NG-monomethyl-L-arginine inhibits the blood flow but not the insulin-like response of forearm muscle to IGF- I: possible role of nitric oxide in muscle protein synthesis.
In 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.
Fryburg
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DA
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA. daf2s@virginia.edu
D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000378:metabolism; D010101:Oxygen Consumption; D010649:Phenylalanine / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D019323:omega-N-Methylarginine
D007773:Lactates; D009124:Muscle Proteins; D009573:Nitrites; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019344:Lactic Acid; D010649:Phenylalanine; D007334:Insulin-Like Growth Factor I; D001120:Arginine; D019001:Nitric Oxide Synthase