Chronic renal failure may be accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys.

SUMMARY. The purpose of this study was to determine the contribution of muscle afferents and central command in regulating sympathetic nerve activity during static exercise in humans. In 20 healthy subjects, we recorded heart rate, arterial pressure, and efferent sympathetic nerve activity in the leg during arm exercise. Microelectrodes were inserted percutaneously into a fascicle of the peroneal nerve to measure sympathetic discharge to muscle. Measurements were obtained in nine subjects during sustained handgrip (30% maximal voluntary contraction) followed by relaxation or by arrested circulation of the forearm. Heart rate and arterial pressure increased during the first and second minutes of handgrip. Muscle sympathetic nerve activity increased from 261 ± 46 to 504 ± 97 units (mean ± SE; units = burst frequency x amplitude; P < 0.05) during the second minute of handgrip. During forearm ischemia following handgrip, heart rate returned promptly to control, whereas arterial pressure and muscle sympathetic nerve activity (631 ±115 units) remained elevated. In contrast, muscle sympathetic nerve activity returned toward control during relaxation without arrested circulation. These data indicate that muscle sympathetic nerve activity is increased by stimulation of chemically sensitive muscle afferents. To determine the influence of central command on muscle sympathetic nerve activity, we compared responses during ar. involuntary and a voluntary biceps contraction, each at 20% maximal voluntary contraction. Both maneuvers raised arterial pressure, but heart rate increased only during voluntary contraction. More importantly, muscle sympathetic nerve activity rose during involuntary contraction, but fell during voluntary effort. These studies demonstrate that during sustained handgrip in humans, stimulation of chemically sensitive muscle afferents increases muscle sympathetic nerve activity in the leg, and central command causes tachycardia, but inhibits muscle sympathetic outflow in the leg. (Circ Res 57: 461-469, 1985)

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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...