Thromboxane and Pulmonary Hypertension Following E. Coli Endotoxin Infusion in Sheep: Effect of an Imidazole Derivative

We assessed the effect of a specific thromboxane synthetase inhibitor (an imidazole derivative) on pulmonary hemodynamics and the concentrations of TxB2 (TxA2), 6-keto-PGF1 alpha (PGI2), and PGF2 in pulmonary lymph and transpulmonary blood samples following intravenous administration of E. coli endotoxin (1 microgram/kg) in sheep. In control animals the rise in pulmonary artery pressure correlated with increases in plasma and lymph TxB2 concentrations and large transpulmonary concentration gradients of this metabolite were measured. In imidazole treated animals both pulmonary hypertension as well as increases in plasma and lymph TxB2 concentrations were substantially reduced. In contrast, peak concentrations of 6-keto-PGF1 alpha (PGI2) and PGF2 alpha were severalfold higher than those measured in control animals. This suggests a shunting of endoperoxide metabolism towards prostacyclin and primary prostaglandins and documents the specificity of the thromboxane synthetase inhibitor. Our study provides evidence that endotoxin-induced pulmonary hypertension is mediated by pulmonary synthesis of TxA2.