- The sympathetic nervous system is integral to the control of blood pressure and skeletal muscle blood flow at rest and during exercise.
- Aerobic exercise training modulates sympathetic vasoconstrictor responsiveness and enhances functional sympatholysis through a nitric oxide–dependent mechanism.
- Exercise training may be effective in the treatment and prevention of chronic diseases characterized by elevated sympathetic nerve activity and vascular dysfunction.
The sympathetic nervous system is of primary importance in the regulation of peripheral vascular resistance and is therefore integral to the control of systemic blood pressure and the distribution of cardiac output to vital organs and tissues (23). Skeletal muscle is one of the largest vascular beds in the body; as such, it receives a considerable portion of cardiac output at rest and during exercise and substantially contributes to the regulation of total peripheral resistance.
In response to exercise, the cardiovascular system must satisfy the competing demands of adequately perfusing active skeletal muscle while simultaneously maintaining systemic blood pressure (23). Cardiac output increases, and local vasodilation in active skeletal muscle facilitates the matching of local O2 delivery to local O2 demand (23). Efferent sympathetic nerve activity increases concomitantly and constricts blood vessels in nonactive tissue to direct blood toward exercising muscle, whereas in active skeletal muscle, vasoconstriction balances the robust local vasodilatation to prevent a profound decrease in peripheral vascular resistance and a decline in blood pressure.
In contracting skeletal muscle, the vasoconstrictor response to sympathetic nerve activity is blunted, and this contraction-mediated inhibition of vasoconstriction has been termed functional sympatholysis (22). Our present understanding is that, in response to exercise, the active skeletal muscle and/or endothelium-release molecules that inhibit sympathetic neurotransmitter release and/or blunt the responsiveness of postsynaptic sympathetic receptor (33,34). The local blunting of sympathetic vasoconstrictor responsiveness in active muscle allows sympathetic nerve activity to constrict inactive tissue, while simultaneously optimizing perfusion of active muscle and the maintenance of blood pressure. Although there is no definitive evidence that any one molecule is required for sympatholysis, the vasodilator nitric oxide (NO) is produced by both the endothelium and skeletal muscle in response to exercise and has been shown to inhibit sympathetic vasoconstriction in resting and contracting skeletal muscle (9,10,32,34).
Aerobic exercise training has been shown to reduce blood pressure and enhance skeletal muscle vascular function and the control of muscle blood flow at rest and during exercise (30). The basic physiological mechanisms that underlie exercise training–mediated improvements in vascular function have not been elucidated fully. However, exercise training has consistently been shown to increase NO bioavailability and enhance NO-dependent vascular function in experimental models of endothelial dysfunction (30). In healthy people and animals, training adaptations in endothelial function seem to be dependent on the limb, muscle, vascular segment investigated, and training paradigm used (10,11,19,28).
In this article, we address the novel hypothesis that exercise training alters sympathetic vasoconstrictor responsiveness and contraction-mediated inhibition of sympathetic vasoconstriction through an NO-dependent mechanism (Fig. 1). Advancing our understanding of the fundamental, mechanistic effects of exercise training on sympathetic vascular control may be particularly important in the treatment and prevention of chronic disease conditions that are characterized by elevated sympathetic nerve activity and vascular dysfunction.
EXERCISE TRAINING AND EFFERENT SYMPATHETIC NERVE ACTIVITY
Inputs from several brain stem nuclei that regulate the cardiovascular system, neurotransmitters, signal molecules (e.g., glutamate, angiotensin II, NO), and peripheral reflexes (e.g., baroreceptors, chemoreceptors) are integrated to determine the level of efferent muscle sympathetic nerve activity (MSNA) at rest and during exercise (14).
Exercise training does not seem to alter resting MSNA in healthy people (2). During exercise, the direct measurement of MSNA to contracting muscle is technically challenging and therefore, our understanding of how exercise training impacts sympathetic activity during exercise is based largely on measures of plasma norepinephrine (NE). Although the available evidence is limited and plasma catecholamines may not be reflective of efferent sympathetic activity directed to active muscle (4), the increase in plasma NE in response to exercise seems to be reduced after exercise training in humans (21,25).
