Effect of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl]urea], a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, in a porcine model of acute pulmonary embolism.

Abstract

The aim of this study was to evaluate the effect of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl]urea], a dual thromboxane A2 synthase inhibitor and receptor antagonist, on the hemodynamic response to acute pulmonary embolism. Six anesthetized pigs were infused with placebo (placebo group) and compared with six other pigs receiving a continuous infusion of BM-573 (BM group). Pulmonary embolization with 0.3 g/kg autologous blood clots was carried out 30 min after the start of the infusion. Right ventricular pressure-volume loops were recorded using a conductance catheter, and end-systolic ventricular elastance was periodically assessed by varying right ventricular preload. Pulmonary vascular properties were studied by use of a four-element windkessel model. Hemodynamic data, including assessment of right ventricular-arterial coupling, were collected at baseline and every 30 min for 4 h. Blood samples were collected to assess gas exchange, thromboxane A2, and prostacyclin plasma levels and to evaluate platelet aggregation. Mean pulmonary arterial pressure in the placebo group increased significantly more than in the BM group, mainly because of an additional increase in pulmonary vascular resistance. Arterial and end-systolic ventricular elastances increased also more in the placebo group, whereas right ventricular efficiency decreased. BM-573 prevented both platelet aggregation induced by U-46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha) or by arachidonic acid, and thromboxane A2 overproduction, whereas prostacyclin liberation was preserved. Oxygenation, however, was not significantly improved. We conclude that in this animal model of acute pulmonary embolism, infusion of BM-573 reduced pulmonary vasoconstriction. As a result, right ventricular-vascular coupling values were maintained at a maximal efficiency level.