Thromboxane generation after thrombin. Protective effect of thromboxane synthetase inhibition on lung fluid balance.
We examined the role of thromboxane in mediating the alterations in pulmonary hemodynamics and in lung fluid and protein exchange after thrombin. Studies were made in control sheep and in sheep pretreated with the thromboxane synthetase inhibitor, Dazoxiben (injection of 10 mg/kg followed by infusion of 4 mg/kg per hr). Thrombin infusion caused an increase in mixed venous and aortic concentrations of thromboxane B2, a stable degradation product of thromboxane A2, whereas the concentrations of 6-keto-PGF1 alpha, a degradation product of prostacyclin, did not change significantly. In sheep pretreated with Dazoxiben, thromboxane B2 concentrations did not increase, indicating effectiveness of the thromboxane synthetase inhibitor. The blood concentrations of 6-keto-PGF1 alpha after thrombin increased in the thromboxane synthetase-inhibited group, indicating shunting towards prostacyclin synthesis. Thrombin in untreated sheep increased pulmonary lymph flow (Qlym) and the lymph protein clearance (Qlym X lymph-to-plasma protein concentration ratio). The increases in lymph parameters were due to an increase in pulmonary vascular permeability to proteins because raising left atrial pressure further increased Qlym but did not change lymph-to-plasma ratio. Dazoxiben prevented the thrombin-induced increase in pulmonary vascular permeability because the increase in left atrial pressure resulted in an increase in Qlym and a decrease in lymph-to-plasma ratio, as was the case after left atrial hypertension in normal animals. Therefore, thrombin results in selective release of thromboxane A2 which precedes the increase in pulmonary vascular permeability. Thromboxane A2 may contribute to the increased permeability after thrombin, since inhibition of thromboxane synthesis prevents the permeability change.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D007093:Imidazoles / Q000627:therapeutic use*; D007700:Kinetics; D008196:Lymph / Q000187:drug effects / Q000502:physiology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011652:Pulmonary Circulation / Q000187:drug effects; D011655:Pulmonary Embolism / Q000503:physiopathology* / Q000517:prevention & control; D012756:Sheep; D013917:Thrombin / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects
D007093:Imidazoles; C029166:dazoxiben; D010088:Oxidoreductases; D013917:Thrombin; D013930:Thromboxane-A Synthase