Pulmonary vascular response to thrombin: effects of thromboxane synthetase inhibition with OKY-046 and OKY-1581.
We examined the effects of thromboxane synthetase inhibition with OKY-1581 and OKY-046 on pulmonary hemodynamics and lung fluid balance after thrombin-induced intravascular coagulation. Studies were made in anesthetized sheep prepared with lung lymph fistulas. Pulmonary intravascular coagulation was induced by i.v. infusion of alpha-thrombin over a 15 min period. Thrombin infusion in control sheep resulted in immediate increases in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), which were associated with rapid 3-fold increase in pulmonary lymph flow (Qlym) and a delayed increase in lymph-to-plasma protein concentration (L/P) ratio, indicating an increase in the pulmonary microvascular permeability to proteins. Thrombin-induced intravascular coagulation also increased arterial thromboxane B2 (a metabolite of thromboxane A2) and 6-keto-PGF1 alpha concentrations (a metabolite of prostacyclin). Both OKY-1581 and OKY-046 prevented thromboxane B2 and 6-keto-PGF1 alpha generation. The initial increments in Ppa and PVR were attenuated in both treated groups. The increases in Qlym were gradual in the treated groups but attained the same levels as in control group. However, the increases in Qlym were associated with decreases in L/P ratio. In both treated groups, the leukocyte count decreased after thrombin infusion but then increased steadily above the baseline value, whereas the leukocyte count remained depressed in the control group after thrombin. These studies indicate that a part of the initial pulmonary vasoconstrictor response to thrombin-induced intravascular coagulation is mediated by thromboxane generation. In addition, thromboxane may also contribute to the increase in lung vascular permeability to proteins that occurs after intravascular coagulation and this effect may be mediated by a thromboxane-neutrophil interaction.
D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced; D006801:Humans; D007958:Leukocyte Count; D008689:Methacrylates / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010976:Platelet Count; D011652:Pulmonary Circulation / Q000187:drug effects*; D012756:Sheep; D013917:Thrombin / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects*
D000179:Acrylates; D008689:Methacrylates; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; D010088:Oxidoreductases; D013917:Thrombin; D013930:Thromboxane-A Synthase; C034364:ozagrel