Hypoxemia interferes with hypoxic pulmonary vasoconstriction (HPV). We investigated the respective roles of the autonomic nervous system and the mixed venous PO2 (PVO2) in the attenuation of HPV by hypoxemia. Pentobarbital-anesthetized dogs had their lungs separately ventilated with a dual-lumen endotracheal tube. Left (Ql) and total (Qt) pulmonary blood flows were determined using electromagnetic flow probes. HPV was initiated by ventilating the left lung with nitrogen for 5-10 min while the right lung received 100% oxygen. The animals were subsequently made hypoxemic by switching the right lung to room air ventilation (5-10 min). Two different protocol groups received either intravenous atropine during hypoxemia (group I) or intravenous propranolol prior to protocol initiation (group II). A third group of dogs (group III) had their mixed venous PO2S maintained above 30 torr during hypoxemia. In response to left lung hypoxia, Ql/Qt decreased from 44 +/- 5, 48 +/- 3 and 46 +/- 2% to 25 +/- 4, 28 +/- 2 and 26 +/- 3% in the three groups, respectively. During hypoxemia Ql/Qt increased to 50 +/- 7 and 47 +/- 3% in groups I and II. In group III dogs, Ql/Qt remained significantly decreased at 31 +/- 3%. Subsequent administration of atropine in group I had no effect on Ql/Qt. We conclude that the loss of flow diversion from a hypoxic lung during hypoxemia may be mediated primarily by a decreased in mixed venous PO2 when PVO2 is allowed to decrease to 15-20 torr.