Thromboxane A2 mediates lung vasoconstriction but not permeability after endotoxin

Abstract

The effect of dazoxiben, a selective thromboxane (Tx) synthetase inhibitor, on systemic and pulmonary hemodynamics, eicosanoids, and lung permeability was assessed in awake goats with lung lymph fistulae following infusion of Escherichia coli endotoxin (1 μg/kg). Animals received endotoxin either with no treatment or pretreatment with a bolus (25 mg/kg) followed by a maintenance infusion (10 mg/kg per h) of dazoxiben. In untreated animals, the peak rise of 26.8 cm H2O in pulmonary artery (Ppa) and of 13.5 cm H2O in wedge (Pw) pressures occurred at the same time as the peak elevations in plasma thromboxane B2 (TxB2). Maximum reduction in cardiac output (Q̇(t)) also occurred at the same time. Lung lymph flow (Q̇(L)) increased during this period and remained elevated for at least 6 h after endotoxin. TxB2 levels had returned from a peak of 13.1 to 0.7 ng/ml by 2 h. In dazoxiben-treated animals, plasma concentrations of TxB2 were never significantly elevated. Increases in Ppa and Pw were markedly reduced and decreased Q̇(t) was transient. Q̇(L) in treated animals began to increase by 30 min after endotoxin and reached a peak by 2 h. Increased Q̇(L) in treated animals was not as great as in the untreated animals. Moreover, lymph-plasma protein ratios increased significantly in treated animals. Plasma prostaglandin (PG)F(2α) and 6-keto-PGF(1α) concentrations were elevated in both groups after endotoxin with values significantly greater in treated animals. We conclude that selective inhibition of Tx ameliorates many adverse hemodynamic consequences of endotoxemia but does not prevent lung permeability changes.