Effects of BM-573, a Novel Thromboxane A2 Inhibitor, on Pulmonary Hemodynamics in Endotoxic Shock

Abstract

Thromboxane A 2 is considered to be partially responsible for the increase in pulmonary vascular resistance observed after endotoxin administration and to participate in proinflammatory reactions. The effects of a novel dual TXA 2 synthase inhibitor and TXA 2 receptor antagonist (BM-573) on pulmonary hemodynamics were investigated in endotoxic shock. 30 mins before the start of a 0.5 mg/kg endotoxin infusion, 6 pigs (Endo group) received a placebo infusion and 6 other pigs (Anta group) received a BM-573 infusion. In Endo group, pulmonary artery pressure increased from 25 ± 1.8 (T0) to 42 ± 2.3 mmHg (T60) (p < 0.05) after endotoxin infusion while, in Anta group, it increased from 23 ± 1.6 (T0) to 25 ± 1.5 mmHg (T60). This difference is due to a reduction in pulmonary vascular resistance in Anta group while pulmonary arterial compliance changes in Endo group remained comparable with the evolution in Anta group. In Endo group, PaO 2 decreased from 131 ± 21 (T0) to 74 ± 12 mmHg (T300) (p < 0.05), while in Anta group, PaO 2 was 241 ± 31 mmHg at the end of the experimental period (T300). These results demonstrate that TXA 2 plays a major role in pulmonary vascular changes during endotoxin insult. Concomitant inhibition of TXA 2 synthesis and of TXA 2 receptors by BM-573 inhibited the pulmonary vasopressive response during the early phase of endotoxin shock as well as the deterioration in arterial oxygenation.