Download EXERCISE TRAINING AND SYMPATHETIC NERVOUS SYSTEM

Clinical and Experimental Pharmacology and Physiology (2007) 34, 377–384
doi: 10.1111/j.1440-1681.2007.04590.x
Activity-Dependent Plasticity in Central Homeostatic Systems
Blackwell Publishing Asia
EXERCISE TRAINING AND SYMPATHETIC NERVOUS SYSTEM
ACTIVITY: EVIDENCE FOR PHYSICAL ACTIVITY DEPENDENT
NEURAL PLASTICITY
Exercise
PJ
Mueller
training and the SNS
Patrick J Mueller
Dalton Cardiovascular Research Center and Department of Biomedical Sciences, University of Missouri-Columbia,
Columbia, Missouri, USA
SUMMARY
1. It has been generally accepted that regular physical activity
is associated with beneficial effects on the cardiovascular system.
In fact, the idea that exercise maintains cardiovascular health is
evident by the direct links between a sedentary lifestyle and the
risk of cardiovascular and other disease states.
2. Cardiovascular diseases, such as hypertension and heart
failure, are often associated with sympathetic nervous system
(SNS) overactivity. Conversely, exercise has been shown to reduce
hypertension and decrease elevated SNS activity. In addition,
there is evidence that exercise may reduce resting blood pressure
and sympathetic outflow in normal individuals.
3. Although somewhat controversial in humans, evidence
from animal studies also indicates that exercise training reduces
baroreflex-mediated and other forms of sympathoexcitation
in normal individuals. Collectively, these data are consistent
with the hypothesis that physical activity may decrease, and
physical inactivity may increase, the incidence of cardiovascular
disease via alterations in SNS activity. Despite the important
clinical implications of this possibility, the mechanisms by
which exercise alters control of SNS activity remain to be fully
elucidated.
4. Recent evidence suggests that central nervous system (CNS)
plasticity occurs under a variety of conditions, including varying
levels of physical activity. The purpose of the present brief review
is to provide evidence that changes within the CNS contribute
importantly to altered regulation of the SNS observed following
exercise training. The primary hypothesis is that physical activity
versus inactivity produces plasticity within neural networks that
regulate SNS activity. This hypothesis is supported by published
Correspondence: Patrick J Mueller, Department of Physiology, Wayne
State University School of Medicine, 540 E. Canfield, Detroit, MI 48201,
USA. Email: [email protected]
Presented at the Experimental Biology Symposium Activity-Dependent
Plasticity in Central Homeostatic Systems, San Francisco, USA, April 2006.
Received 14 June 2006; revision 17 November 2006; accepted 5 December
2006.
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd
and preliminary data that suggest that exercise training may
reduce sympathoexcitation by reducing activation of neurons
within cardiovascular regions of the brain. These mechanisms
are likely to be important in disease states of sympathetic
overactivity and in normal healthy individuals whose risk of
cardiovascular disease is reduced by leading an active versus
sedentary lifestyle.
Key words: cardiovascular disease, exercise, physical inactivity,
sympathetic nervous system.
CARDIOVASCULAR DISEASE, PHYSICAL
ACTIVITY/INACTIVITY AND SYMPATHETIC
NERVOUS SYSTEM ACTIVITY
Despite significant advances in treatment strategies, cardiovascular
disease remains the leading cause of death in the US.1 Among
other risk factors, physical inactivity is considered one of the leading
causes of cardiovascular disease.2,3 In fact, the combination of a
sedentary lifestyle and poor diet has been predicted by the Centers
for Disease Control to overtake tobacco as the leading contributor
to premature death.2 Therefore, an understanding of the mechanisms
by which physical activity and inactivity influence the cardiovascular
system is highly relevant from a clinical, economic and public health
perspective.
Cardiovascular diseases, such as hypertension and heart failure,
are often associated with overactivity of the sympathetic nervous
system (SNS).4,5 It has been suggested that increases in physical
activity produce beneficial effects on the cardiovascular system in
normal and diseased individuals via alterations in neural control of
the circulation.6–8 These effects include reductions in blood pressure
and sympathetic outflow in humans,6,9–13 as well as in animal models
of exercise training.9,14–18 Because morbidity and mortality in cardiovascular disease are often associated with elevations in SNS
activity,19,20 the beneficial effects of physical activity are likely related,
in part, to reductions in sympathetic activity.6,13 Understanding the
mechanisms by which exercise training alters control of the SNS in
health and disease is important for developing new strategies in the
prevention and treatment of cardiovascular disease. In addition, a
further understanding of these mechanisms may help promote public
policy changes that aid in the reversal of the current trends in
physical inactivity.