In healthy animals and animal models of disease characterized by sympatho-excitation (e.g., hypertension, heart failure, myocardial infarction), aerobic exercise training has been shown to reduce resting efferent sympathetic nerve activity (typically measured as renal sympathetic nerve activity) (5,18). Altered central autonomic signaling by glutamate, angiotensin, NO, as well as altered neural reflex function seems to underlie the inhibitory effects of exercise training on sympathetic nerve activity in animal models (5,18). Consistent with findings in animals, exercise training also has been shown to reduce resting MSNA in patient populations (e.g., heart failure, hypertension, metabolic syndrome) with elevated sympathetic activity (2).
In summary, aerobic exercise training has been shown to blunt efferent MSNA at rest and in response to exercise, particularly in conditions characterized by elevated sympathetic nerve activity. Further studies are necessary to fully characterize the effects of exercise training on MSNA, particularly during exercise, and to advance our understanding of the dose-response relation between exercise training and the regulation of efferent sympathetic nerve activity.
EXERCISE TRAINING AND SYMPATHETIC VASOCONSTRICTION
The functional consequence of MSNA in the skeletal muscle vascular bed is vasoconstriction. The neurotransmitters NE, adenosine triphosphate (ATP), and neuropeptide Y (NPY) bind to postsynaptic α1- and α2-adrenoreceptors, purinergic (P2X), and NPY-Y1 receptors on vascular smooth muscle to produce vasoconstriction (Fig. 1). The magnitude of vasoconstriction in a vascular bed is a function of the amount of efferent nerve activity, the quantity of neurotransmitter released per nerve impulse, and the responsiveness of postsynaptic sympathetic receptors. Our premise is that chronic aerobic exercise training alters the magnitude of the vasoconstrictor response to sympathetic nerve activity (sympathetic vasoconstrictor responsiveness) through effects on postsynaptic sympathetic receptors (Fig. 1).
In vitro studies of isolated vascular segments have demonstrated that postsynaptic sympathetic receptors are sensitive to acute changes in their environment (e.g., pH, O2) (29). Chronic exercise training also has been shown to alter the responsiveness of postsynaptic receptors to sympathetic stimuli (13,28,35). In miniature swine, 7 days of treadmill exercise (2 h/d at 3.5 miles/h) augmented the vasoconstrictor response of femoral and brachial arteries to NE (13). In contrast, the vasoconstrictor response to NE was decreased in cremaster arterioles after 6 wk of swim training (1 h/d, 7d/wk) (35) and unchanged in arterioles from gracilis and soleus muscle after 4 wk of mild-intensity (22–28 m/min, 1%–2% grade, 28–36 min/d, 5 d/wk) and 10–12 wk of heavy-intensity treadmill exercise training (30 m/min, 15% grade, 1 h/d, 5 d/wk), respectively (6,28). Collectively, the data from studies in isolated blood vessels have demonstrated that exercise training can alter postsynaptic sympathetic receptor responsiveness; however, the effects of exercise training seem to be dependent on the muscle and vascular segment investigated and the exercise training stimulus. Furthermore, in vitro studies of blood vessels may not be reflective of the effects of exercise training on the integrated regulation of the skeletal muscle resistance vasculature in vivo, and this approach does not permit assessment during muscular contraction.
Recently, our laboratory has used treadmill exercise training and an in vivo anesthetized rat preparation to investigate the effect of aerobic exercise training on evoked sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle. After 4 wk of moderate- (30 m/min, 5 degrees grade, 30 min/d, 5 d/wk) and heavy-intensity (40 m/min, 5 degrees grade, 15 min/d, 5 d/wk) exercise training, sympathetic vasoconstrictor responsiveness in resting skeletal muscle was augmented in a training intensity–dependent manner (Fig. 2A) (7,10). Exercise training also enhanced endothelium-dependent vasodilation (EDD), and the improvement in EDD was correlated with the increase in resting sympathetic vasoconstrictor responsiveness (Fig. 2B). This relation suggests that increased sympathetic vasoconstrictor responsiveness may be necessary to oppose an increase in local vasodilator signaling (7). In agreement, aerobic exercise training has been shown to produce parallel increases in EDD and tonic sympathetic vasoconstriction at rest in middle-aged men (27).
