Is nitric oxide mediated sympatholysis improved with exercise? Yes or nNO?

Exercise causes marked elevations in sympathetic activity to skeletal muscle beds, the magnitude of which is largely dependent on exercise mode, intensity and the amount of active muscle mass. This sympathetic outflow results in vasoconstriction within inactive muscle beds, whilst in active muscle beds exercise induces the release of sympatholytic factors (i.e. ATP, prostaglandins (PGs), and nitric oxide (NO)). These factors act to attenuate or abolish sympathetic vasoconstriction during exercise. Functional sympatholysis reflects this ability of active muscle beds to release sympatholytic factors to locally attenuate the sympathetic vasoconstrictor response associated with exercise. Combined constrictive and sympatholytic processes allow for cardiac output redistribution, which facilitates adequate perfusion and O₂ delivery to metabolically active muscle, and ultimately homeostasis. If a large amount of muscle mass were active (e.g. during whole body exercise), a mismatch between these two processes would lead to either under-perfusion (greater vasoconstriction) or hypotension (greater sympatholysis). While the relevance of functional sympatholysis in clinical/disease populations is unclear, numerous pathophysiological conditions are characterized by elevated sympathetic outflow and impaired sympatholysis contributes to elevated vascular resistance and malperfusion of skeletal muscle during exercise (Saltin & Mortensen, 2012). For example, leg vascular conductance appears to be lower during exercise in hypertensive compared to normotensive adults (Mortensen et al. 2014). Moreover, impaired sympatholysis has been linked to reduced muscle perfusion in elderly versus young individuals during exercise (reviewed in Saltin & Mortensen, 2012). Overall, a complex interplay between blood pressure-regulating reflexes (i.e. baroreflex, muscle metaboreflex, central command, etc.), their consequent sympathetic outflow, and the production of local sympat-holytic factors determine cardiac output distribution to contracting skeletal muscle. However, the integration of these processes is poorly understood.

In a recent issue of The Journal of Physiology, using a highly controlled animal model, Jendzjowsky et al. (2014) elegantly partitioned the roles of the neuronal and endothelial isoforms of nitric oxide synthase (nNOS and eNOS, respectively) in mediating the inhibition of sympathetic vasoconstriction during rest and exercise in both sedentary and exercise-trained rats. Following 4 weeks of exercise training, and sedentary time control interventions, both groups underwent experimental procedures involving: (1) cannulation for intra-arterial monitoring of blood pressure and measurement of leg blood flow by a flow probe, (2) stimulation of the right sciatic nerve for triceps surae contraction, and (3) electrical stimulation of the lumbar sympathetic chain.

Femoral vascular conductance (FVC) was measured during lumbar sympathetic stimulation (2 Hz and 5 Hz) at the L3/L4 level at rest and during rhythmic contraction of the triceps surae muscles at 60% of maximal contractile force. This intervention was completed both prior to and during selective nNOS inhibition with S-methyl-l-thiocitrulline (SMTC) and non-selective NOS inhibition with N^ω-nitro-l-arginine methyl ester hydrochloride (l-NAME). By sequen-tially administering these drugs during sympathetic activation at both rest and contraction, the investigators were able to effectively partition the roles of neuronally and endothelially released NO (nNO and eNO, respectively) in mediating sympathetic vasoconstrictor responsiveness. The primary finding was that exercise training enhanced nNO mediated inhibition of sympathetic vasoconstriction during muscle contraction. Consistent with the enhanced nNO mediated inhibition of sympathetic vasoconstriction, skeletal muscle nNOS enzyme expression was increased following exercise training. Collectively, these findings merit further discussion on the redundancies of peripheral vascular control in the context of both vasoactive and sympathetic factors.

Redundant mechanisms in peripheral vascular control: vasoactive factors

The enhanced role of nNO in the inhibition of sympathetic vasoconstric-tion during muscle contraction clearly represents a benefit of exercise training. However, selective and non-selective NOS blockade did not abolish sympatholysis in exercise-trained rats. Additionally, whilst sympatholysis was reduced in sedentary rats, they were also able to inhibit sympathetic vasoconstriction during exercise. These findings highlight the redundant nature of peripheral vascular control and the potential contributions from other sympatholytic factors such as PGs, adenosine, ATP, or endothelium-derived hyperpolarizing factors to the inhibition of sympathetic vasoconstriction. Whether or not exercise training also enhances other sympatholytic mechanisms will require further investigation to establish. For example, studies in humans have shown that NO is not obligatory for the inhibition sympathetic vasoconstriction; however, simultaneous NO and PG inhibition augments sympathetic vasoconstrictor responsiveness, highlighting the potential synergistic effects between vasodilatory/sympatholytic factors (reviewed in Saltin & Mortensen, 2012). To add further complexity to this matter, it has been reported that although ATP causes functional sympatholysis, its effect is through downstream release of NO and PGs. Moreover, local or systemic inhibition of vasoactive factors may have a differing impact on functional sympatholysis. Indeed, systemic, but not local, NOS inhibition reduces functional sympatholysis in humans (reviewed in Saltin & Mortensen, 2012). Thus, it seems clear that the integrative regulation of vascular tone, sympathetic vasoconstrictor responsiveness and functional sympatholysis is highly complex and cannot be explained in its entirety by summating the results from the isolation of individual vasoactive factors.

