Prostaglandins have been implicated as possible modulators of normoxic and hypoxic pulmonary tone partly because of studies using cyclooxygenase inhibitors, but these drugs may exert effects that are independent of prostaglandin cyclooxygenase. We evaluated the hemodynamic effects of the acute intravenous administration of 3 cyclooxygenase inhibitor drugs in doses that inhibit prostaglandin synthesis in intact anesthetized dogs: indomethacin 5 mg/kg, meclofenamate 5 mg/kg, and ibuprofen 12.5 mg/kg. During room air ventilation, the administration of indomethacin produced an increase in mean pulmonary arterial pressure (8.0 +/- 1.27 to 13.1 +/- 1.52 mmHg, p less than 0.01) and pulmonary vascular resistance (1.2 +/- 0.23 to 2.7 +/- 0.39, p less than 0.01), whereas meclofenamate and ibuprofen had no effect. Indomethacin given during hypoxic ventilation slightly but insignificantly increased pulmonary artery pressure and pulmonary vascular resistance when compared with hypoxia alone and with the administration of vehicle or meclofenamate. Treatment with indomethacin methacin or meclofenamate 5 mg/kg given subcutaneously twice daily for 2 days had no effect on normoxic or hypoxic pulmonary tone. The combined cyclooxygenase-lipoxygenase inhibitor BW 755C in doses of 25 mg/kg given intravenously did not inhibit hypoxic pulmonary vasoconstriction. We conclude that prostaglandins do not appear to play a major physiologic role in modulating normoxic or hypoxic pulmonary vasomotor tone in intact anesthetized dogs, and that the indomethacin-induced increases in pressure and resistance are independent of inhibition of prostaglandin cyclooxygenase.