To explore the mechanism underlying the augmented sympathetic vasoconstrictor responsiveness in resting skeletal muscle after exercise training, we used selective α-adrenoreceptor antagonists to dissect the contributions of α1- and α2-adrenoreceptors to evoked vasoconstriction in sedentary and exercise-trained rats. Both α1- and α2-adrenoreceptor–mediated vasoconstrictor responses were augmented in resting skeletal muscle of exercise-trained compared with sedentary rats (9,12). Selective α2-adrenoreceptor blockade did not alter evoked vasoconstriction in sedentary rats but significantly blunted vasoconstrictor responses in mild- and heavy-intensity-exercise–trained rats, suggesting that α2-adrenoreceptors contribute to evoked vasoconstrictor responses in resting muscle in the exercise-trained state (9). Selective α1-adrenoreceptor antagonism blunted evoked vasoconstrictor responses at rest in both sedentary and exercise-trained rats (12). However, α1-adrenoreceptor blockade abolished the difference in resting sympathetic vasoconstrictor responsiveness between sedentary and exercise-trained rats, suggesting that α1-adrenoreceptor–mediated vasoconstriction in resting skeletal muscle was augmented after exercise training (12).
EXERCISE TRAINING AND SYMPATHOLYSIS
In 1962, Remensnyder et al. (22) demonstrated that direct stimulation of sympathetic nerves produced a smaller vasoconstriction in contracting, compared with resting, skeletal muscle of dogs. This contraction-mediated inhibition of vasoconstriction has been demonstrated repeatedly in animals and humans and has been termed functional sympatholysis. Despite considerable research, the mechanism(s) responsible for sympatholysis has not been identified. However, our present understanding is that a vasoactive molecule released from the endothelium, skeletal muscle, or possibly red blood cells may inhibit the release of sympathetic neurotransmitters or the responsiveness of postsynaptic sympathetic receptors (16,20,34).
Recent studies have demonstrated that aerobic exercise training enhances sympatholysis in rodents (10,11,15) and humans (16). Indeed, studies from our laboratory have shown that aerobic exercise training in rats enhances sympatholysis in a training intensity–dependent manner (Fig. 3) (9–12). Furthermore, our studies suggest that the mechanistic basis for enhanced sympatholysis after exercise training was augmented blunting of α-adrenoreceptor–mediated vasoconstriction and enhanced NO-dependent inhibition of vasoconstriction. Selective α2-adrenoreceptor blockade did not alter sympatholysis in sedentary and mild-intensity-exercise–trained rats but modestly reduced sympatholysis in heavy-intensity-exercise–trained rats (9). The decline in sympatholysis in the presence of selective α2-adrenoreceptor blockade suggests that the enhanced sympatholysis after heavy-intensity exercise training was partly attributable to an increased ability to inhibit α2-adrenoreceptor–mediated vasoconstriction (9). However, sympatholysis remained greater in exercise-trained compared with sedentary rats in the presence of selective α2-adrenoreceptor blockade indicating that exercise training also may have augmented contraction-mediated inhibition of α1-adrenoreceptor– or nonadrenoreceptor-mediated vasoconstriction (9). In a subsequent study, selective α1-adrenoreceptor blockade abolished exercise training–induced improvements in sympatholysis, demonstrating that exercise training–augmented contraction mediated blunting of α1-adrenoreceptor vasoconstriction (12). Collectively, our data suggest that the regulation of α-adrenoreceptor–mediated vasoconstriction in the skeletal muscle vasculature becomes more complex after exercise training. The relative contributions of α1- and α2-adrenoreceptors to evoked vasoconstrictor responses are altered, and α-adrenoreceptors become more susceptible to inhibition during contraction after aerobic exercise training. These adaptations to training may enhance local control of vasoconstriction and the distribution of blood flow between and within skeletal muscles at rest and during exercise. Consistent with this notion, the distribution of muscle blood flow has been shown to change in response to exercise training.
NO MEDIATED SYMPATHOLYSIS
NO is synthesized through the conversion of L-arginine to L-citrulline in a reaction catalyzed by the enzyme NO synthase (NOS). NO is a potent vasodilator and several studies have demonstrated that NO contributes to, but is not required for, the control of skeletal muscle blood flow at rest and in response to exercise (3,8,10,24,27,34). NO also has been shown to inhibit sympathetic vasoconstriction in resting and contracting skeletal muscle of animals and humans (3,10,34).
