To elucidate the role of
thromboxane A2 in the development of
endotoxin shock following administration of
endotoxin, the effects of three
thromboxane A2 synthetase inhibitors, (E)-3-(4-(1-imidazolyl)phenyl)-2-propenoic
acid hydrochloride monohydrate (OKY-046),
sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methylacrylate (OKY-1581) and
imidazole were examined.
Intravenous administration of E. Coli
endotoxin (3 mg/kg) produced
shock and all rats died within ten hours. Pretreatment with
thromboxane A2 synthetase inhibitors markedly improved the survival rates. The untreated
endotoxin shock group showed marked increase in
thromboxane B2 levels in the venous blood, while no such changes were seen in the pretreated groups. There were no statistically significant differences in 6-keto
prostaglandin F1 alpha levels in the venous blood. In the untreated
shock group, microthrombi were observed in 64% of the glomeruli in the kidneys two hours after
endotoxin injection. In the groups pretreated with
OKY-046,
OKY-1581 and
imidazole, microthrombi were seen only in 22, 19 and 24%, respectively. Thus,
thromboxane A2 plays an important role in the development of
endotoxin shock and
thromboxane A2 synthetase inhibitors, in particular
OKY-046 and -1581, are prophylactic.