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Contraction-induced modulation of sympathetic vasoconstriction in human skeletal muscle, with special reference to alpha-adrenoreceptor subtypes, nitric oxide, adenosine and ATP.

Jaya Birgitte Rosenmeier 

Summary

Many of the cardiovascular adaptations to dynamic exercise are caused by an activation of the sympathetic nervous system. Increases in efferent sympathetic nervous activity affects heart rate and thereby cardiac output as well as vascular resistance and thus arterial pressure. These hemodynamic responses have been attributed both to sympathetic reflexes arising within the exercising muscle mediated primarily by chemically and mechanically sensitive muscle afferents, termed the metabo or mechano reflex and neural impulses arising within the central nervous system, associated with the voluntary component of exercise, termed central command. Evidence suggests that activation of the muscle metaboreflex triggers a parallel increase in sympathetic nervous activity targeted not only to resting, but also to the active skeletal muscle. The function of such sympathetic activation in skeletal muscle represents a major unsolved problem in cardiovascular physiology. While vasoconstriction in exercising muscles would counteract metabolic vasodilation and presumably help maintain systemic blood pressure, it would also decrease muscle perfusion and lead to detrimental effects on muscle metabolism and performance. Studies in rodents, dogs and humans have however demonstrated that α - adrenoreceptor mediated vasoconstriction can be attenuated in contracting muscle, a concept termed "functional sympatholysis".
Studies in a variety of animals have shown greater sensitivity of α2 compared with α1 -adrenoreceptor mediated vasoconstriction to metabolic modulation. This may be caused by the spatial distribution of these adrenoreceptor subtypes within the microvasculature. During exercise α2 -adrenoreceptors located in nutritive arterioles cause vasodilation, whereas α1 -adrenoreceptors located in the resistance arterioles preserves blood pressure via vasoconstriction. Although the distribution of α-adrenoreceptors is unknown in humans, this thesis has provided evidence that, unlike animal studies, both types of α- adrenergic adrenoreceptors were equally attenuated during exercise. This could potentially mean that blood pressure regulation during exercise might be different in humans. If both α-adrenoreceptors are equally blunted during muscle contraction, it challenges the idea that sympathetic nerves limit active muscle hyperemia.
Many metabolites have been implicated in this attenuation of α-adrenergic vasoconstriction among which adenosine and nitric oxide have been thoroughly studied. They both play a role in the regulation of basal vascular tone and they have also been reported to be capable of attenuating α-adrenergic vasoconstriction in other species. While the contribution of NO and adenosine in exercise hyperemia is still under debate, the contribution of adenosine and NO in functional sympatholysis in humans is also questioned in this thesis. Using the isolated forearm model in humans together with the infusion of adenosine or a NO donor (sodium nitroproside) in combination with the sympatho-excitatory drug tyramine, it was not found that NO and adenosine administration was capable of blunting the tyramine-induced α-adrenergic vasoconstriction. This is in contrast to the positive sympatho-inhibitory effects observed in previous in vivo studies in various animals.
Adding to the complexity of muscle circulatory control, recent evidence in exercising humans has demonstrated that increases in plasma ATP, a known potent vasodilator, is tightly correlated to reductions in the oxygenation state of hemoglobin (Hb). This suggests that the red blood cells acts as an O2 sensor releasing ATP when metabolic demand increases. At the same time, contraction induced hypoxia has been implicated as a primary metabolic event leading to functional sympatholysis.
Therefore the contribution of ATP in functional sympatholysis was explored, using the same isolated limb approach as described above. Novel evidence was provided demonstrating that circulating ATP can override the sympathetically mediated vasoconstriction at rest in a similar manner as exercise, thus suggesting that this compound is sufficient to cause metabolic inhibition of α-adrenergic vasoconstriction in the absence of muscle contraction.
Based on these data one could speculate that the RBC, by virtue of its ability to release ATP, overrides the sympathetic vasoconstriction locally in contracting skeletal muscles under conditions where a high local perfusion is in demand. Indeed the red blood cell may serve as an active O2 sensor and as an ultimate controller of perfusion to meet the increased metabolic need seen during exercise or at rest during hypoxia.