As described earlier, our laboratory has reported that aerobic exercise training enhanced sympatholysis in a training intensity–dependent manner. Exercise training has been shown to increase NO bioavailability and improve NO-mediated vascular function in human and animal experimental models (10,11,15), making NO an attractive potential mediator of enhanced sympatholysis after exercise training. Pharmacological blockade of NOS reduced sympatholysis in exercise-trained rats, demonstrating that exercise training augmented NO-mediated sympatholysis (Fig. 3) (10). Consistent with our findings, exercise training also has been shown to enhance sympatholysis in hypertensive rats and NOS inhibition ameliorated the augmented sympatholysis (15). To our knowledge, the effect of exercise training on NO-mediated sympatholysis in humans has not been investigated. However, lifelong physical activity seems to maintain functional sympatholysis and NO bioavailability in older adults (17,19).
The cellular mechanism of NO-mediated sympatholysis has not been identified; however, NO has been shown to inhibit both α1-and a2-adrenoreceptor–mediated vasoconstriction in isolated arteries (20). To determine if increased NO-mediated inhibition of α1-or α2-adrenoreceptor vasoconstriction underlies enhanced NO-dependent sympatholysis after exercise training, we investigated the effects of combined pharmacological blockade of NO production and α1- or α2-adrenoreceptors on sympathetic vasoconstriction (9,12). In the presence of selective blockade of α2-adrenoreceptors, NOS inhibition reduced the magnitude of sympatholysis in heavy-intensity-exercise–trained rats, suggesting that exercise training enhanced NO-mediated inhibition of α1-adrenoreceptor- or nonadrenoreceptor vasoconstriction (9).
Consistent with that interpretation, NOS inhibition in the presence of selective of α1-adrenoreceptor blockade did not alter sympatholysis in sedentary and exercise-trained rats, suggesting that functional α1-adrenoreceptors are required for NO-dependent sympatholysis (12). Similar findings have been reported in untrained dogs, where NOS inhibition abolished contraction-mediated inhibition of α1-adrenoreceptors but did not change the blunting of α2-adrenoreceptor–mediated vasoconstriction during exercise (1). Taken together, the data from these studies indicate that the mechanism responsible for enhanced sympatholysis after exercise training was primarily augmented NO-dependent inhibition of α1-adrenoreceptor–mediated vasoconstriction. Furthermore, the data suggest that NO is not required to inhibit α2-adrenoreceptor and nonadrenoreceptor–mediated vasoconstriction in contracting skeletal muscle.
WHAT IS THE SOURCE OF NO?
Three isoforms of the NOS enzyme exist: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) (26). The eNOS and nNOS isoforms are expressed in skeletal muscle, and the endothelium and both eNOS and nNOS have been implicated in the regulation of skeletal muscle blood flow at rest and in response to exercise (26). During exercise, endothelial shear stress increases eNOS-mediated NO production and an increase in skeletal muscle cytosolic [Ca2+] stimulates NO production by nNOS resulting in an increase in NO bioavailability (26).
Investigation of the NOS isoform-specific contributions to the inhibition of sympathetic vasoconstriction is important to advance our understanding of the mechanistic regulation of skeletal muscle vascular resistance but also is of clinical relevance. Several chronic diseases (e.g., heart failure, hypertension, metabolic syndrome) are characterized by elevated sympathetic outflow, diminished vascular function, decreased NO bioavailability, and exercise intolerance (5,15,24,32). Elucidation of NOS isoform-specific regulation of vascular tone will help to identify therapeutic targets in the treatment of vascular dysfunction and exercise intolerance.
Indeed, a reduced ability to inhibit sympathetic vasoconstriction during muscular contraction has been reported in humans and rodents with diminished nNOS expression (24,32), suggesting that NO derived from nNOS is essential for sympatholysis. Whether findings from disease populations/models reflect NOS isoform-specific contributions to the inhibition of sympathetic vasoconstriction in health has not been investigated. Our laboratory recently used isoform-specific blockade of nNOS followed by nonselective NOS blockade to partition the relative contributions of NO derived from nNOS and eNOS to the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle (8,11). The rationale for the experimental approach was that an increase in sympathetic vasoconstrictor responsiveness in the presence of selective nNOS blockade would be reflective of nNOS-mediated inhibition of sympathetic vasoconstriction, and the difference between the constrictor response in the selective nNOS and nonselective NOS blockade would reflect eNOS-mediated inhibition of sympathetic vasoconstriction. This approach also allowed determination of the fractional contribution of NO derived from nNOS to total NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. In resting skeletal muscle, NO derived from both eNOS and nNOS inhibited sympathetic vasoconstriction; however, NO derived from eNOS was particularly important for the inhibition of sympathetic vasoconstriction under resting conditions and was responsible for approximately 70% of total NO-mediated inhibition (8). During exercise, both eNOS and nNOS continued to inhibit vasoconstriction; however, nNOS made a proportionally larger contribution to the inhibition of vasoconstriction in contracting skeletal muscle (~50%). These data suggest that nNOS-mediated NO production increases markedly in response to exercise and newly derived NO from nNOS is critical to inhibit vasoconstriction in contracting skeletal muscle (8,11).