378
PJ Mueller
EFFECTS OF PHYSICAL ACTIVITY (EXERCISE
TRAINING) ON SNS ACTIVITY
Human studies
One of the difficulties in establishing a conclusive effect of physical
activity on SNS activity in humans is likely due to the variety of
studies that have attempted to address this seemingly straightforward
question. As reviewed by Ray and Hume21 and examined more
recently in a meta-analysis by Cornelissen and Fagard,6 it is clear
that individual studies report a variety of effects of exercise training
on measures of SNS activity. Exercise training may also influence
increases in SNS activity during exercise and in response to other
stressors that cause sympathoexcitation, including baroreceptor
unloading.21 Furthermore, the type of measurement used to assess
SNS activity may influence conclusions on the effects of physical
activity in SNS regulation. For example, most studies have used one
or more of three basic techniques to assess resting SNS activity:
plasma noradrenaline (NA) levels, regional NA spillover or direct
microneurographic recordings from nerves innervating skeletal muscle
(i.e. muscle sympathetic nerve activity; MSNA). Ray and Hume21
concluded that training has no effect on resting MSNA, whereas Cornelissen and Fagard6 suggest that training reduces plasma NA levels
by up to 40%. These data suggest that training may alter NA kinetics
or that there may be regionally specific effects of training on SNS
activity. The latter hypothesis is supported by at least one study in
which training elicited a reduction in renal NA spillover with no
change in cardiac NA spillover.10
The significant effects of exercise training on SNS activity may
also be influenced by additional factors. These include intersubject
variability (for examples, see Jennings et al.22 and Grassi et al.23),
age and gender,24 previous and attained fitness levels21,25 and different degrees of adiposity in trained and sedentary subjects.26 Finally,
other factors, including the type of training programme, the duration,
intensity and frequency of individual bouts and the overall duration
of the training programme are all likely to be important factors that
warrant further investigation.6,21
Animal studies
In contrast with somewhat equivocal results in humans, evidence from
animal studies suggests that increases in physical activity produce
consistent reductions in resting and reflex control of sympathetic
outflow in normal animals.16 For example, studies of exercise training in rats15,27 and rabbits28,29 indicate a suppression of resting and
baroreflex-mediated increases in renal sympathetic nerve activity
(RSNA). In addition to a reduction in RSNA, previous studies have
also reported blunted baroreflex activation of lumbar sympathetic
nerve activity in spontaneous wheel-running rats.30 Finally, there is
indirect evidence that treadmill training in rats16,31 and mice14 reduces
cardiac sympathetic nerve activity. Therefore, data from well-controlled
animal studies appear to indicate a more global effect of exercise
training on SNS activity.
EFFECT OF PHYSICAL ACTIVITY VERSUS
PHYSICAL INACTIVITY
Perhaps a subtle but important viewpoint that deserves mentioning
is that most studies have had the perspective of examining the effects
of ‘exercise training’ on cardiovascular variables. This is completely
logical because epidemiological studies suggest that physical fitness
is beneficial to cardiovascular health.32,33 That said, it is becoming
increasingly apparent that a sedentary lifestyle contributes significantly to chronic disease.34 Therefore, if one identifies the trained
group as the control or ‘healthy’ group, as has been suggested previously,3 importantly different and significant conclusions can be
reached.3 For example, the above-mentioned animal studies suggest
that exercise training blunts baroreflex-mediated sympathoexcitation. However, if the trained group is considered the control group,
then one could then conclude that sympathoexcitation is actually
exacerbated by sedentary conditions. Given the relationship between
excess SNS activity and cardiovascular disease and mortality,19,20 it
is easy to see how a sedentary lifestyle may be a risk factor for cardiovascular disease due, at least in part, to alterations in SNS activity.
That is, physical activity dependent alterations in sympathetic control
of the cardiovascular system occurring in otherwise normal ‘healthy’
individuals may be important in reducing the incidence of cardiovascular disease.
ACTIVITY DEPENDENT PLASTICITY IN THE
CENTRAL NERVOUS SYSTEM
Increasing scientific evidence is emerging that supports the existence
of physical activity dependent plasticity in the central nervous system (CNS). Of particular interest are functional improvements, such
as those reported for memory and cognition,35–39 that are associated
with changes in the number, structure and function of neurons.35,40
Recent studies indicate that physical activity produces these changes
by altering genes involved in synaptic plasticity.41–43 These improvements are associated with factors that are produced within the brain
or outside the brain, including, among others, brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)-I.41,44
Although these studies provide strong support that physical activity
beneficially alters cognitive function through alterations in plasticity
related genes, it is not known whether exercise produces similar
changes in gene expression in regions of the brain that control SNS
activity. Evidence discussed below supports the possibility that
neurons involved in the control of the SNS also undergo neural plasticity
following periods of activity or inactivity.
‘PHYSICAL’ ACTIVITY DEPENDENT
PLASTICITY IN NEURAL CONTROL OF THE
CIRCULATION
Many studies have now suggested that alterations within the CNS
are important in the effects of physical (in)activity on SNS function
under both normal and diseased states.8,17,45–52 For example, in spontaneously hypertensive rats (SHR), exercise training reduces the elevated firing rate of caudal hypothalamic neurons.53 These changes
are associated with blood pressure reductions and a restoration of
GABAergic transmission in this brain region of the SHR.54 Exercise
training also affects measures of nitric oxide synthase (NOS) activity
in the paraventricular nucleus (PVN) of SHR50 and in rats with heart
failure.8,51 Changes in NOS within the PVN have been suggested to
contribute to training-induced reductions in sympathetic outflow in
heart failure animals.8,51 It is important to note that the specific examples mentioned above pertain to the effects of exercise training in
animal models of cardiovascular disease and, thus, have important
clinical relevance in the treatment of cardiovascular disease with
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd
Exercise training and the SNS
exercise therapies. However, as mentioned, it is now recognized that
a sedentary lifestyle has a significant impact on chronic diseases,
including cardiovascular disease.2,3 Thus, it is becoming increasingly
relevant to compare physical activity with sedentary conditions and
to determine the mechanisms by which a sedentary lifestyle alone
may contribute to the incidence of cardiovascular disease. It is quite
possible that physical activity induced neuroplasticity within central
cardiovascular networks contributes to long-term cardiovascular
health. In particular, several laboratories,45,46,55–58 including our own,49,59
have begun to examine alterations within the CNS that occur in
response to physical activity in otherwise normal healthy animals.
Some of the earliest evidence for CNS-mediated alterations following increases in physical activity in otherwise healthy animals
is based on the elegant work of DiCarlo et al.29,47,48 Although earlier
work had provided indirect evidence that training influenced autonomic control of the vasculature,60,60–63 DiCarlo and Bishop were the
first to demonstrate directly that exercise training blunted baroreflexmediated sympathoexcitation by recording direct efferent outflow
from renal nerves in conscious treadmill-trained rabbits.29 The
important subsequent studies by this group reported no influence of
exercise training on arterial baroreceptor47 or cardiopulmonary
afferent sensitivity,48 despite producing blunted baroreflex-mediated
sympathoexcitation.28–30 Thus, along with others,15 DiCarlo et al.
suggested that centrally mediated alterations were important in the
reflex control of the SNS following exercise training.47,48 More recent
studies have supported these hypotheses by demonstrating changes
in neuronal structure46 and intrinsic firing properties45 of neurons
from physically active versus sedentary animals.
