Cerebral blood flow is highly sensitive to alterations in the partial pressures of O(2) and CO(2) (P(O(2)) and P(CO(2)), respectively) in the arterial blood. In humans, the extent to which nitric oxide (NO) is involved in this regulation is unclear. We hypothesized that the NO synthase (NOS) inhibitor N(G)-monomethyl-l-arginine (l-NMMA), attenuates the sensitivity of middle cerebral artery blood velocity (V(p)) to isocapnic hypoxia (end-tidal P(O(2)) = 50 Torr) and euoxic hypercapnia (end-tidal P(CO(2)) = +9 Torr above resting values) in 10 volunteers (age, 28.7 +/- 1.3 years; height, 179.2 +/- 2.4 cm; weight, 78.0 +/- 3.7 kg; mean +/- s.e.m.). The techniques of transcranial Doppler ultrasound and dynamic end-tidal forcing were used to measure(V(p)), and control end-tidal P(O(2)) and end-tidal P(CO(2)), respectively. At baseline (isocapnic euoxia), following intravenous administration of l-NMMA, mean arterial blood pressure (MAP) increased (76.3 +/- 7.3 to 86.2 +/- 9.4 mmHg) and heart rate (HR) decreased (59.5 +/- 9.0 to 55.2 +/- 9.5 beats min(-1)) but (V(p)) was unchanged. Hypoxia-induced increases in MAP, HR and were similar with and without l-NMMA (5.0 +/- 0.7 versus 7.1 +/- 1.0 mmHg, 11.5 +/- 1.4 versus 12.4 +/- 1.5 beats min(-1), 6.5 +/- 0.8 versus 6.6 +/- 0.8 cm s(-1) for DeltaMAP, DeltaHR and Delta , respectively). Hypercapnia-induced increases in MAP, HR and (V(p)) were similar with and without l-NMMA (7.4 +/- 3.1 versus 8.1 +/- 2.2 mmHg, 10.4 +/- 4.6 versus 10.0 +/- 4.2 beats min(-1), 16.5 +/- 1.5 versus 17.6 +/- 1.5 cm s(-1) for DeltaMAP, DeltaHR and Delta(V(p)) , respectively) but the sensitivity of the(V(p)) response at the removal of hypercapnia was attenuated with l-NMMA. In young healthy humans, pharmacological blockade of nitric oxide synthesis does not affect the increases in cerebral blood flow with hypoxia and hypercapnia, suggesting that nitric oxide is not required for the cerbrovascular responses to hypoxia and hypercapnia.