We also have investigated the effect of aerobic exercise training on NOS isoform-specific inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle (11). In agreement with our previous study (8), NO derived from both eNOS and nNOS inhibited vasoconstriction in resting skeletal muscle (11). The relative contributions of NO derived from eNOS (~65%) and nNOS (~35%) to total NO inhibition were similar to our prior study and were not different between sedentary and exercise-trained rats, indicating that exercise training does not alter NOS isoform-specific blunting of vasoconstriction under resting conditions. In contracting skeletal muscle, nNOS made a proportionally larger contribution to the inhibition of vasoconstriction in both sedentary and exercise-trained rats in agreement with our earlier findings. However, the fractional contribution of nNOS-derived NO to total NO inhibition of vasoconstriction in skeletal muscle was substantially larger in exercise-trained (~75%) compared with sedentary (~50%) rats (11). Indeed, selective nNOS blockade abolished the enhanced sympatholysis in exercise-trained rats, and subsequent nonselective NOS blockade did not further reduce sympatholysis (Fig. 4) (11). These data demonstrate that the exercise training–induced enhancement of NO-dependent sympatholysis was attributable to augmented nNOS-dependent sympatholysis. Consistent with enhanced nNOS-mediated vascular function, skeletal muscle nNOS expression was greater in exercise-trained compared with sedentary rats (Fig. 5) (11). The training-induced increase in nNOS expression seemed to occur in muscle with a high proportion of Type II, fast-twitch, glycolytic muscle fibers. It has been argued that vasoconstriction is more readily inhibited during contraction of glycolytic compared with oxidative skeletal muscle (31). Thus, although speculative, it is possible that aerobic exercise training produces adaptations in the fibers or blood vessels of glycolytic muscles that enhance NO-mediated sympatholysis. Further research is required to establish the role of skeletal muscle fiber types in training-induced adaptations in sympatholysis.
In summary, the accumulated evidence from our recent studies suggests that exercise training may be beneficial in the treatment of conditions characterized by reduced nNOS expression (assuming the absence of a genetic mutation impacting nNOS expression) and NO-dependent vascular dysfunction.
SUMMARY AND FUTURE DIRECTIONS
The sympathetic nervous system is an important regulator of the cardiovascular system. Sympathetic activation at the onset of exercise is critical to increase and redistribute cardiac output to exercising skeletal muscles. In the active skeletal muscle, sympathetic vasoconstriction and local vasodilation function in an integrative manner to regulate vascular resistance and optimize the perfusion of active muscle/fibers.
In this article, we have presented evidence that the sympathetic nervous system is highly responsive to aerobic exercise training and that there is considerable plasticity in the control of sympathetic vasoconstriction in the skeletal muscle vascular bed.
Exercise training altered vascular reactivity to sympathetic stimulation and the relative contributions of postsynaptic α-adrenoreceptors to evoked vasoconstriction in resting and contracting skeletal muscle. Exercise training also enhanced functional sympatholysis in a training-intensity–dependent manner through an NO-dependent mechanism. The augmented NO-dependent sympatholysis in the exercise-trained state was attributable to enhanced nNOS-mediated inhibition of vasoconstriction and augmented blunting of α1-adrenoreceptor–mediated vasoconstriction (Fig. 1).
Further research is required in several areas to advance our mechanistic and integrative understanding of the effects of aerobic exercise training on the regulation of sympathetic vasoconstriction at rest and during exercise (Fig. 1). Knowledge of the effect of exercise training on central and neural reflex control of MSNA during exercise would advance our understanding of how adaptations in the control of efferent sympathetic outflow are integrated with adaptations in sympathetic vasoconstrictor responsiveness in the control of skeletal muscle vascular resistance and blood pressure.
Investigation of the effects of exercise training on the expression and distribution of postsynaptic sympathetic receptors and the cellular mechanisms responsible for exercise training–induced alterations in sympathetic vasoconstrictor responsiveness is required to fully elucidate the effects of exercise training on sympathetic vasoconstriction (Fig. 1).
