) were first determined by pretreating male Sprague-Dawley rats 5 min, 24 h or 48 h prior to an LD90 dose of the thromboxane mimetic U 46619. Administration of a single dose of BM 13.505 5 min or 24 h prior to the challenge with U 46619 protected completely against sudden death (100% survival, p less than 0.01), while injection of BM 13.505 48 h prior to the U 46619 challenge did not protect against death. In a separate group of conscious rats, endotoxemia (30 mg/kg i.v. Salmonella enteritidis endotoxin) produced a decrease in the number of circulating platelets to 45 +/- 4% and 20 +/- 4% of the initial value at 1 and 6 h, respectively. The number of circulating white blood cells was reduced to 21 +/- 4% of the initial value at 1 h and returned to 68 +/- 9% of the initial value at 6 h. Survival following endotoxin administration was 44% at 48 h. In endotoxemic animals pretreated with BM 13.505 (30 mg/kg, i.v.), the endotoxin-induced thrombocytopenia was significantly attenuated (p less than 0.05), but there was no effect on either the endotoxin-induced early leukopenia or late leukocytosis. Survival in the BM 13.505-treated endotoxemic group was 31% at 48 h (p greater than 0.05, compared to the endotoxin + vehicle group).(ABSTRACT TRUNCATED AT 250 WORDS)
Smith
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Smith Kline and French Laboratories, Department of Pharmacology, King of Prussia, PA 19406.
Jugus
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Kinter
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D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D010648:Phenylacetates / Q000494:pharmacology*; D010976:Platelet Count / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012477:Salmonella enteritidis; D012772:Shock, Septic / Q000401:mortality / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D004731:Endotoxins; D010648:Phenylacetates; D011450:Prostaglandin Endoperoxides, Synthetic; D013449:Sulfonamides; D013931:Thromboxanes; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C051762:daltroban