Thromboxane A2 mediates lung vasoconstriction but not permeability after endotoxin.
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 microgram/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 (T X B2). Maximum reduction in cardiac output (Qt) also occurred at the same time. Lung lymph flow (QL) increased during this period and remained elevated for at least 6 h after endotoxin. T X B2 levels had returned from a peak of 13.1 to 0.7 ng/ml by 2 h. In dazoxiben-treated animals, plasma concentrations of T X B2 were never significantly elevated. Increases in Ppa and Pw were markedly reduced and decreased Qt was transient. QL in treated animals began to increase by 30 min after endotoxin and reached a peak by 2 h. Increased QL 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)F2 alpha and 6-keto-PGF1 alpha 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.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000032:analysis; D002199:Capillary Permeability / Q000187:drug effects*; D004731:Endotoxins / Q000008:administration & dosage; D006041:Goats; D007093:Imidazoles / Q000008:administration & dosage; D007970:Leukopenia / Q000209:etiology; D008168:Lung / Q000098:blood supply* / Q000503:physiopathology; D008196:Lymph / Q000032:analysis / Q000503:physiopathology; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D013928:Thromboxane A2 / Q000097:blood / Q000502:physiology*; D013931:Thromboxanes / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D001798:Blood Proteins; D004731:Endotoxins; D007093:Imidazoles; D013931:Thromboxanes; C029166:dazoxiben; D013928:Thromboxane A2