Finally, there is no consensus on the optimal dose of exercise training to improve vascular health and function (Fig. 1). We (7,9,10) and others (13,35) have shown that vascular adaptations are sensitive to the intensity and volume of exercise training. However, further knowledge of how the vasculature responds to each component of an exercise training paradigm (frequency, intensity, duration, and mode) as well as the time course of adaptations would inform the development of exercise prescriptions for the treatment and prevention of vascular dysfunction and exercise intolerance.
The authors thank Nicholas Jendzjowsky for his contributions to the projects presented in this article.
This study was supported by grants from the Natural Sciences and Engineering Research Council of Canada and the Canadian Foundation for Innovation.
1. Buckwalter JB, Taylor JC, Hamann JJ, Clifford PS. Role of nitric oxide
in exercise sympatholysis
. J. Appl. Physiol
. 2004; 97:417–23. discussion 6.
2. Carter JR, Ray CA. Sympathetic neural adaptations to exercise training in humans. Auton. Neurosci
. 2015; 188:36–43.
3. Chavoshan B, Sander M, Sybert TE, Hansen J, Victor RG, Thomas GD. Nitric oxide
-dependent modulation of sympathetic neural control of oxygenation in exercising human skeletal muscle. J. Physiol
. 2002; 540(Pt 1):377–86.
4. Grassi G, Esler M. How to assess sympathetic activity in humans. J. Hypertens
. 1999; 17:719–34.
5. Haack KK, Zucker IH. Central mechanisms for exercise training-induced reduction in sympatho-excitation in chronic heart failure. Auton. Neurosci
. 2015; 188:44–50.
6. Jasperse JL, Laughlin MH. Vasomotor responses of soleus feed arteries from sedentary and exercise-trained rats. J. Appl. Physiol
. 1999; 86:441–9.
7. Jendzjowsky NG, DeLorey DS. Short-term exercise training augments sympathetic vasoconstrictor responsiveness and endothelium-dependent vasodilation in resting skeletal muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol
. 2012; 303:R332–9.
8. Jendzjowsky NG, DeLorey DS. Role of neuronal nitric oxide
in the inhibition of sympathetic vasoconstriction
in resting and contracting skeletal muscle of healthy rats. J. Appl. Physiol
. 2013; 115:97–106.
9. Jendzjowsky NG, DeLorey DS. Short-term exercise training augments alpha2-adrenoreceptor-mediated sympathetic vasoconstriction
in resting and contracting skeletal muscle. J. Physiol
. 2013; 591:5221–33.
10. Jendzjowsky NG, DeLorey DS. Short-term exercise training enhances functional sympatholysis
through a nitric oxide
-dependent mechanism. J. Physiol
. 2013; 591:1535–49.
11. Jendzjowsky NG, Just TP, DeLorey DS. Exercise training augments neuronal nitric oxide
synthase-mediated inhibition of sympathetic vasoconstriction
in contracting skeletal muscle of rats. J. Physiol
. 2014; 592:4789–802.
12. Just TP, DeLorey DS. Exercise training and α1-adrenoreceptor-mediated sympathetic vasoconstriction
in resting and contracting skeletal muscle. Physiol. Rep
. 2016; 4. pii: e12707.
13. McAllister RM, Laughlin MH. Short-term exercise training alters responses of porcine femoral and brachial arteries. J. Appl. Physiol
. 1997; 82:1438–44.
14. Mischel NA, Subramanian M, Dombrowski MD, Llewellyn-Smith IJ, Mueller PJ. (In)activity-related neuroplasticity in brainstem control of sympathetic outflow: unraveling underlying molecular, cellular, and anatomical mechanisms. Am. J. Physiol. Heart Circ. Physiol
. 2015; 309:H235–43.
15. Mizuno M, Iwamoto GA, Vongpatanasin W, Mitchell JH, Smith SA. Exercise training improves functional sympatholysis
in spontaneously hypertensive rats through a nitric oxide
-dependent mechanism. Am. J. Physiol. Heart Circ. Physiol
. 2014; 307:H242–51.
16. Mortensen SP, Nyberg M, Gliemann L, Thaning P, Saltin B, Hellsten Y. Exercise training modulates functional sympatholysis
and α-adrenergic vasoconstrictor responsiveness in hypertensive and normotensive individuals. J. Physiol
. 2014; 592:3063–73.
17. Mortensen SP, Nyberg M, Winding K, Saltin B. Lifelong physical activity preserves functional sympatholysis
and purinergic signalling in the ageing human leg. J. Physiol
. 2012; 590:6227–36.
18. Mueller PJ. Exercise training and sympathetic nervous system activity: evidence for physical activity dependent neural plasticity. Clin. Exp. Pharmacol. Physiol
. 2007; 34:377–84.
19. Nyberg M, Blackwell JR, Damsgaard R, Jones AM, Hellsten Y, Mortensen SP. Lifelong physical activity prevents an age-related reduction in arterial and skeletal muscle nitric oxide
bioavailability in humans. J. Physiol
. 2012; 590:5361–70.
20. Ohyanagi M, Nishigaki K, Faber JE. Interaction between microvascular alpha 1- and alpha 2-adrenoceptors and endothelium-derived relaxing factor. Circ. Res
. 1992; 71:188–200.
21. Péronnet F, Cléroux J, Perrault H, Cousineau D, de Champlain J, Nadeau R. Plasma norepinephrine response to exercise before and after training in humans. J. Appl. Physiol. Respir. Environ. Exerc. Physiol
. 1981; 51:812–5.
22. Remensnyder JP, Mitchell JH, Sarnoff SJ. Functional sympatholysis
during muscular activity. Observations on influence of carotid sinus on oxygen uptake. Circ. Res
. 1962; 11:370–80.
23. Rowell LB. Human Cardiovascular Control
. New York (NY): Oxford University Press; 1993, p. 520.
24. Sander M, Chavoshan B, Harris SA, et al. Functional muscle ischemia in neuronal nitric oxide
synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy. Proc. Natl. Acad. Sci. U. S. A
. 2000; 97:13818–23.
25. Sinoway L, Shenberger J, Leaman G, et al. Forearm training attenuates sympathetic responses to prolonged rhythmic forearm exercise. J. Appl. Physiol
. 1996; 81:1778–84.
26. Stamler JS, Meissner G. Physiology of nitric oxide
in skeletal muscle. Physiol. Rev
. 2001; 81:209–37.
27. Sugawara J, Komine H, Hayashi K, et al. Systemic alpha-adrenergic and nitric oxide
inhibition on basal limb blood flow: effects of endurance training in middle-aged and older adults. Am. J. Physiol. Heart Circ. Physiol
. 2007; 293:H1466–72.
28. Sun D, Huang A, Koller A, Kaley G. Short-term daily exercise activity enhances endothelial NO synthesis in skeletal muscle arterioles of rats. J. Appl. Physiol
. 1994; 76:2241–7.
29. Tateishi J, Faber JE. Inhibition of arteriole alpha 2- but not alpha 1-adrenoceptor constriction by acidosis and hypoxia in vitro. Am. J. Physiol
. 1995; 268(5 Pt 2):H2068–76.
30. Thijssen DH, Maiorana AJ, O'Driscoll G, Cable NT, Hopman MT, Green DJ. Impact of inactivity and exercise on the vasculature in humans. Eur. J. Appl. Physiol
. 2010; 108:845–75.
31. Thomas GD, Hansen J, Victor RG. Inhibition of alpha 2-adrenergic vasoconstriction
during contraction of glycolytic, not oxidative, rat hindlimb muscle. Am. J. Physiol
. 1994; 266:H920–9.
32. Thomas GD, Sander M, Lau KS, Huang PL, Stull JT, Victor RG. Impaired metabolic modulation of alpha-adrenergic vasoconstriction
in dystrophin-deficient skeletal muscle. Proc. Natl. Acad. Sci. U. S. A
. 1998; 95:15090–5.
33. Thomas GD, Segal SS. Neural control of muscle blood flow during exercise. J. Appl. Physiol
. 2004; 97:731–8.
34. Thomas GD, Victor RG. Nitric oxide
mediates contraction-induced attenuation of sympathetic vasoconstriction
in rat skeletal muscle. J. Physiol
. 1998; 506(Pt 3):817–26.
35. Wiegman DL, Harris PD, Joshua IG, Miller FN. Decreased vascular sensitivity to norepinephrine following exercise training. J. Appl. Physiol. Respir. Environ. Exerc. Physiol
. 1981; 51:282–7.
Keywords:© 2016 American College of Sports Medicine
nitric oxide; sympatholysis; autonomic nervous system; adrenergic receptor; vasoconstriction