A recent study in humans (Mortensen et al. 2014) reported a reduced vasoconstrictor responsiveness of the leg to the infusion of tyramine (to stimulate noradrenaline release) at rest and during exercise following exercise training. Whether the reduced vasoconstrictor response to tyramine following training is due to changes in postsynaptic adrenergic receptor responsiveness, improved inhibition of sympathetic vasoconstriction by NO (or another sympatholytic factor) or enhanced β-adrenergic receptor mediated vasodilatation will require further study to establish. Although changes in α- and/or β-receptor responsiveness due to exercise training may also alter sympathetic vasoconstrictor responsiveness during exercise, the cellular mechanisms underlying changes in receptor responsiveness remain to be elucidated (Mortensen et al. 2014). Moreover, it is unclear if exercise training alters receptor density and distribution in both humans and/or rats.

Redundant mechanisms in peripheral vascular control: sympathetic factors

Sympathetic outflow during exercise is resultant from the integration of several different inputs to the nucleus of the solitary tract (NTS). Two primary afferent signals integrating at this site are baroreflex and muscle metaboreflex signals. While the way in which these two reflexes interact within the NTS is not fully understood, interpretation of these interactions for functional sympatholysis is crucial. Pertaining to this study, a localized sympathetic stimulus was evoked within the hind limb, while the active muscle was dissected free from surrounding tissue. As such the evoked contraction via sciatic stimulation would not completely represent the ‘normal’ physiological afference and subsequent efference in an intact model, animal or human (i.e. integration within the NTS). However, irrespective of the method used to examine functional sympatholysis (i.e. tyramine infusion, Mortensen et al. 2014; lumbar stimulation, Jendzjowsky et al. 2014), it will necessitate superimposing a sympathetic stimulus on top of that naturally occurring during rest or exercise. Whilst the implica-tions of these differences between sympathetically mediated responses from external stimulation and normal physiological processes are unclear, superimposing sympathetic stimuli may affect the interpretation of sympatholytic responses in all related studies, such as those utilizing both lumbar stimulation in rats (Jendzjowsky & DeLorey, 2013; Jendzjowsky et al. 2014; Mizuno et al. 2014) and tyramine infusion in humans (Mortensen et al. 2014).

While the investigation of peripheral vascular control is inherently complex and a number of questions about the regulation of sympathetic vasoconstriction and exercise training remain unresolved, the recent study by Jendzjowsky et al. provides great insight into the mechanisms regulating both sympathetic vasoconstrictor responsiveness and functional sympatholysis in sedentary and exercise-trained rats. Improvement in functional sympatholysis and reduced sympathetic vasoconstrictor responsiveness during exercise have been shown with exercise training in both normotensive and hypertensive rats (Jendzjowsky & DeLorey, 2013; Jendzjowsky et al. 2014; Mizuno et al. 2014) and humans (Mortensen et al. 2014). Exercise-induced improvements in functional sympatholysis in rats is due in part to an increased effect of NO (Jendzjowsky & DeLorey, 2013; Jendzjowsky et al. 2014; Mizuno et al. 2014), indicating a potential mechanism underlying the exercise training induced improvements in sympatholysis observed in humans (Mortensen et al. 2014). These studies collectively highlight that NO must be a key factor in functional sympatholysis, while the magnitude of NO mediated sympathetic inhibition appears to be responsive to exercise training in an intensity dependent manner (Jendzjowsky & DeLorey, 2013) while also related to an exercise training induced increase in skeletal muscle nNOS expression (Jendzjowsky et al. 2014). Thus, it appears that exercise may be an effective intervention to improve functional sympatholysis in clinical populations, acting through improvements in NO-mediated sympatholysis. A complete characterization of the precise mechanistic regulation of exercise training induced improvements in functional sympatholysis will require further investigation. However, Jendzjowsky et al. have provided both novel and relevant information by partitioning the relative influence of nNOS and eNOS isoforms on NO mediated functional sympatholysis, thereby improving upon our current understanding of peripheral vascular control. Translation into human studies remains an exciting challenge.

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Competing interests

None declared.