The neuronal isoform of nitric oxide synthase (nNOS) is highly expressed in mammalian skeletal muscle, but its functional role has not been defined. NO has been implicated in the local metabolic regulation of blood f low in contracting skeletal muscle in part by antagonizing sympathetic vasoconstriction. We therefore hypothesized that nNOS in skeletal muscle is the source of the NO mediating the inhibition of sympathetic vasoconstriction in contracting muscle. In the mdx mouse, a model of Duchenne muscular dystrophy in which dystrophin deficiency results in greatly reduced expression of nNOS in skeletal muscle, we found that the normal ability of skeletal muscle contraction to attenuate ␣-adrenergic vasoconstriction is defective. Similar results were obtained in mutant mice that lack the gene encoding nNOS. Together these data suggest a specific role for nNOS in the local metabolic inhibition of ␣-adrenergic vasoconstriction in active skeletal muscle.To sustain physical activity, increases in skeletal muscle blood flow must closely match oxygen and substrate delivery to the increased metabolic rate of the contracting muscles. Although contracting skeletal muscle produces a number of vasodilator metabolites, the precise contributions of the various metabolites in mediating exercise-induced increases in muscle blood flow have been difficult to define.One of the ways in which metabolites produced in contracting skeletal muscle may contribute to blood flow regulation during exercise is by opposing adrenergic vasoconstriction. An emerging body of evidence indicates that in mammalian skeletal muscle ␣-adrenergic vasoconstriction is very sensitive to inhibition by local metabolic products of skeletal muscle contraction (1-4). Although such metabolic modulation negates an otherwise deleterious effect of adrenergic vasoconstriction on muscle perfusion, little is known about the specific metabolites involved. NO may be one such metabolite, as suggested by increasing evidence demonstrating NO-mediated antagonism of ␣-adrenergic vasoconstriction both in isolated blood vessels and in intact vascular beds (5-10). Further support for the concept that NO is involved in the local metabolic modulation of adrenergic vasoconstriction is provided by a recent study in rats demonstrating that inhibition of NO synthase (NOS) enhances sympathetic vasoconstriction in the contracting hindlimb (11).Until recently, the source of NO involved in muscle blood flow regulation during exercise was assumed to be the vascular endothelium, in which the endothelial isoform of NOS (eNOS) is abundantly expressed (12). In contracting muscle, the increased shear stress caused by elevated blood flow would seem to be an ideal stimulus to activate eNOS and increase endothelial NO production (13). However, the recent identification of the neuronal isoform of NOS (nNOS) in skeletal muscle provides another potential source of NO (14,15). Conceivably, NO produced by nNOS in the skeletal muscle fibers could diffuse to nearby arterioles, resulting in vaso...

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