As suggested, these studies can be viewed as beneficial changes
induced by exercise training in normal subjects or, conversely, as deleterious alterations induced in individuals that remain sedentary. The
remainder of the present review will focus on physical (in)activity
induced alterations in the CNS control of SNS activity. Our general
hypothesis is that exercise training (vs sedentary conditions) results
in differential alterations in the primary central pathways by which
SNS activity is regulated. We speculate that these changes ultimately
influence cardiovascular health and well-being due to the direct and
indirect influences of the SNS on the cardiovascular system and other
organ systems that impact the incidence of cardiovascular disease.
REVIEW OF RECENT WORK
Owing to the consistent effects of physical activity on baroreflex
control of SNS activity in animals, our initial experiments started
by examining the basic reflex pathways by which SNS activity is
regulated within the brain stem (Fig. 1). Cardiovascular afferents,
including those from arterial and cardiopulmonary baroreceptors,
terminate at the level of the nucleus tractus solitarius (NTS).64 The
NTS is an important brain region involved in both resting and reflex
control of arterial pressure and SNS activity.65–67 Neurons within the
NTS provide a tonic inhibitory influence on SNS activity (primarily
via arterial baroreceptors), as evidenced by large increases in arterial
pressure and sympathetic outflow produced by inhibition of the
NTS.68–71 We hypothesized that the NTS may be overactive in
exercise-trained animals and, thus, contribute to reduced sympathoexcitation in the trained state. To test this hypothesis, we inhibited the
NTS with bilateral microinjections of the neuroinhibitory compound
muscimol in groups of treadmill-trained and sedentary animals.49 We
expected that if the NTS was overactive in exercise-trained rats, it
379
Fig. 1 Basic pathways by which sympathetic nervous system (SNS)
activity is regulated by nuclei within the brain stem. NTS, nucleus tractus
solitarius; CVLM, caudal ventrolateral medulla; RVLM, rostral ventrolateral
medulla; EAA, excitatory amino acids.
would contribute to greater sympathoinhibition under basal conditions.
Therefore, inhibition of neurons in the NTS with muscimol would
produce a greater sympathoexcitatory response in trained animals.
However, as shown in Fig. 2, we observed blunted pressor and
sympathoexcitatory responses to NTS inhibition in trained animals.
These data are similar to the blunted baroreflex-mediated sympathoexcitation in most animal models of exercise training15,28–30 and
suggested to us that that the NTS was not required for expression
of blunted sympathoexcitation following exercise training. In
addition, a lack of a role for exercise training-induced changes on
sympathetic control at the level of the NTS was also supported by
additional experiments in which the NTS was activated by glutamate
microinjections. Under these conditions, sympathoinhibitory responses
to generalized activation of the NTS were not altered by treadmill
training.49 Collectively, these data suggested that alterations downstream from the NTS were responsible for blunted sympathoexcitation observed after exercise training. Our subsequent studies have
focused on alterations that may occur at the level of the rostral ventrolateral medulla (RVLM), a brain region critical in the generation
of SNS activity.72–74
Rostral ventrolateral medulla neurons project directly to sympathetic preganglionic neurons and inhibition of the RVLM produces
blood pressures similar to those observed after complete transection
of the spinal cord.72–74 These ‘presympathetic’ RVLM neurons are
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd
380
PJ Mueller
believed to be inhibited tonically by GABA, predominantly via GABAA
receptors. As demonstrated in Fig. 1, this GABAergic inhibition is
generally thought to be mediated by both arterial baroreceptor-dependent
and -independent mechanisms.72,74 We hypothesized that during
Fig. 2 Sympathetic nervous system response to nucleus tractus solitarius
(NTS) inhibition. (a) Mean arterial pressure (MAP) and (b) lumbar
sympathetic nerve activity (LSNA) responses to inhibition of the NTS with
bilateral microinjections of muscimol (1 mmol / L, 90 nL or 90 pmol per side).
Muscimol produced increases in MAP and LSNA in sedentary (Sed; n = 8)
rats that were significantly blunted in exercise-trained (ExTr; n = 9) rats.
*P < 0.05 compared with Sed rats. Data are modified from Mueller et al.49
baroreceptor unloading a greater remaining level of GABAergic inhibition of RVLM neurons could be responsible for blunted baroreflexmediated sympathoexcitation in trained animals. If so, we would
predict that sympathoexcitatory responses to blockade of GABAA
receptors in the RVLM of exercise-trained rats would be enhanced.
However, as shown in Fig. 3a, bilateral blockade of GABAA receptors with bicuculline resulted in attenuated sympathoexcitatory
responses in trained rats.59 These data suggest that exercise training
reduces the sympathoexcitation that occurs via withdrawal of
GABAergic transmission, whether it was produced by baroreceptor
unloading15,28–30 or by blockade of GABAA receptors in the RVLM.59
These data also suggest that GABAA-ergic inhibition of the RVLM
was not augmented by exercise training; otherwise, we would have
expected to see a greater response to GABA blockade in trained
animals. Therefore, we hypothesized that perhaps a reduced
activation of RVLM neurons was occurring and was responsible for
diminished sympathoexcitatory responses.
To test whether responses to generalized excitation of the RVLM
were reduced by training, we activated the RVLM with microinjections of glutamate (1, 3 and 10 mmol/L) in sedentary and treadmilltrained rats.59 Consistent with our hypothesis of blunted excitation,
glutamate produced sympathoexcitation that was significantly
attenuated in exercise-trained compared with sedentary rats (Fig. 3b).
A reduced responsiveness of the RVLM to excitatory amino acids
following exercise training is supported by a recent report demonstrating reduced pressor responses to glutamate in the RVLM of
swim-trained rats.56 Collectively, these data are consistent with the
concept that, following various forms of exercise training in rats,
the RVLM is less sensitive to generalized activation with excitatory
amino acids.
