2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid and Pulmonary-Embolism

We investigated the effects of OKY-046 and OKY-1580, thromboxane A2 (TxA2) synthetase inhibitors, on plasma levels of 6-keto PGF1 alpha and TxB2 in anesthetized dogs with experimentally induced air embolism. The percentage increase of tracheal pressure induced by room air infusion was suppressed significantly by premedication with OKY-046. The percentage increase of pulmonary artery blood pressure was suppressed significantly by premedication with OKY-046 compared to that in control group. By room air infusion after the premedication with OKY-046 and OKY-1580, systemic artery blood pressure did not show any significant changes. Plasma 6-keto PGF1 alpha level showed a marked increase by an intravenous infusion of room air, and such an increase became more predominant by the premedication with OKY-046 and OKY-1580. On the other hand, plasma TxB2 level showed a marked increase by an intravenous infusion of room air, and such an increase became less predominant by the premedication with OKY-046 and OKY-1580. These results may suggest that OKY-046 and OKY-1580 are not only TxA2 synthetase inhibitors but also PGI2 synthetase accelerators and are useful drugs for treatment and prevention of thromboembolism.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Anesthesia; Animals; Blood Pressure; Dogs; Embolism, Air; Methacrylates; Pulmonary Artery; Pulmonary Embolism; Thromboxane B2; Thromboxane-A Synthase

To evaluate the potential beneficial effect of a thromboxane synthetase inhibitor, OKY-1581, on increased pulmonary vascular permeability in pulmonary microembolization, we have measured the filtration coefficient in the nonembolized lung after unilateral microembolization in dogs. The unilateral microembolization caused marked elevations in pulmonary artery pressure and blood flow to the nonembolized lung, while pulmonary venous pressure in nonembolized lung did not change. The pulmonary vascular resistance in nonembolized lung did not increase significantly. The filtration coefficient (Kf) in nonembolized lung increased to 0.14 +/- 0.02 from the baseline value of 0.07 +/- 0.01 ml/min/mmHg/100g at 30 min after microembolization when the initial hemodynamic changes reduced toward the baseline value. In OKY-1581 treated dogs, similar hemodynamic changes did not result in the increase in the filtration coefficient in nonembolized lung. Platelet aggregation was also inhibited after microembolization in OKY-1581 treated dogs. Based on these results, we could conclude that OKY-1581 could prevent the increase in pulmonary vascular permeability following pulmonary microembolization by inhibiting platelet aggregation and possibly by preventing the release of thromboxane A2.

Topics: Acrylates; Animals; Blood Cell Count; Capillary Permeability; Dogs; Female; Hemodynamics; Lung; Male; Methacrylates; Oxidoreductases; Pulmonary Circulation; Pulmonary Embolism; Thromboxane-A Synthase; Time Factors

To evaluate the potential beneficial effect of a thromboxane synthetase inhibitor, OKY-1581, on increased pulmonary vascular permeability in pulmonary microembolization, we have measured the filtration coefficient in the nonembolized lung after unilateral microembolization in dogs. The unilateral microembolization caused marked elevations in pulmonary artery pressure and blood flow to the nonembolized lung, while pulmonary venous pressure in nonembolized lung did not change. The pulmonary vascular resistance in nonembolized lung did not increase significantly. The filtration coefficient (kf) in nonembolized lung increased to 0.14 +/- 0.02 from te base line value of 0.07 +/- 0.01 ml/min/mmHg/100 g at 30 min after microembolization when the initial hemodynamic changes reduced toward the base line value. In OKY-1581 treated dogs, similar hemodynamic changes did not result in the filtration coefficient in nonembolized lung. Platelet aggregagation was also inhibited after microembolization in OKY-1581 treated dogs. Based on these results, we could conclude that OKY-1581 will serve as a potent beneficial protective drug against pulmonary edema by inhibiting the release of thromboxane A2 following microembolization in the pulmonary vascular bed.

Topics: Acrylates; Animals; Capillary Permeability; Dogs; Female; Hemodynamics; Lung; Male; Methacrylates; Platelet Aggregation; Pulmonary Edema; Pulmonary Embolism; Thromboxane-A Synthase