Effect Of An Inhibitor Of Thromboxane Synthesis (UK-37, 248-01) On Thrombin Induced Pulmonary Insufficiency In The Rat

Abstract

Severe trauma in man may be followed by an acute and/or delayed respiratory insufficiency due to microembolism in the lungs, the early and delayed microembolism syndrome, respectively. These conditions can be simulated in the rat by injection of thrombin and a fibrinolysis inhibitor. We have investigated the effect of a new inhibitor of thromboxane synthesis in this model.Intravenous injection of 500 IE thrombin/kg body weight in rats pretreated with trans-4-aminomethyl-cyclohexane-carboxylic acid 200 mg/kg b.w. resulted in a rapid, strong increase in the pulmonary arterial pressure (PAP) and a decrease in the mean arterial pressure (MAP). These reactions were followed by a progressive, slow increase in PAP, a slow decrease MAP and a heavy increase in the weight of the lungs due to interstitial and alveolar oedema.In rats pretreated with UK-37, 248-01 (Pfizer, England) 4 mg/kg b.w. the immediate increase in PAP and decrease in MAP was strongly inhibited. No effect on the later changes in PAP, MAP or lung weight was seen.The results speak for the release of thromboxane A2 being of importance in the early microembolism syndrome but not in the delayed syndrome. Thromboxane may be synthesized in platelets or leucocytes trapped in the lungs. Rats with depletion of the polymorphonuclear cells due to injection of a leucocyte antiserum reacted to the thrombin injection in the same way as rats pretreated with UK-37, 248-01 indicating a relationship between thromboxane A2 and the leucocytes trapped in the lungs.