Regulation of cerebral blood flow during physiological activation including exercise remains unknown but may be related to the arterial lactate-to-pyruvate (L/P) ratio. We evaluated whether an exercise-induced increase in middle cerebral artery mean velocity (MCA Vmean) relates to the arterial L/P ratio at two plasma lactate levels. MCA Vmean was determined by ultrasound Doppler sonography at rest, during 10 min of rhythmic handgrip exercise at approximately 65% of maximal voluntary contraction force, and during 20 min of recovery in seven healthy male volunteers during control and a approximately 15 mmol/l hyperglycemic clamp. Cerebral arteriovenous differences for metabolites were obtained by brachial artery and retrograde jugular venous catheterization. Control resting arterial lactate was 0.78 +/- 0.09 mmol/l (mean +/- SE) and pyruvate 55.7 +/- 12.0 micromol/l (L/P ratio 16.4 +/- 1.0) with a corresponding MCA Vmean of 46.7 +/- 4.5 cm/s. During rhythmic handgrip the increase in MCA Vmean to 51.2 +/- 4.6 cm/s was related to the increased L/P ratio (23.8 +/- 2.5; r2 = 0.79; P < 0.01). Hyperglycemia increased arterial lactate and pyruvate to 1.9 +/- 0.2 mmol/l and 115 +/- 4 micromol/l, respectively, but it did not significantly influence the L/P ratio or MCA Vmean at rest or during exercise. Conversely, MCA Vmean did not correlate significantly, neither to the arterial lactate nor to the pyruvate concentrations. These results support that the arterial plasma L/P ratio modulates cerebral blood flow during cerebral activation independently from the plasma glucose concentration.