Hypoxic pulmonary vasoconstriction (HPV) has been reported to decrease during severe hypoxia in isolated lungs, but it remains unknown whether this decrease occurs in the intact animal and how it is affected by cyclooxygenase inhibition. We investigated the HPV stimulus-response relationship in eight pentobarbital sodium-anesthetized intact dogs with a naturally occurring response to hypoxia ("responders"). The pulmonary arterial minus wedge pressure difference (Ppa-Ppw) was measured at 11 inspired O2 fraction (FIO2) values between 0.40 and 0.04 while ventilation, cardiac output, and acid-base status were kept constant. Ppa-Ppw increased by 8 +/- 1 mmHg between FIO2 of 0.40 and 0.10 (alveolar PO2 of approximately 40 Torr) and decreased by 3 +/- 1 mmHg between FIO2 of 0.10 and 0.04. To assess the effects of cyclooxygenase inhibition, similar stimulus-response curves were obtained after administration of 20 mg/kg of acetylsalicylic acid (ASA) in 16 more dogs selected as either nonresponders or responders to hypoxia. ASA restored HPV in nonresponders and enhanced HPV in responders, with the difference between Ppa-Ppw at FIO2 of 0.10 and 0.40 increasing from 1 +/- 1 to 8 +/- 1 mmHg (P < 0.001) and from 7 +/- 1 to 10 +/- 1 mmHg (P < 0.05), respectively. In both groups, the shape of the stimulus-response curve after ASA was comparable to that of spontaneous HPV, with a maximum at FIO2 of 0.10 and a significant decrease at lower FIO2. We conclude that severe hypoxia attenuates HPV in the intact animal and that ASA restores or enhances HPV by affecting the magnitude of the hypoxic response and not the sensitivity to hypoxia.