The effects of increased intracranial pressure (ICP) and increased cardiac output (&OV0422;T) on the pulmonary vascular response to regional alveolar hypoxia were compared in pentobarbital-anesthetized, closed-chested dogs. A bronchial divider was inserted, the right lung (RL) was continuously ventilated with 100% O2, and the left lung (LL) was ventilated with either 100% O2(hyperoxia) or a hypoxic gas mixture (hypoxia). Sulfur hexafluoride (SF6) was used to measure differential lung blood flow and the multiple inert gas technique assessed gas exchange. The response to LL alveolar hypoxia (hypoxic pulmonary vasoconstriction, HPV) was studied in each animal prior to, during, and after the ICP was increased by infusing mock cerebrospinal fluid (CSF) into a lateral ventricle so that cerebral perfusion pressure was 25 mmHg. During both control periods, &OV0422;Twas randomly altered by opening (high &OV0422;T) or closing (normal &OV0422;T) two arteriovenous fistulas. Increasing ICP significantly increased &OV0422;T(P< 0.01), pulmonary artery pressure (PAP) (P< 0.05), and mixed venous oxygen tension (Pvo2) (P< 0.05), compared with normal &OV0422;Tcontrols. Opening the arteriovenous fistulas achieved similar increases in &OV0422;T(P< 0.01), PAP (P< 0.05), and P, (P< 0.05). The percentage of blood flow to the LL(&OV0422;L/&OV0422;T%) during hyperoxia was 43.9 ± 0.8% (mean ± SE) and did not vary with manipulation of &OV0422;Tor ICP. &OV0422;L/&OV0422;T% during LL hypoxia was significantly increased by both increased ICP (24.6 ± 3.5%) and high &OV0422;T(23.1 ± 1.0%) compared with normal &OV0422;T(16.8 ± 2.1) controls (P< 0.05). Therefore, flow diversion with HPV was reduced equally by both increasing ICP and increasing &OV0422;T(P< 0.05). Ventilation-perfusion matching was unchanged by increased ICP. These results suggest that impaired oxygenation with increased ICP may be partly secondary to an attenuation of regional HPV, caused by increased cardiac output.