EFFECT OF THE PLATELET-ACTIVATING-FACTOR ANTAGONIST (-CIS-3,5-DIMETHYL-2-(3-PYRIDYL)THIAZOLIDIN-4-ONE HYDROCHLORIDE ON ENDOTOXIN-INDUCED HYPOTENSION AND HEMATOLOGICAL PARAMETERS IN RATS())

The intravenous administration of endotoxin to anesthetized rats resul ted in different hypotensive reactions depending on its dosage. More t han 10 mg/kg of endotoxin induced biphasic hypotension; the first phas e consisted in a small and transient depression (approximately 15 mmHg ) of mean arterial pressure occurred within 1 min after the administra tion, and the second phase was a large and sustained depression (maxim ally 40 mmHg) observed from 1 h after the injection. At less than 3 mg /kg of endotoxin, the first phase of hypotension did not occur whereas the second phase of hypotension was observed. Pre-treatment or post-t reatment with a specific platelet activating factor (PAF) antagonist, SM-12502 +)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl, CAS 1 19383-00-5) inhibited the second phase of endotoxin (1 mg/kg)induced h ypotension. In addition, pot-treatment with another PAF antagonist, (3 -(4-(2-chlorophenyl)-9-methyl-6H-thieno (3,2-f) (1,2,4)-thiazolo-pheno ne) also inhibited the second phase of hypotension. Blood PAF-like sub stance level, measured by the PAF radioimmunoassay, slightly increased at 1 min after administration of endotoxin (30 mg/kg). At 90 min afte r the injection, endotoxin (1 mg/kg) induced a significant increase of PAF-like substance level. Endotoxin, at a dose which induced the seco nd phase of hypotension but not the first phase, induced changes in he matological parameters, such as fibrinogen level, prothrombin time (PT ), partial thromboplastin time (PTT), platelet count and fibrin and fi brinogen degradation products (FDP), which are used for diagnostic ind ications of disseminated intravasular coagulation (DIC). SM-12502 (3-1 0 mg/kg i.v.) inhibited the endotoxin-induced changes in hematological parameters in a dose-dependent manner. These results strongly suggest that PAF production observed during the second phase of hypotension i s involved in the development of endotoxin shock and endotoxin-induced DIC and that SM-12502 may be a novel therapeutic agent for shock and DIC.