I n human skeletal muscle, insulin-like growth factor-I (IGF-I) exerts both growth hormone-like (increase in protein synthesis) and insulin-like (decrease in protein degradation and increase in glucose uptake) actions and augments forearm blood flow two- to threefold. This study was designed to address whether (a) the increase in blood flow due to IGF-I could be blocked by an inhibitor of nitric oxide synthase; and (b) the metabolic actions of IGF-I were altered by use of a nitric oxide synthase inhibitor. Forearm blood flow, glucose, lactate, oxygen, nitrite, and phenylalanine balances and phenylalanine kinetics were studied in a total of 17 healthy, adult volunteers after an overnight fast in two different protocols. In protocol 1, after basal samples IGF-I was infused alone for 4 h with samples repeated during the last 30 min. After the 4-h sample period, NG-monomethyl-L-arginine (L-NMMA) was infused into the brachial artery for 2 h to bring flow back to baseline and repeat samples were taken (6 h). In response to IGF-I alone, forearm blood flow rose from 3.8 +/- 1.0 (bas) to 7.9 +/- l.9 (4 h) ml/min/100 ml (P < 0.01) and was reduced back to baseline by L-NMMA at 6 h (P < 0.01). In protocol 1, IGF-I alone increased forearm nitrite release at 4 h (P < 0.03), which was reduced back to baseline by L-NMMA at 6 h (P < 0.05). Despite the reduction in flow with L-NMMA, IGF+L-NMMA yielded increases in glucose uptake (P < 0.005), lactate release (P < 0.04), oxygen uptake (P < 0.01), and a positive shift in phenylalanine balance (P < 0.01) due to both an increase in muscle protein synthesis (P < 0.02) and a decrease in protein degradation (P < 0.03). In protocol 2, L-NMMA was coinfused with IGF-I for 6 h, with the dose titrated to keep blood flow +/- 25% of baseline. Coinfusion of L-NMMA restrained blood flow to baseline and also yielded the same, significant metabolic effects, except that no significant increase in muscle protein synthesis was detected. These observations suggest: (a) that IGF-I increases blood flow through a nitric oxide-dependent mechanism; (b) that total blood flow does not affect the insulin-like response of muscle to IGF-I; and (c) that nitric oxide may be required for the protein synthetic (growth hormone-like) response of muscle to IGF-I.