Attenuated sympathetic vasoconstriction in contracting muscles: just say NO

Precise matching of blood flow and metabolism is required for all living tissues. This is especially important for skeletal muscle where metabolism can change dramatically during periods of repeated contractions. It may not be widely appreciated that blood flow to skeletal muscle subserves two important, but potentially conflicting functions: oxygen delivery and blood pressure regulation (see Fig. 1). Vasodilatation to enhance blood flow and oxygen delivery appears to be a local phenomenon although the specific mechanism underlying exercise hyperaemia has been an unyielding enigma despite intense research efforts spanning the last century. On the other hand, there is accumulating evidence that sympathetic vasoconstriction in active skeletal muscle contributes to the maintenance of systemic blood pressure during dynamic exercise. Experiments in both animals and humans demonstrate that there is an increase in sympathetic efferent nerve activity directed toward exercising muscle. Moreover, administration of adrenergic antagonists has revealed that both α1 and α2 adrenergic receptors restrain blood flow to exercising skeletal muscles, even at high intensities of exercise (Buckwalter & Clifford, 1999). Blood flow in exercising skeletal muscle is ultimately a balance between metabolic vasodilatation and sympathetic vasoconstriction. Figure 1 Competing influences on skeletal muscle blood flow One factor which affects the magnitude of sympathetic vasoconstriction in muscle is a decreased sensitivity to sympathetic stimulation or adrenergic agonists in contracting muscles. This phenomenon, first termed ‘functional sympatholysis’ by Remensnyder et al. 1962, is responsible for enhanced blood flow to exercising skeletal muscle in the face of widespread sympathetic vasoconstriction. Over the last decade, data from three different laboratories have provided convincing demonstrations of exercise-induced attenuation of sympathetic vasoconstriction and advanced the hypothesis that postjunctional α1 and α2 adrenergic receptors exhibit a differential sensitivity to attenuation (Anderson & Faber, 1991; Thomas et al. 1994, Buckwalter et al. 2001). During muscle contractions or exercise, there is a blunted vasoconstrictor response to stimulation of α1 and α2 adrenergic receptors, with the response to stimulation of α2 receptors being blunted to greater extent than α1-mediated vasoconstriction. Faber's group also provided the important observation that there is substantial heterogeneity in the distribution of α1 and α2 adrenoreceptors in the microvasculature of skeletal muscle with both subtypes present on large arterioles and only α2 receptors on terminal arterioles. The functional importance of a differential distribution and sensitivity of α-adrenergic receptors may be to provide a selective means of directing blood flow to areas of high metabolic activity within active skeletal muscle during exercise. The steps in the neuroeffector pathway which are responsible for functional sympatholysis have not been fully elucidated. Although presynaptic release of norepinephrine may be diminished by products of muscle contraction, a reduced response to intraarterial administration of selective adrenergic agonists suggests a reduction in postsynaptic receptor responsiveness. There is evidence in support of two mechanisms for the reduction in postsynaptic receptor responsiveness: metabolites or nitric oxide (NO). Skeletal muscle contractions may produce acidosis, regional hypoxia, and localized ischaemia - all factors which have been shown to inhibit adrenergic vasoconstriction. The α2 receptor seems to be exquisitely sensitive to changes in pH. During exercise two potential sources of NO include release from myocytes during contraction or from vascular endothelial cells as a consequence of increased shear stress. In this issue of The Journal of Physiology, Chavoshan et al. (2002) add valuable new data to previous publications from their laboratory which reported less attenuation of sympathetic vasoconstriction after acute inhibition of NO synthase in rats, in NOS deficient muscle of mice, and in patients with Duchenne muscular dystrophy. Studies employing pharmacological inhibitors of NO synthase have an inherent limitation in that systemic administration of such compounds increases blood pressure which produces baroreflex-mediated inhibition of sympathetic outflow. In the present study, the investigators overcame this limitation by directly measuring sympathetic efferent nerve activity to muscle and titrating the dose of lower body negative pressure to produce identical sympathoexcitatory stimuli before and after blocking NO production. Sympathetic vasoconstrictor responses in the microcirculation were inferred from near-infrared spectroscopy. The data support the postulated role of NO as a modulator of sympathetic vasoconstriction in exercising human muscle. This finding adds to the weight of evidence produced by this proficient research team supporting the production of NO as the mechanism for attenuation of sympathetic vasoconstriction in contracting skeletal muscle.