Previous studies have demonstrated a significant pressure gradient from carotid artery to pial or middle cerebral arteries. This pressure gradient suggests that large cerebral arteries contribute to cerebral resistance. We have tested the hypothesis that large cerebral arteries contribute to regulation of cerebral blood flow during changes in blood gases and arterial pressure. Microspheres were used to measure brain blood flow in anesthetized dogs. Resistance of large cerebral arteries was estimated by determining the pressure gradient between common carotid and wedged vertebral artery catheters. Systemic hypercapnia and hypoxia dilated large cerebral arteries, and hypocapnia constricted large cerebral arteries. Resistance of large arteries was 0.6+/-0.1 (mean +/- SE) mm Hg per ml/min per 100 g during normocapnia. During hypercapnia and hypoxia, large artery resistance decreased significantly to 0.2 +/- 0.03 and 0.3 +/- 0.05, respectively. During hypocapnia large artery resistance increased significantly to 1.0 +/- 0.1. In other experiments, we found that large cerebral arteries participate in auto-regulatory responses to hemorrhagic hypotension. When arterial pressure was reduced from 110 to 58 mm Hg, autoregulation maintained cerebral blood flow constant, and resistance of large cerebral arteries decreased significantly from 1.0 +/- 0.2 to 0.6 +/- 0.1 mm Hg per ml/min per 100 g. In absolute terms, we calculated that 20-45% of the change in total cerebral resistance during these interventions was accounted for by changes in large artery resistance. These studies indicate that large cerebral arteries, as well as arterioles, participate actively in regulation of cerebral blood flow during changes in arterial blood gases and during autoregulatory responses to hemorrhagic hypotension.