Reactive oxygen species enter the tug-of-war between metabolic vasodilatation and sympathetic vasoconstriction.

Sympathetic nervous system activity increases with exercise and in addition to augmenting cardiac output and ventilation, provides essential control of arteriolar resistance in non-active and visceral organs in an effort to redistribute blood to the working muscles. Net skeletal muscle vasodilatation prevails as a result of exercise; however, evidence also indicates that sympathetically mediated vasoconstriction correspondingly occurs to some extent within the active muscle. Collectively, this sympathetic regulation of peripheral resistance guards against the extreme vasodilator capacity of skeletal muscle invoked by exercise and aids in the prevention of hypotension (Marshall et al. 1961)). While for some time it was debated as to how sympathetic constriction and metabolic vasodilatation may cooperatively interact during exercise, it is now apparent that vasoactive substances associated with muscle contractions blunt α-adrenergic receptor responsiveness to sympathetic stimulation (functional sympatholysis) (Buckwalter & Clifford, 2001)). This regulatory scheme appears optimal in healthy humans as a means of balancing an ideal control of both tissue oxygen delivery and mean arterial blood pressure. However, in various disease states sympathetic overactivity and vasoconstrictor influence may be disproportionate such that hypertension and hypoperfusion ensues (Thomas et al. 2001)). Therefore, elucidation of the specific means by which functional sympatholysis occurs in healthy humans and is impaired with disease is of utmost importance. Although the underlying cause for how sympathetic neural vasoconstriction is lessened during exercise may yet to be fully apparent, the investigation by Fadel and colleagues published in a recent issue of The Journal of Physiology (Fadel et al. 2012)) presents a strong case that oxidative stress within skeletal muscle may be a means by which functional sympatholysis can be impaired. Thus, these data lend further insight into the underlying mechanisms whereby modulation of sympathetic vasoconstriction may be at detriment in diseased populations exhibiting elevated skeletal muscle reactive oxygen species. In a highly innovative and well-crafted translational approach, the authors chose to stimulate an enhanced production of skeletal muscle superoxide (O2−) in healthy rats and humans by means of chronic nitroglycerin treatment. Noticeably, nitroglycerin pretreatment facilitated a greater production of reactive oxygen species, which in turn was associated with an impaired ability to blunt sympathetically mediated vasoconstriction. Although not determined in humans, acute reversal of both oxidative stress and the consequent augmentation in constriction was observed in the rat hindlimb infused with tempol (O2− scavenger), confirming the likely contribution of reactive oxygen species to the marked impairment in functional sympatholysis. Though suggestion of oxidative stress in the augmentation of sympathetic vasoconstriction in contracting skeletal muscle has previously been put forth in animals by this group (Thomas et al. 2001)), these findings begin a new chapter on this topic in humans in vivo. Several findings deserve further comment. Interestingly, in the nitroglycerin pretreatment group, exercise hyperaemia without superimposed sympathetic stimulation was not attenuated nor was there an augmented sympathetic vasoconstriction at rest. This makes the point that simply a loss of ‘vasodilatory bioavailability’per se does not enhance vasoconstrictor responsiveness, but rather a specific loss of sympatholytic function during exercise resulted from an increase of O2−. Additionally, it is particularly thought-provoking to consider these general observations with regard to the normal production of reactive oxygen species produced by contracting muscles, as oxidative stress is well understood to occur during acute exercise. In this respect, one is forced to ponder, ‘How much reactive oxygen species production is too much?’. Accordingly, tempol appeared to decrease the authors’ index of O2− (ethidium fluorescence) production during contractions in the non-nitroglycerin treatment group, yet no greater modulation of vasoconstrictor responsiveness was observed. These data indicate that: (a) reactive oxygen species are certainly not a requisite for the phenomenon of functional sympatholysis, and moreover, (b) that the level of reactive oxygen species produced by this muscle contraction intensity is not sufficient enough to interfere with the signalling pathways that attenuate sympathetic vasoconstriction. Together, this suggests a potential oxidative stress ‘threshold’ in relation to impaired functional sympatholysis. Nevertheless, these observations ring true to the theme that unregulated oxidative stress may aid in limited cardiovascular control of blood flow and blood pressure in various pathophysiological states. These collective observations highlight for the first time in humans the direct impact of elevated oxidative stress on functional sympatholysis. Importantly, these data build upon previous demonstrations of impaired endothelium-dependent vasodilatation and exercise hyperaemia in populations who present with elevated reactive oxygen species production (Kirby et al. 2009)). Therefore, it may seem as though these populations undergo a double hit comprised of diminished vasodilatory function and loss of sympatholytic capability which may jointly aid in limiting exercise tolerance via hypoperfusion and promotion of undue hypertension, thus increasing cardiac strain by increasing afterload on the heart. In an effort to mitigate such outcomes, future strides need to be initiated to further identify the specific signalling underlying functional sympatholysis on the whole, and how best to augment sympatholytic vasodilating factors such that vasodilatation is not excessively restrained in these specific disease states. Whether the latter are via exercise training, pharmacological intervention or some other means, we anxiously await how this ‘tug-of-war’ unfolds.