The role of nitric oxide (NO) as a regulator of vasomotor tone has been investigated in resting and exercising human skeletal muscle. At rest, NO synthase (NOS) inhibition by intraarterial infusion of N-G-monomethyl-L-arginine decreased femoral artery blood flow (FABF, ultrasound Doppler) from 0.39 +/- 0.08 to 0.18 +/- 0.03 l/min (P < 0.01), i.e., by similar to 52%, and increased leg O-2 extraction from 62.1 +/- 9.8 to 100.9 +/- 4.5 ml/l (P < 0.004); thus leg O-2 uptake ((V) over doto(2), 22 +/- 4 ml/min, similar to 0.75 ml.min(-1).100 g(-1)) was unaltered [not significant (P = NS)]. Mean arterial pressure (MAP) increased by 8 +/- 2 mmHg (P < 0.01). Heart rate (HR, 53 +/- 3 beats/min) was unaltered (P = NS). The NOS inhibition had, however, no effect on the initial rate of rise or the magnitude of FABF (4.8 +/- 0.4 l/min, similar to 163 ml.min(-1).100 g(-1)), MAP (117 +/- 3 mmHg), HR (98 +/- 5 beats/min), or leg (V) over doto(2) (704 +/- 55 ml/min, similar to 24 ml.min(-1).100 g(-1), P = NS) during submaximal, one-legged, dynamic knee-extensor exercise. Similarly, FABF (7.6 +/- 1.0 l/min, similar to 258 ml.min(-1).100 g(-1)), MAP (140 +/- 8 mmHg), and leg (V) over doto(2) (1,173 +/- 139 ml/min, similar to 40 ml.min(-1).100 g(-1))were unaffected at termination of peak effort (P = NS). Peak HR (137 +/- 3 beats/min) was, however, lowered by 10% (P < 0.01). During recovery, NOS inhibition reduced FABF by similar to 34% (P < 0.04), which was compensated for by an increase in the leg O-2 extraction by similar to 41% (P < 0.04); thus leg (V) over doto(2) was unaltered (P = NS). In conclusion, these findings indicate that NO is not essential for the initiation or maintenance of active hyperemia in human skeletal muscle but support a role for NO during rest, including recovery from exercise. Moreover, changes in blood flow during rest and recovery caused by NOS inhibition are accompanied by reciprocal changes in O-2 extraction, and thus (V) over doto(2) is maintained.