This study aimed to study the role of thromboxane A2 (TXA 2) and endothelin-1 (ET-1) in the pulmonary hypertension induced by interaction of heparin-protamine in anesthetized dogs. The effect of inhaled nitric oxide (NO) was also investigated in this model. Dogs were anesthetized and instrumented for acquisition of mean arterial blood pressure, mean arterial pulmonary pressure (MPAP), and pulmonary pressure gradient (PPG). Cardiac index (CI), heart rate, and index of systemic vascular resistance were also obtained. Intravenous administration of heparin (500 IU/kg) 3 minutes before protamine (10 mg/kg) caused marked pulmonary hypertension, as evaluated by the increase in MPAP and PPG. This was accompanied by systemic hypotension, CI decrease, and tachycardia. Indomethacin (10 mg/kg), dazoxiben (10 mg/kg), or tezosentan (10-mg/kg bolus plus 10-mg/kg/h infusion) significantly reduced the increase in MPAP and PPG, but had no effect on the systemic hypotension. 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