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)