Because we assessed sympathoexcitatory output from the RVLM
by recording lumbar sympathetic nerve activity, it is possible that
blunted sympathoexcitation observed in exercise-trained rats could
be occurring at the level of the spinal cord, the sympathetic ganglia or
both. To address this question, we used Fos immunohistochemistry
to examine activation of RVLM neurons in conscious sedentary and
treadmill-trained rats. Fos is the protein product of the immediate
early gene c-fos and is produced in response to neuronal activation.75,76 Fos expression has been used as a marker to identify neural
pathways involved in control of SNS activity.77 In preliminary studies,78
we produced similar levels of hypotension (< 70 mmHg) in conscious
sedentary and trained rats in order to unload arterial baroreceptors
Fig. 3 Sympathetic nervous system
response to disinhibition or excitation
of the rostral ventrolateral medulla
(RVLM). (a) Lumbar sympathetic
nerve activity (LSNA) responses to
blockade of GABAA receptors in the
RVLM with bilateral microinjections
of bicuculline (90 nL, 5 mmol/L or
450 pmol per side). Bicuculline
produced increases in LSNA in
sedentary (Sed; n = 15) rats that were
blunted in exercise-trained (ExTr;
n = 12) rats. (b) Lumbar sympathetic
nerve activity responses to activation
of the RVLM with unilateral microinjections of glutamate (30 nL, 10 mmol/L or 300 pmol). Glutamate produced increases in LSNA in Sed rats (n = 8) that
were significantly attenuated in ExTr rats (n = 6). *P < 0.05 compared with Sed rats. Data modified from Mueller et al.59
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd
Exercise training and the SNS
381
of baseline sympathetic nerve activity, the present results in trained
rats would be consistent with previous studies in humans and
animals that have concluded that exercise training reduces resting
sympathetic outflow.6,10,15,27
CROSS-STRESSOR ADAPTATION HYPOTHESIS
Fig. 4 Fos in the rostral ventrolateral medulla (RVLM), showing the
number of Fos-positive nuclei in the RVLM under (a) control conditions or
(b) in response to hypotensive conditions in conscious sedentary (Sed; n = 3)
rats and exercise-trained (ExTr; n = 4) rats. The ExTr rats exhibited
significantly fewer Fos-positive neurons under control conditions and in
response to hypotension (†P < 0.05 effect of training; *P < 0.05 effect of
hypotension).
and activate neurons within the RVLM, similar to previous studies.79–81 Figure 4 demonstrates the number of Fos-positive neurons
in the RVLM of sedentary and trained rats under control and hypotensive conditions. Hypotension produced an increase in the number
of Fos-positive neurons in the RVLM of both groups compared with
control conditions. However, the number of hypotension-induced Fospositive cells was significantly attenuated in exercise-trained animals
compared with sedentary animals. These data suggest that the
RVLM was less activated in trained animals despite similar hypotensive stimuli. The afferent input to the brain was also likely similar
in both groups because previous studies have reported no change in
baroreceptor afferent sensitivity in rats that trained spontaneously
on running wheels.47 These data further support our hypothesis that
exercise training is associated with centrally mediated reductions in
sympathoexcitation via reduced activation of the RVLM. Whether
this reduced activation occurs because of changes in input to the
RVLM, alterations in RVLM neurons themselves or both has yet to
be determined. A recent report by Nelson et al.46 suggests that
neurons in the region of the RVLM that are activated by exercise do not
undergo alterations in dendritic branching in response to chronic
wheel running. Therefore, future studies are necessary to determine
whether differential input to RVLM neurons or more subtle changes
in RVLM neuronal structure or function contribute to alterations in
SNS activity following periods of physical activity versus inactivity.
Exercise-trained rats also had significantly less Fos-positive nuclei
in the RVLM under control conditions compared with sedentary
animals (Fig. 4). Although differences in Fos expression under resting
conditions are somewhat controversial, these data could suggest that
activation of neurons in the RVLM under resting conditions may also
be reduced by exercise training. A similar but opposite argument has
been made for increases in baseline SNS activity in various models
hypertension, where increased Fos in the RVLM appears to be indicative of sympathetic overactivity in animal models of hypertension.82
If Fos expression in the RVLM under resting conditions is a reflection
In addition to the mechanisms by which physical activity influences
the SNS, we are also interested in the conditions and the extent to
which physical activity affects sympathoexcitation. In particular,
from data already presented, it is fairly well established that increases
in physical activity reduce sympathoexcitation in response to baroreceptor unloading in most animal15,28–30 and some human26 studies.
Increases in physical activity could produce a beneficial, chronic
reduction in SNS activity simply by reducing the amount of sympathoexcitation that occurs in response to conditions that produce
baroreceptor unloading. Alternatively, exercise may produce a generalized reduction in the response to a variety of stimuli and blunted
baroreflex-mediated sympathoexcitation is merely an example of
this generalized reduction. This hypothesis is by no means novel and has
been termed previously, in a broader context, as the Cross-Stressor
Adaptation Hypothesis.83 The theory suggests that exercise training, as a stressor on the body, may alter responsiveness to other types
of stressors.83 There is support for this theory with specific regard
to SNS-mediated responses. For example, pressor responses to
different forms of stress are blunted in trained humans21,84 and
animals.85,86 In addition, reduced activation of the RVLM has also
been shown in response to stress in rats that exercised spontaneously
on running wheels.57 Finally, the data presented from our laboratory
and others suggest that training reduces cardiovascular responses to
generalized activation of the RVLM with microinjections of excitatory agents.56,58,59
To further explore the possibility that increases in physical activity
may produce a generalized reduction in sympathoexcitation, we have
started to examine differences in the responsiveness of trained and
sedentary animals to other stimuli that produce sympathoexcitation.
Although muscle contraction has been used as a means to activate
RVLM neurons,87 we wanted to circumvent potential changes in
skeletal muscle produced by exercise training that would influence
our interpretation of centrally mediated changes in SNS regulation.
Direct electrical stimulation of the sciatic nerve produces a sympathoexcitatory reflex known as the somatosympathetic reflex.88–90
For the purposes of our study, this reflex was particularly applicable
because it has been shown to not only activate neurons within the
RVLM,88 but also require the RVLM for full expression of the
cardiovascular response.89,90 Furthermore, this reflex uses excitatory
amino acid receptors (i.e. glutamate) at the level of the RVLM to
produce increases in arterial pressure.90 Because our treadmill-trained
rats have blunted sympathoexcitatory responses to glutamate microinjections in the RVLM (Fig. 3b), we hypothesized that activation
of the somatosympathetic reflex would produce blunted sympathoexcitation in trained animals. We tested this hypothesis by stimulation of the central cut end of the sciatic nerve similar to that
performed previously.88–90 Our preliminary results,91 shown in Fig. 5a,
demonstrate that sciatic nerve stimulation produces increases in
sympathetic nerve activity and blood pressure in anaesthetized rats.
Furthermore, Fig. 5b represents preliminary data91 that indicate that
treadmill training blunts sympathoexcitation produced by activation
of the somatosympathetic reflex. It is possible that the blunting of
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd
382
PJ Mueller
Fig. 5 Somatosympathetic
reflex
activation. (a) Raw record from one
sedentary (Sed) animal in which the
sciatic nerve was stimulated at varying
intensities (100, 250 and 1000 mA; all
1 msec, 15 Hz, approximately 10 s) to
elicit the somatopressor reflex. Sciatic
nerve stimulation produced intensity
dependent increases in arterial pressure
(AP) and lumbar sympathetic nerve
activity (LSNA). (b) Lumbar
sympathetic nerve activity (LSNA)
responses to activation of the somatosympathetic reflex in Sed (n = 2; )
and exercise-trained (n = 2; ) rats.
Sciatic nerve stimulation produced
intensity dependent increases in
LSNA that appeared to be blunted by
exercise training. RMS, root mean
squared (i.e. integrated and rectified
LSNA). The bar indicates the period
of sciatic nerve stimulation.
this reflex involves excitatory amino acid mechanisms at the level
of the RVLM; however, additional studies are required to test this
hypothesis. Nonetheless, our data and the work of others suggest that
exercise training appears to reduce sympathoexcitation to a variety
of centrally mediated sympathoexcitatory stimuli. If so, a reduction
in sympathoexcitation may contribute, in part, to the reduced
incidence of cardiovascular disease in physically active individuals.
Conversely, sedentary conditions may produce relatively heightened
sympathoexcitatory responses that, over time, could contribute to
cardiovascular disease.
CONCLUSIONS
Sympathetic overactivity is common in many cardiovascular disease
states and is related to a higher incidence of morbidity and mortality.
Reductions in sympathetic outflow, whether at rest or during conditions
that produced sympathoexcitation, may occur following exercise
training. Alterations in cardiovascular regions of the brain stem and
other regions that are influenced by levels of physical activity are
likely to play a role in long-term cardiovascular health. Future studies will be important in further identifying the central mechanisms
that are involved in physical activity dependent changes in the
control of SNS activity.
ACKNOWLEDGEMENTS
The author thanks Sean Stoneking, Kris Paggett and Sarah Friskey
for excellent technical assistance and a number of undergraduate
students, namely Amy Stuck, Brandon Benefield, Michele Watson
and Kayla Terry, for their assistance with this project. The author
acknowledges Dr Eileen Hasser and the Neurohumoral Control of
the Circulation group at the University of Missouri-Columbia for
valuable input on these projects. The author also appreciates Dr
Hasser’s and Dr Paul Fadel’s helpful comments on this manuscript.
Finally, a special thanks to Pam Thorne from Dr Harold Laughlin’s
laboratory for her assistance with the training of our animals. The
author’s research reported herein was supported by grants from the
Heartland Affiliate of the American Heart Association: Beginning
Grant in Aid (no. 0265264Z) and Grant in Aid (no. 0650161Z) and
by the National Institutes of Health: HL-55306 (EMH and PJM).
The author’s research reported herein was conducted in a facility
constructed with support from Research Facilities Improvement
Program Grant Number C06 RR-16498 from the National Center
for Research Resources, National Institutes of Health.
REFERENCES
1. Thom T, Haase N, Rosamond W et al. American heart association
statistics committee and stroke statistics subcommittee. Heart disease
and stroke statistics, 2006 update: A report from the American heart
association statistics committee and stroke statistics subcommittee.
Circulation 2006; 113: E85–151.
2. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of
death in the United States, 2000. JAMA 2004; 291: 1238–45.
3. Lees SJ, Booth FW. Sedentary death syndrome. Can. J. Appl. Physiol.
2004; 29: 447–60.
4. Julius S, Nesbitt S. Sympathetic overactivity in hypertension. A moving
target. Am. J. Hypertens. 1996; 9: 113S–20S.
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd
Exercise training and the SNS
5. Schlaich MP, Lambert E, Kaye D et al. Sympathetic augmentation in
hypertension. Role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. Hypertension 2004; 43: 169 –75.
6. Cornelissen VA, Fagard RH. Effects of endurance training on blood
pressure, blood pressure-regulating mechanisms, and cardiovascular
risk factors. Hypertension 2005; 45: 667–75.
7. Billman GE. Aerobic exercise conditioning: A nonpharmacological
antiarrhythmic intervention. J. Appl. Physiol. 2002; 92: 446–54.
8. Zucker IH, Patel KP, Schultz HD, Li Y-F, Wang W, Pliquett RU.
Exercise training and sympathetic regulation in experimental heart
failure. Exerc. Sport Sci. Rev. 2004; 32: 107–11.
9. Tipton CM. Exercise, training, and hypertension: An update. Exerc.
Sport Sci. Rev. 1991; 19: 447–505.
10. Meredith IT, Friberg P, Jennings GL et al. Exercise training lowers resting renal but not cardiac sympathetic activity in humans. Hypertension
1991; 18: 575–82.
11. Iwasaki K-I, Zhang R, Zuckerman JH, Levine BD. Dose-response
relationship of the cardiovascular adaptation to endurance training in
healthy adults: How much training for what benefit? J. Appl. Physiol.
2003; 95: 1575–83.
12. Pescatello LS, Franklin BA, Fagard R, Farquhar WB, Kelley GA, Ray
CA. American college of sports medicine position stand. Exercise and
hypertension. Med. Sci. Sports Exerc. 2004; 36: 533 –53.
13. Roveda F, Middlekauff HR, Rondon MU et al. The effects of exercise
training on sympathetic neural activation in advanced heart failure: A
randomized controlled trial. J. Am. Coll. Cardiol. 2003; 42: 854–60.
14. De Angelis K, Wichi RB, Jesus WRA et al. Exercise training changes
autonomic cardiovascular balance in mice. J. Appl. Physiol. 2004; 96:
2174–8.
15. Negrao C-E, Irigoyen MC, Moreira ED, Brum P-C, Freire PM, Krieger
E-M. Effect of exercise training on RSNA, baroreflex control, and
blood pressure responsiveness. Am. J. Physiol. 1993; 265: R365–70.
16. Krieger EM, Da Silva GJJ, Negrao CE. Effects of exercise training on
baroreflex control of the cardiovascular system. Ann. N.Y. Acad. Sci.
2001; 940: 338–47.
17. Kramer JM, Beatty JA, Plowey ED, Waldrop TG. Exercise and hypertension: A model for central neural plasticity. Clin. Exp. Pharmacol.
Physiol. 2002; 29: 122– 6.
18. Collins HL, Rodenbaugh DW, DiCarlo SE. Daily exercise attenuates
the development of arterial blood pressure related cardiovascular
risk factors in hypertensive rats. Clin. Exp. Hypertens. 2000; 22:
193–202.
19. Benedict CR, Shelton B, Johnstone DE et al. Prognostic significance
of plasma norepinephrine in patients with asymptomatic left ventricular
dysfunction. SOLVD Investigators. Circulation 1996; 94: 690–7.
20. Zoccali C, Mallamaci F, Parlongo S et al. Plasma norepinephrine
predicts survival and incident cardiovascular event in patients with
end-stage renal disease. Circulation 2002; 105: 1354 – 9.
21. Ray CA, Hume KM. Sympathetic neural adaptation to exercise training
in humans: Insights from microneurography. Med. Sci. Sports Exerc.
1998; 30: 387–91.
22. Jennings G, Nelson L, Nestel P et al. The effects of changes in physical
activity on major cardiovascular risk factors, hemodynamics, sympathetic function, and glucose utilization in man: A controlled study of
four levels of activity. Circulation 1986; 73: 30 – 40.
23. Grassi G, Seravalle G, Calhoun DA, Mancia G. Physical training and
baroreceptor control of sympathetic nerve activity in humans.
Hypertension 1994; 23: 294 –301.
24. Ng AV, Callister R, Johnson DG, Seals DR. Endurance exercise training is associated with elevated basal sympathetic nerve activity in
healthy older humans. J. Appl. Physiol. 1994; 77: 1366 –74.
25. Fadel PJ, Stromstad M, Hansen J et al. Arterial baroreflex control of
sympathetic nerve activity during acute hypotension: Effect of fitness.
Am. J. Physiol. Heart Circ. Physiol. 2001; 280: H2524 –32.
26. Alvarez GE, Halliwill JR, Ballard TP, Beske SD, Davy KP. Sympathetic
neural regulation in endurance-trained humans: Fitness vs. fatness. J.
Appl. Physiol. 2005; 98: 498 –502.
27. Krieger EM, Brum PC, Negrao CE. Influence of exercise training on
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
383
neurogenic control of blood pressure in spontaneously hypertensive
rats. Hypertension 1999; 34: 720–3.
DiCarlo SE, Bishop VS. Exercise training enhances cardiac afferent
inhibition of baroreflex function. Am. J. Physiol. 1990; 258: H212–20.
DiCarlo SE, Bishop VS. Exercise training attenuates baroreflex regulation of nerve activity in rabbits. Am. J. Physiol. 1988; 255: H974 – 9.
Chen CY, DiCarlo SE. Daily exercise and gender influence arterial
baroreflex regulation of heart rate and nerve activity. Am. J. Physiol.
1996; 271: H1840–8.
Negrao CE, Moreira ED, Brum PC, Denadai MLDR, Krieger EM.
Vagal and sympathetic control of heart rate during exercise by sedentary
and exercise-trained rats. Braz. J. Med. Biol. Res. 1992; 25: 1045 –52.
Blair ML, Goodyear NN, Gibbons LW, Cooper KH. Physical fitness
and incidence of hypertension in healthy normotensive men and women.
JAMA 1984; 252: 487–90.
Blair SN, Franklin BA, Jakicic JM, Kibler WB. New vision for health
promotion within sports medicine. Am. J. Health Promot. 2003; 18:
182–5.
Booth FW, Chakravarthy MV, Gordon SE, Spangenburg EE. Waging
war on physical inactivity: Using modern molecular ammunition
against an ancient enemy. J. Appl. Physiol. 2002; 93: 3–30.
Ang ET, Dawe GS, Wong PT, Moochhala S, Ng YK. Alterations in
spatial learning and memory after forced exercise. Brain Res. 2006;
1113: 186–93.
Fordyce DE, Farrar RP. Physical effects on hippocampal and parietal
cortical cholinergic function and spatial learning in F344 rats. Behav.
Brain Res. 1991; 43: 115–23.
Fordyce DE, Farrar RP. Enhancement of spatial learning in F344 rats
by physical activity and related learning-associated alterations in
hippocampal and cortical cholinergic functioning. Behav. Brain Res.
1991; 46: 123–33.
Samorajski T, Delaney C, Durham L, Ordy JM, Johnson JA, Dunlap WP.
Effect of exercise on longevity, body weight, locomotor performance,
and passive-avoidance memory of C57BL/6J mice. Neurobiol. Aging
1985; 6: 17–24.
Anderson BJ, Rapp DN, Baek DH, McCloskey DP, Coburn-Litvak PS,
Robinson JK. Exercise influences spatial learning in the radial arm
maze. Physiol. Behav. 2000; 70: 425–9.
Van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances
neurogenesis, learning, and long-term potentiation in mice. Proc. Natl
Acad. Sci. USA 1999; 96: 13 427–31.
Farmer J, Zhao X, Van Praag H, Wodtke K, Gage FH, Christie BR.
Effects of voluntary exercise on synaptic plasticity and gene expression
in the dentate gyrus of adult male Sprague-Dawley rats in vivo.
Neuroscience 2004; 124: 71–9.
Cotman CW, Engesser-Cesar C. Exercise enhances and protects brain
function. Exerc. Sport Sci. Rev. 2002; 30: 75–9.
Dishman RK, Berthoud H-R, Booth FW et al. Neuobiology of exercise.
Obesity 2006; 14: 345–56.
Carro E, Nunez A, Busiguina S, Torres-Aleman I. Circulating insulin-like
growth factor I mediates effects of exercise on the brain. J. Neurosci.
2000; 20: 2926–33.
Jackson K, Vieira Silva HM, Zhang W, Michelini LC, Stern JE. Exercise training differentially affects intrinsic excitability of autonomic and
neuroendocrine neurons in the hypothalamic paraventricular nucleus.
J. Neurophysiol. 2005: 3211–20.
Nelson AJ, Juraska JM, Musch TI, Iwamoto GA. Neuroplastic
adaptations to exercise: Neuronal remodeling in cardiorespiratory and
locomotor areas. J. Appl. Physiol. 2005; 99: 2312–22.
Chen CY, DiCarlo SE, Scislo TJ. Daily spontaneous running attenuated
the central gain of the arterial baroreflex. Am. J. Physiol. Heart Circ.
Physiol. 1995; 268: H662–9.
Scislo TJ, DiCarlo SE, Collins HL. Daily spontaneous running did not
alter vagal afferent reactivity. Am. J. Physiol. Heart Circ. Physiol. 1993;
265: H1564–70.
Mueller PJ, Hasser EM. Putative role of the NTS in alterations in neural
control of the circulation following exercise training in rats. Am. J.
Physiol. Regul. Integr. Comp. Physiol. 2006; 290: R383–92.
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd
384
PJ Mueller
50. DiCarlo SE, Zheng H, Collins HL, Rodenbaugh DW, Patel KP. Daily
exercise normalizes the number of diaphorase (NOS) positive neurons
in the hypothalamus of hypertensive rats. Brain Res. 2002; 955:
153–60.
51. Zheng H, Li YF, Cornish KG, Zucker IH, Patel KP. Exercise training
improves endogenous nitric oxide mechanisms within the paraventricular
nucleus in rats with heart failure. Am. J. Physiol. Heart Circ. Physiol.
2005; 288: H2332– 41.
52. Mueller PJ, Cunningham JT, Patel KP, Hasser EM. Proposed role of
the paraventricular nucleus in cardiovascular deconditioning. Acta
Physiol. Scand. 2003; 177: 27–35.
53. Beatty JA, Kramer JM, Plowey ED, Waldrop TG. Physical exercise
decreases neuronal activity in the posterior hypothalamic area
of spontaneously hypertensive rats. J. Appl. Physiol. 2005; 98:
572–8.
54. Kramer JM, Beatty JA, Little HR, Plowey ED, Waldrop TG. Chronic
exercise alters caudal hypothalamic regulation of the cardiovascular
system in hypertensive rats. Am. J. Physiol. Regul. Integr. Comp. Physiol.
2001; 280: R389–97.
55. De Souza CG, Michelini LC, Fior-Chadi DR. Receptor changes in the
nucleus tractus solitarii of the rat after exercise training. Med. Sci.
Sports Exerc. 2001; 33: 1471– 6.
56. Martins-Pinge MC, Becker LK, Garcia MR et al. Attenuated
pressor responses to amino acids in the rostral ventrolateral medulla
after swimming training in conscious rats. Auton. Neurosci. 2005;
122: 21–8.
57. Greenwood BN, Kennedy S, Smith TP, Campeau S, Day HEW,
Fleshner M. Voluntary free wheel running selectively modulates
catecholamine content in peripheral tissue and c-fos expression in the
central sympathetic circuit following exposure to uncontrollable stress
in rats. Neuroscience 2003; 120: 269 – 81.
58. Becker LK, Santos RAS, Campagnole-Santos MJ. Cardiovascular
effects of angiotensin II and angiotensin-(1–7) at the RVLM of trained
normotensive rats. Brain Res. 2005; 1040: 121– 8.
59. Mueller PJ. Exercise training attenuates increases in lumbar sympathetic nerve activity produced by stimulation of the rostral ventrolateral
medulla. J. Appl. Physiol. 2007 (in press).
60. Bedford TG, Tipton CM. Exercise training and the arterial baroreflex.
J. Appl. Physiol. 1987; 63: 1926 –32.
61. Tipton CM, Matthes RD, Bedford TG. Influence of training on the
blood pressure changes during lower negative pressure in rats. Med.
Sci. Sports Exerc. 1982; 14: 81–90.
62. Paynter DE, Tipton CM, Tcheng TK. Responses of immunosympathectomized rats to training. J. Appl. Physiol. 1977; 42: 935 – 40.
63. Raven PB, Pawelczyk JA. Chronic endurance exercise training: A condition of inadequate blood pressure regulation and reduced tolerance
to LBNP. Med. Sci. Sports Exerc. 1993; 25: 713 –21.
64. Ciriello J, Hochstenbach SL, Roder S. Central projections of baroreceptor and chemoreceptor afferent fibers in the rat. In: Barraco IRA
(ed.). The Nucleus of the Solitary Tract. CRC Press, Boca Raton. 1994;
35–50.
65. Andresen MC, Kunze DL. Nucleus tractus solitarius: Gateway to neural
circulatory control. Annu. Rev. Physiol. 1994; 56: 93 –116.
66. Sved AF, Gordon FJ. Amino acids as central neurotransmitters in the
baroreceptor reflex pathway. News Physiol. Sci. 1994; 9: 243–5.
67. Sapru HN. Neurotransmitters in the nucleus tractus solitarius mediating
cardiovascular function. In: Dun NJ, Machado BH, Pilowsky PM (eds).
Neural Mechanisms of Cardiovascular Regulation. Kluwer Academic
Publishers, Norwell, MA. 2004; 81– 98.
68. Doba N, Reis DJ. Acute fulminating neurogenic hypertension produced
by brainstem lesions in the rat. Circ. Res. 1973; 32: 584 – 93.
69. Talman WT, Perrone MH, Reis DJ. Acute hypertension after the local
injection of kainic acid into the nucleus tractus solitarii of rats. Circ.
Res. 1981; 48: 292–8.
70. Sved AF, Imaizumi T, Talman WT, Reis DJ. Vasopressin contributes
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
to hypertension caused by nucleus tractus solitarius lesions. Hypertension 1985; 7: 262–7.
Schreihofer AM, Sved AF. Nucleus tractus solitarius and control of
blood pressure in chronic sinoaortic denervated rats. Am. J. Physiol.
1992; 263: R258–66.
Guyenet PG, Stornetta RL. The presympathetic cells of the rostral
ventrolateral medulla (RVLM). Anatomy, physiology and role in the
control of circulation. In: Dun NJ, Machado BH, Pilowsky PM (eds).
Neural Mechanisms of Cardiovascular Regulation. Kluwer Academic
Publishers, Norwell, MA. 2004; 187–218.
Sved AF, Ito S, Sved JC. Brainstem mechanisms of hypertension: Role of
the rostral ventrolateral medulla. Curr. Hypertens. Rep. 2003; 5: 262– 8.
Dampney RAL. Functional organization of central pathways regulating
the cardiovascular system. Physiol. Rev. 1994; 74: 323–64.
Morgan JI, Cohen DR, Hempstead JL, Curran T. Mapping patterns of
c-fos expression in the central nervous system after seizure. Science
1987; 237: 192–7.
Dragunow M, Faull R. The use of c-fos as a metabolic marker in
neuronal pathway tracing. J. Neurosci. Methods 1989; 29: 261–5.
Dampney RAL, Polson JW, Potts PD, Hirooka Y, Horiuchi J.
Functional organization of brain pathways subserving the baroreceptor
reflex: Studies in conscious animals using immediate early gene expression. Cell. Mol. Neurobiol. 2003; 23: 597–616.
Mueller PJ, Watson MA, Cunningham JT, Hasser EM. Hypotensioninduced fos expression in rostral ventrolateral medulla of exercise
trained rats. Med. Sci. Sports Exerc. 2005; 37: S153–4 (Abstract).
Potts PD, Polson JW, Hirooka Y, Dampney RAL. Effects of sinoaortic
denervation on fos expression in the brain evoked by hypertension and
hypotension in conscious rabbits. Neuroscience 1997; 77: 503 –20.
Li Y-W, Dampney RAL. Expression of Fos-like protein in brain following sustained hypertension and hypotension in conscious rabbits.
Neuroscience 1994; 61: 613–34.
Curtis KS, Cunningham JT, Heesch CM. Fos expression in brain stem
nuclei of pregnant rats after hydralazine-induced hypotension. Am. J.
Physiol. 1999; 277: R532–40.
Lohmeier TE, Hilderbrandt DA, Warren S, May PJ, Cunningham JT.
Recent insights into the interactions between the baroreflex and the
kidneys in hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol.
2005; 288: R828–36.
Sothmann MS, Buckworth J, Claytor RP, Cox RH, White-Welkley JE,
Dishman RK. Exercise training and the cross-stressor adaptation
hypothesis. Exerc. Sport Sci. Rev. 1996; 24: 267–87.
O’Sullivan SE, Bell C. Training reduces autonomic cardiovascular
responses to both exercise-dependent and -independent stimuli in humans.
Auton. Neurosci. 2001; 91: 76–84.
Morimoto K, Tan N, Nishiyasu T, Sone R, Murakami N. Spontaneous
wheel running attenuates cardiovascular responses to stress in rats.
Pflügers Arch. 2000; 440: 216–22.
Overton JM, Kregel KC, Davis-Gorman G, Seals DR, Tipton CM,
Fisher LA. Effects of exercise training on responses to central injection
of CRF and noise stress. Physiol. Behav. 1991; 49: 93–8.
Bauer RM, Waldrop TG, Iwamoto GA, Holzwarth MA. Properties of
ventrolateral medullary neurons that respond to muscular contraction.
Brain Res. Bull. 1992; 28: 167–78.
Morrison SF, Reis DJ. Reticulospinal vasomotor neurons in the RVL
mediate the somatosympathetic reflex. Am. J. Physiol. 1989; 256:
R1084–97.
Stornetta RL, Morrison SF, Ruggiero DA, Reis DJ. Neurons of rostral
ventrolateral medulla mediate somatic pressor reflex. Am. J. Physiol.
1989; 256: R448–62.
Kiely JM, Gordon FJ. Non-NMDA receptors in the rostral ventrolateral
medulla mediate somatosympathetic pressor responses. J. Auton. Nerv.
Syst. 1993; 43: 231–40.
Mueller PJ. Blunted centrally mediated sympathoexcitation in exercise
trained rats. FASEB J. 2006; 20: A1414 (Abstract).
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd