Selective inhibition of thromboxane synthesis during experimental endotoxemia in the goat: effects on pulmonary haemodynamics and lung lymph flow.
1 The effects of a selective thromboxane synthetase inhibitor, dazoxiben (UK 37248), on haemodynamics, eicosanoid levels, and lung vascular permeability were assessed in three unanesthetized goats with chronic lung lymph fistulae following infusions of E. coli endotoxin (1 microgram/kg). Each animal received an infusion of endotoxin in both a control and treatment trial. In the control trial endotoxin alone was infused. In the treatment trial endotoxin administration was preceded by a bolus intravenous infusion of dazoxiben 25 mg/kg followed by a maintenance infusion of 10 mg/kg/h. 2 In animals receiving endotoxin alone the peak elevation in pulmonary artery and wedge pressures, the initial increase in lymph flow, and the fall in cardiac output correlated with the peak elevation in plasma thromboxane B2 (TXB2) concentration at 30 min after endotoxin. Although TXB2 levels had returned to baseline by 3 h, lung lymph flow remained elevated for at least 6 h after endotoxin. The lymph/plasma protein ratio (L/P) did not fall. 3 In dazoxiben-treated animals the rise in plasma concentrations of TXB2 after endotoxin was prevented and, in concert, the increase in pulmonary artery and wedge pressures, the fall in cardiac output, and the initial increase in lymph flow were greatly attenuated. The increase in lymph flow at 2-6 h after endotoxin, however, was not prevented in dazoxiben-treated animals, and again L/P did not change. 4 Plasma 6-keto-prostaglandin F1 alpha concentrations were not significantly altered by dazoxiben treatment except for an earlier peak. 5 We conclude that selective total inhibition of thromboxane synthesis can be achieved by dazoxiben. The inhibition ameliorates many of the adverse haemodynamic consequences of experimental endotoxaemia and reduces, but does not prevent pulmonary oedema formation. This seems to be due to an increase in lung microvascular permeability which is not mediated by TXA2.
D000818:Animals; D004731:Endotoxins / Q000506:poisoning*; D004926:Escherichia coli; D006041:Goats; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects; D008208:Lymphatic System / Q000187:drug effects*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011652:Pulmonary Circulation / Q000187:drug effects*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors
D004731:Endotoxins; D007093:Imidazoles; C029166:dazoxiben; D013929:Thromboxane B2; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase