Indomethacin, a cyclo-oxygenase inhibitor, stimulates virtually continuous breathing movements in the fetal sheep. We measured blood flow (radioactive microsphere distribution) to major brain regions and analyzed arterial and sagittal vein blood samples for oxygen and carbon dioxide tensions, pH and for oxygen contents and glucose concentrations in 13 fetal lambs between 122-132 days of gestation. The measurements were done before and again after 4 to 5 h of an indomethacin infusion. We found that indomethacin caused a mild arterial acidosis and hypoxemia and a 23 +/- 6% (SEM, P less than 0.01) decrease in blood flow to the cerebral hemispheres. Similar decreases were also observed in all other brain regions except for the cerebellum. Arteriovenous concentration differences for both oxygen and glucose widened such that there was no significant change in cerebral metabolism. Sagittal vein hydrogen ion concentration was 44.3 +/- 0.06 nmoles 1(-1) during control and rose by 4.5 +/- 1.4 nmol.1(-1) (P less than 0.01) with the indomethacin. These results are consistent with the hypothesis that one mechanism by which indomethacin augments the incidence of fetal respiratory efforts is by stimulating central chemoreceptors.