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Nervous System
Exercise Training Restores Baroreflex Sensitivity in
Never-Treated Hypertensive Patients
Mateus C. Laterza, Luciana D.N.J. de Matos, Ivani C. Trombetta, Ana M.W. Braga, Fabiana Roveda,
Maria J.N.N. Alves, Eduardo M. Krieger, Carlos E. Negrão, Maria U.P.B. Rondon
Abstract—The effects of exercise training on baroreflex control of sympathetic nerve activity in human hypertension are
unknown. We hypothesized that exercise training would improve baroreflex control of muscle sympathetic nerve
activity (MSNA) and heart rate (HR) in patients with hypertension and that exercise training would reduce MSNA and
blood pressure (BP) in hypertensive patients. Twenty never-treated hypertensive patients were randomly divided into 2
groups: exercise-trained (n⫽11; age: 46⫾2 years) and untrained (n⫽9; age: 42⫾2 years) patients. An age-matched
normotensive exercise-trained group (n⫽12; age: 42⫾2 years) was also studied. Baroreflex control of MSNA
(microneurography) and HR (ECG) was assessed by stepwise intravenous infusions of phenylephrine and sodium
nitroprusside and analyzed by linear regression. BP was monitored on a beat-to-beat basis. Exercise training consisted
of three 60-minute exercise sessions per week for 4 months. Under baseline conditions (before training), BP and MSNA
were similar between hypertensive groups but significantly increased when compared with the normotensive group.
Baroreflex control of MSNA and HR was similar between hypertensive groups but significantly decreased when
compared with the normotensive group. In hypertensive patients, exercise training significantly reduced BP (P⬍0.01)
and MSNA (P⬍0.01) levels and significantly increased baroreflex control of MSNA and HR during increases (P⬍0.01
and P⬍0.03, respectively) and decreases (P⬍0.01 and P⬍0.03, respectively) in BP. The baseline (preintervention)
difference in baroreflex sensitivity between hypertensive patients and normotensive individuals was no longer observed
after exercise training. No significant changes were found in untrained hypertensive patients. In conclusion, exercise
training restores the baroreflex control of MSNA and HR in hypertensive patients. In addition, exercise training
normalizes MSNA and decreases BP levels in these patients. (Hypertension. 2007;49:1298-1306.)
Key Words: hypertension 䡲 baroreflex sensitivity 䡲 sympathetic nerve activity 䡲 exercise 䡲 blood pressure
T
studies have demonstrated that regular exercise causes significant changes in baroreflex control of HR in experimental
hypertension. Exercise training improves baroreflex control
of HR during the increase and decrease of BP in spontaneously hypertensive rats.11,12 Furthermore, these studies indicate that the improvement in baroreflex sensitivity is, in part,
mediated by the enhancement of the aortic depressor nerve
sensitivity. In humans with hypertension, little information
exists regarding the effects of exercise training on the
baroreflex sensitivity. One of the few studies showed that
exercise training caused a modest improvement in baroreflex
bradycardia.13 Thus, the effects of regular exercise on the
baroreflex control of sympathetic nerve activity in humans
with hypertension are unknown.
It has been consistently shown that exercise training is a
powerful nonpharmacological strategy to reduce BP levels in
humans with hypertension.14 –16 However, the mechanisms
involved in the BP reduction after exercise training are still a
matter of discussion. In the present study, we investigated the
here is accumulated evidence that arterial baroreflex
plays an important role in the regulation of the cardiovascular system. During spontaneous variation of blood
pressure (BP), stimulation or deactivation of the arterial
baroreceptors located in the carotid sinus and aortic arch
causes reflex bradycardia and tachycardia, respectively. At
the vascular level, stimulation of the arterial baroreceptors
results in sympathetic inhibition and, in consequence, reflex
vasodilation. In contrast, the deactivation of the arterial
baroreceptors elicits sympathetic-mediated vasoconstriction.1
All of these responses work in concert to maintain the BP
levels in the reference range.1
It has been described that arterial baroreflex sensitivity can
be profoundly altered in some cardiovascular diseases.2,3 In
hypertension, some investigators,4 – 6 but not all,7–9 observed
that baroreflex control of heart rate (HR) and sympathetic
nerve activity is significantly reduced. This autonomic dysfunction seems to correlate with an increase in sympathetic
outflow and in BP levels.10 On the other hand, previous
Received December 4, 2006; first decision December 19, 2006; revision accepted March 22, 2007.
From the Heart Institute (InCor) (M.C.L., L.D.N.J.d.M., I.C.T., A.M.W.B., F.R., M.J.N.N.A., E.M.K., C.E.N., M.U.P.B.R.), University of São Paulo
Medical School, São Paulo, Brazil; and the School of Physical Education and Sports (C.E.N.), University of São Paulo, São Paulo, Brazil.
Correspondence to Maria U.P.B. Rondon, Instituto do Coração (InCor), Unidade de Reabilitação Cardiovascular e Fisiologia do Exercı́cio, Av Dr Enéas
de Carvalho Aguiar, 44-1° SS, Cerqueira César, São Paulo-SP, CEP 05403– 000, Brazil. E-mail [email protected]
© 2007 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/HYPERTENSIONAHA.106.085548
1298
Laterza et al
impact of regular exercise on muscle sympathetic nerve
activity (MSNA) and BP levels in hypertensive patients. In
addition, we sought to determine whether there was any
relationship between the changes in MSNA and the changes
in BP levels in exercise-trained hypertensive patients. Our
hypotheses were as follows: (1) exercise training would
improve baroreflex control of MSNA and HR during the
increase and decrease of BP in never-treated hypertensive
patients; (2) exercise training would reduce MSNA and BP in
these patients; and (3) the changes in BP levels after exercise
training would be associated with changes in MSNA.
Methods
Study Population
Twenty consecutive never-treated hypertensive patients were selected to participate in the study. An additional normotensive
age-paired control group (N⫽12) was also enrolled in the study.
They were ⬍55 years old, had no evidence of metabolic disorders,
renal vascular hypertension, cerebral ischemic disease, obstructive
coronary artery disease, or musculoskeletal abnormality (eg, arthritis) and were not involved in regular exercise training for ⱖ6
months. In addition, the hypertensive patients had never been treated
with antihypertensive drugs and were taking no medications 3
months before the study. Thereafter, the hypertensive patients were
randomly divided into the exercise-trained group (n⫽11) and the
untrained group (n⫽9). The normal control group was also submitted
to exercise training. The study was approved by the University of
São Paulo Medical School Ethical Committee for Human Research
Protocols, and the participants gave their written informed consent.
Baroreflex Restoration in Hypertension
1299
ceptors. The infusion of phenylephrine and sodium nitroprusside was
maintained for 3 minutes per dose. Mean BP, MSNA, and HR were
averaged for 3 minutes before infusion and every minute of each step
infusion. Baroreflex sensitivity for control of MSNA and HR for
each individual was estimated by the slope (“a”) of the linear
regression equation generated by calculation of the absolute change
in MSNA burst frequency and the absolute change in HR in relation
to the absolute change in mean BP induced by phenylephrine and
sodium nitroprusside infusion.19,20 The 9 points generated during the
stepwise infusion (3 points for each dose) were used in the linear
regression analysis.
Exercise Training Program
Subjects underwent exercise training under supervision at the Heart
Institute. The 4-month training program consisted of three 60-minute
exercise sessions per week. Each exercise session consisted of 5
minutes of stretching exercises, 40 minutes of cycling on an
ergometer bicycle, 10 minutes of local strengthening exercises
(sit-ups, push-ups, and pull-ups), and 5 minutes of cool down with
stretching exercises. The exercise intensity was established by HR
levels that corresponded with the anaerobic threshold up to 70% of
peak oxygen uptake, obtained by a progressive cardiopulmonary
exercise test. The anaerobic threshold was determined to occur at the
point where there was a loss of linearity between oxygen uptake and
carbon dioxide production or at the point where the ventilatory
equivalent for oxygen or end-tidal oxygen partial pressure curves
reached their respective minimum values and began to rise during the
progressive exercise test. The peak oxygen uptake was considered at
the end of the bicycle cardiopulmonary exercise test (ramp protocol
with 10-, 15-, or 20-W increments every minute up to exhaustion)
when the subject no longer maintained the bicycle velocity at 60
rpm. Untrained patients were instructed to avoid any regular exercise
program (supervised or unsupervised) for 4 months.
Measurements and Procedures
Clinic BP
The clinic BP levels were obtained in the left arm of the sitting
patients, after 5 minutes of quiet rest, with a mercury sphygmomanometer. A minimum of 3 BP readings was taken on 2 separate
occasions. Systolic and diastolic BP were recorded at the first
appearance (phase I) and the disappearance (phase V) of Korotkoff
sounds. The subjects were classified as hypertensive if the average of
the systolic and diastolic BP levels were ⬎140 and/or 90 mm Hg,
respectively.15
MSNA
MSNA was recorded directly from the peroneal nerve using the
microneurography technique.17,18 Multiunit postganglionic muscle
sympathetic nerve recordings were made using a tungsten microelectrode (tip diameter: 5 to 15 ␮m). The signals were amplified by a
factor of 50 000 to 100 000 and bandpassed filtered (700 to 2000
Hz). For recordings and analysis, nerve activity was rectified and
integrated (time constant: 0.1 seconds) to obtain a mean voltage
display of sympathetic nerve activity that was recorded on paper. All
of the recordings of MSNA met previously established and described
criteria. MSNA was quantified as burst frequency (bursts per minute)
and burst incidence (burst per 100 heart beats).
Miscellaneous Measurements
BP was monitored noninvasively by a finger photoplethysmography
device (Finapres 2300, Ohmeda) on a beat-to-beat basis. HR was
monitored continuously through lead II of ECG.
Arterial Baroreflex Measurements
Baroreflex sensitivity for control of MSNA and HR was studied by
the technique of infusion of vasoactive drugs.2 Briefly, phenylephrine was infused incrementally through a cannula placed in the
antecubital vein at doses of 0.4, 0.8, and 1.2 ␮g/kg⫺1 min⫺1 to
stimulate the baroreceptors. Sodium nitroprusside was also infused
incrementally through a cannula placed in the antecubital vein at
doses of 0.4, 0.8, and 1.2 ␮g kg⫺1 min⫺1 to deactivate the barore-
Experimental Protocol
All of the studies were performed at ⬇7:30 AM, with the subjects
lying in supine position in a quiet air-conditioned room (22°C to
24°C). After obtaining an adequate microneurographic nerve recording site in the leg and placing the cannula in the antecubital vein for
drugs infusions, all of the participants rested for 15 minutes. The
experimental protocol started with a 3-minute period of baseline
measures of BP, MSNA, and HR (Figure 1). After this period,
phenylephrine infusion was started and maintained for a 9-minute
period. The end of the phenylephrine infusion was separated from
the beginning of the sodium nitroprusside infusion by a recovery
period of 45 minutes. After this period, a new 3-minute period for
baseline measures of mean BP, MSNA, and HR was started. Sodium
nitroprusside infusion started immediately after the baseline measures and was maintained for a 9-minute period (Figure 1). Mean BP,
MSNA, and HR were continuously recorded throughout experimental protocols. Cardiopulmonary exercise test, clinic BP, and experimental protocol were repeated after 4 months in all of the groups.
The second examination was performed 48 hours after the last
exercise session.
Statistics
Data are presented as mean⫾SE. Unpaired t test was used to test the
baseline differences between hypertensive patients and normotensive
individuals. A ␹2 test was used to assess the gender differences
between hypertensive patients and normotensive individuals. Pearson correlation coefficient was used to evaluate the correlation
between the change in BP and the change in MSNA and the change
in baroreflex sensitivity and the change in BP and MSNA. Two-way
ANOVA with repeated measures was performed to test the differences among untrained hypertensive patients, exercise-trained hypertensive patients, and normal control individuals before and after
intervention. When significant difference was found, Scheffé’s
posthoc comparison test was used. Significant differences were
assumed to be at P⬍0.05.
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Figure 1. Timeline of experimental protocol
(see Experimental Protocol section for more
details).
Results
Baseline Measurements
Physical characteristics, hemodynamic and neural measurements, and functional capacity of the hypertensive patients
and normotensive individuals are shown in Table 1. There
were no significant differences in sex, age, height, weight,
body mass index, HR, and functional capacity between
hypertensive patients and normotensive individuals. Clinical
systolic, diastolic, and mean BP levels were significantly
TABLE 1. Baseline Physical Characteristics, Hemodynamic
and Neural Measurements, and Functional Capacity in
Hypertensive Patients and Normotensive Individuals
Hypertensive
Patients
(N⫽20)
Normotensive
Individuals
(N⫽12)
P
13/7
9/3
0.55
Age, year
44⫾1
42⫾2
0.23
Height, m
1.70⫾0.02
1.67⫾0.02
0.29
Measurements
Physical characteristics
Sex, men/women
Weight, kg
77⫾3
69⫾3
0.11
Body mass index, kg/m2
26⫾1
25⫾1
0.18
Clinic systolic BP, mm Hg
145⫾2
117⫾2
0.001
Clinic diastolic BP, mm Hg
94⫾1
78⫾1
0.001
110⫾1
91⫾2
0.001
77⫾3
78⫾3
0.77
MSNA, bursts per minute
35⫾1
22⫾2
0.001
MSNA, bursts per 100
heart beats
57⫾3
34⫾5
0.001
25⫾1
30⫾2
0.06
Hemodynamic measurements
Clinic mean BP, mm Hg
HR, bpm
Neural measurements
Functional capacity
VO2 peak, mL/kg/min
Values are mean⫾SE or n/n (for sex).
higher in hypertensive patients than in normotensive individuals. MSNA burst frequency and burst incidence were also
significantly higher in hypertensive patients than in normotensive individuals. The baroreflex control of MSNA during
increase of mean BP, analyzed by the slope of the linear
regression equation, was significantly lower in hypertensive
patients when compared with normotensive individuals (Figure 2A and 2B). Similarly, the baroreflex control of MSNA
during decrease of mean BP was significantly lower in
hypertensive patients than in normotensive individuals (Figure 2A and 2B). The baroreflex control of HR during increase
in mean BP, analyzed by the slope of the linear regression
equation, was significantly lower in hypertensive patients
when compared with normotensive individuals (Figure 2C
and 2D). In addition, the baroreflex control of HR during
decrease in mean BP was also significantly lower in hypertensive patients than in normotensive individuals (Figure 2C
and 2D).
Effects of Exercise Training
Compliance with the exercise program was excellent, reaching an average of 96%⫾3% and 96%⫾3% of exercise
sessions attended by both hypertensive patients and normotensive individuals, respectively. The effects of exercise
training on hemodynamic measurements are shown in Table
2. Exercise training significantly reduced clinical systolic,
diastolic, and mean BP levels in hypertensive patients. The
comparison between hypertensive groups showed that
exercise-trained hypertensive patients had clinical systolic,
diastolic, and mean BP levels significantly lower than untrained hypertensive patients. Exercise training significantly
decreased the baseline and standard 60-W workload HR in
hypertensive patients and normotensive individuals. No significant changes were found in untrained hypertensive patients over the 4-month duration of the study. Exercise
training significantly decreased MSNA burst frequency and
burst incidence in hypertensive patients. Consequently,
Laterza et al
Baroreflex Restoration in Hypertension
1301
Figure 2. Baroreflex control of MSNA and HR during increase and decrease of mean BP (MBP), analyzed by the slope (“a”) of the linear regression equation, in hypertensive patients and normotensive individuals. Note that the baroreflex control of MSNA was significantly lower in hypertensive patients (n⫽17) when compared with normotensive individuals (n⫽10; A and B). Similarly, the baroreflex
control of HR was significantly lower in hypertensive patients (n⫽20) when compared with normotensive individuals (n⫽12; C and D).
*Significant difference between groups, P⬍0.05.
MSNA burst frequency and burst incidence were significantly lower in exercise-trained hypertensive patients when
compared with untrained hypertensive patients and similar
when compared with normotensive individuals (Figure 3A
and 3B). Further analysis showed a significant correlation
between the changes in MSNA and the changes in mean BP
(values measured after 4 months of study minus baseline) in
exercise-trained and untrained hypertensive patients (Figure
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TABLE 2. Hemodynamic Measurements Preintervention and Postintervention in
Hypertensive Patients and Normotensive Individuals
Hypertensive
Exercise-Trained
(N⫽11)
Hypertensive
Untrained
(N⫽9)
Normotensive
Exercise-Trained
(N⫽12)
Preintervention
145⫾2*
145⫾4*
117⫾2
Postintervention
130⫾5†*
146⫾6*‡
116⫾2
Preintervention
94⫾2*
94⫾2*
78⫾1
Postintervention
84⫾3†
93⫾4*‡
78⫾2
Hemodynamic Measurements
Clinic systolic BP, mm Hg
Clinic diastolic BP, mm Hg
Clinic mean BP, mm Hg
Preintervention
Postintervention
110⫾2*
98⫾3†*
110⫾2*
91⫾2
112⫾4*‡
91⫾1
Baseline HR, bpm
Preintervention
80⫾5
72⫾3
78⫾4
Postintervention
70⫾4†
73⫾4
69⫾3†
60-W HR, bpm
Preintervention
114⫾4
119⫾6
121⫾6
Postintervention
102⫾4†
118⫾6*‡
106⫾5†
Values are mean⫾SE.
*Significant difference vs normotensive control subjects, P⬍0.05.
†Significant difference preintervention vs postintervention, P⬍0.05.
‡Significant difference vs exercise-trained hypertensive patients, P⬍0.05.
4). Of note, 1 patient who had a substantial increase in BP and
MSNA was an untrained hypertensive woman. No significant
changes in BP and MSNA were found in normotensive
individuals over the 4-month exercise training period.
Examples of MSNA tracing and pulse pressure at baseline,
both under phenylephrine and sodium nitroprusside infusion
before and after intervention in 1 exercise-trained hypertensive patient are shown in Figure 5. Exercise training im-
proved baroreflex control of MSNA and HR significantly in
hypertensive patients (Figure 6A and 6B and 6C and 6D,
respectively). Consequently, at the end of the 4-month intervention period, baroreflex sensitivity in exercise-trained hypertensive patients exceeded that observed in untrained hypertensive patients and was similar to that observed in
normotensive control subjects. No significant changes were
found in the baroreflex control of MSNA and HR in normotensive individuals over the 4 months of the exercise training
period.
Exercise training significantly increased peak oxygen uptake in hypertensive patients (25⫾1 versus 29⫾3 mL/kg/min;
P⫽0.04) and normotensive individuals (30⫾2 versus 34⫾2
mL/kg/min; P⫽0.02). No significant changes were found in
untrained hypertensive patients over the 4-month duration of
the study (26⫾1 versus 25⫾2 mL/kg/min; P⫽0.90).
Discussion
Figure 3. MSNA burst frequency (A) and burst incidence (B) in
exercise-trained hypertensive patients (n⫽8), untrained hypertensive patients (n⫽9), and exercise-trained normotensive individuals (n⫽10). Note that exercise training significantly reduced
MSNA burst frequency and burst incidence in hypertensive
patients. *Significant difference vs normotensive individuals,
P⬍0.05; †Significant difference pre- vs postinterventions,
P⬍0.05; ‡Significant difference vs exercise-trained hypertensive
patients, P⬍0.05.
One of the major findings of the present study is that
moderate exercise training improves the baroreflex control of
MSNA, which is depressed in never-treated hypertensive
patients. In addition, exercise training normalizes MSNA and
significantly reduces BP levels in never-treated hypertensive
patients.
Our study shows that the baroreflex control of HR and
MSNA is impaired in hypertensive patients. The reduced
baroreflex control of HR is consistent with results of previous
studies.4,6,8 However, the impairment in baroreflex control of
MSNA is in agreement with some5,6 but not all previous
observational studies.7–9 It seems that one major explanation
for this controversy is the change in BP in studies about
baroreflex control. Our results showed that the difference in
Laterza et al
Baroreflex Restoration in Hypertension
1303
Figure 4. Relationship between the absolute changes (values after 4 months of
training minus baseline) in MSNA and the
absolute changes in mean BP (MBP) in
exercise-trained (n⫽8, E) and untrained
(n⫽9, Œ) hypertensive patients.
baroreflex control of MSNA between normotensive and
hypertensive subjects was apparent only in larger changes in
BP (20 to 30 mm Hg; Figure 2). These large changes in BP
were not achieved in other studies in which the baroreflex
control of MSNA was similar between normotensive and
hypertensive subjects.7–9 We cannot rule out the possibility
that some methodologic differences explain the controversy
among studies. We studied baroreflex sensitivity during
increase and decrease of BP provoked by intravenous infusion of vasoactive drugs, whereas others9 studied baroreflex
sensitivity during spontaneous fluctuation of BP. The drug
infusion allows the investigation of the baroreflex control in
a large range of BP variation, which rarely occurs during
resting spontaneous BP variation. The hypertensive patients
who participated in the study by Rea et al7 were younger than
those involved in our study. In the study by Grassi et al,8 the
normotensive individuals had higher BP and MSNA levels
than those who took part in the present study. Grassi et al8
determined baroreflex control by calculating the percentage
of change in MSNA in relation to the change in BP caused by
each dose of phenylephrine and nitroprusside, the average
ratio of percent changes in MSNA, and the corresponding
Figure 5. Sympathetic neurograms and simultaneous recordings of BP in 1 exercise-trained hypertensive patient (male, 45 years old).
A, MSNA and BP at baseline and during increase of BP by 1.2-␮g kg⫺1 min⫺1 infusion of phenylephrine. B, MSNA and BP at baseline
and during decrease of BP by 1.2-␮g kg⫺1 min⫺1 infusion of sodium nitroprusside.
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Figure 6. Baroreflex control of MSNA and HR analyzed by the slope (“a”) of the linear regression equation, in exercise-trained hypertensive patients, untrained hypertensive patients, and normotensive individuals. MBP indicates mean BP. *Significant difference vs postexercise normotensive and hypertensive individuals, P⬍0.05; †Significant difference vs normotensive individuals, P⬍0.05; ‡Significant
difference pre- vs postinterventions, P⬍0.05; §Significant difference vs exercise-trained hypertensive patients, P⬍0.05.
changes in BP. We studied the baroreflex control by calculating the linear regression equation between the absolute
change in MSNA and the absolute change in BP induced by
phenylephrine and sodium nitroprusside infusion.
The effect of exercise training on baroreflex control of HR
has been described in animals and humans with hypertension.
In spontaneously hypertensive rats, exercise training improves baroreflex bradycardia and tachycardia.11,12 In hypertensive patients, regular exercise enhances baroreflex bradycardia.13 Our study confirms that exercise training improves
both baroreflex bradycardia and baroreflex tachycardia in
hypertensive patients, but, for the first time, it demonstrates
Laterza et al
that regular exercise enhances baroreflex control of MSNA in
hypertensive patients. The mechanism by which exercise
training improves baroreflex sensitivity is out of the scope of
the present study. However, it is conceivable to attribute the
augmentation in baroreflex sensitivity, at least in part, to the
aortic depressor nerve sensitivity. In a previous study, we
found that the increase in baroreflex sensitivity in exercisetrained spontaneously hypertensive rats was associated with
an improvement in aortic baroreceptor gain sensitivity directly measured in an aortic baroreceptor multifiber preparation.12 This beneficial effect of exercise training may be
mediated by an enhancement in arterial compliance that acts
to increase stimulus transduction and afferent responsiveness.21 It has been described that a reduction in compliance of
the large elastic arteries in which the arterial baroreceptors are
located is a key mechanism underlying impairment in cardiovagal baroreflex sensitivity in older subjects.22 On the other
hand, 3 months of regular aerobic exercise significantly
increases the carotid arterial compliance in previously sedentary middle-aged and older individuals.23,24 In addition, the
age-related reduction in carotid artery compliance is significantly attenuated in endurance exercise-trained subjects when
compared with sedentary healthy adults.23 But what are the
possible explanations for the amelioration in arterial compliance after exercise training? So far, there is no definite
information regarding this vascular change in hypertensive
patients. However, further analysis in the present study may
provide some hints for future investigations in this area. We
found a significant correlation between the exercise-induced
changes in baroreflex control of MSNA during increase and
decrease of BP and changes in BP levels (r⫽0.72, P⬍0.01
and r⫽0.50, P⬍0.05, respectively). Thus, it is possible that
the reduction in BP levels is implicated in the amelioration of
arterial compliance after exercise training in hypertensive
patients. We cannot exclude the possibility that the improvement in baroreflex control of MSNA is mediated by alterations in the central and efferent components of the baroreflex pathway. There is growing evidence that regular exercise
normalizes plasma and central angiotensin II concentration
and central angiotensin II type 1 receptor messenger RNA.25
A previous study demonstrated that long-term central infusion of angiotensin II reduced the gain of the cardiac
baroreflex in rabbits, whereas long-term treatment with the
angiotensin II type 1 receptor antagonist produced an increase
in baroreflex gain.26
Another interesting piece of information in our study is that
exercise training reverses the increased MSNA to normal
levels in hypertensive patients. This remarkable effect of
exercise has been described in other human syndromes, such
as obesity and heart failure.27,28 Although we have no
definitive information with regard to the mechanisms underlying the reduction in sympathetic nerve activity in humans,
recent observations in animal models provide suggestive
explanations for the reduction in MSNA after exercise training observed presently in hypertensive patients. Some investigators29 described that the reduction in basal renal sympathetic nerve activity after exercise training was associated
with significant attenuation of chemoreflex-mediated sympathoexcitation in pacing-induced heart failure rabbits. The
Baroreflex Restoration in Hypertension
1305
reduction in sympathetic nerve activity after exercise training
has been attributed to a decrease in central angiotensin II
concentration or an increase in central NO production by
means of an enhancement in neuronal NO synthase expression.25 However, we cannot rule out the possibility that a
reduction of sympathetic activity may occur with a loss of
excitatory synapses. A reduced synaptic activity seems to
correlate with structural neuroplasticity. Nelson et al30 observed that chronic exercise resulted in attenuated dendritic
arborization of the cardiorespiratory and locomotor centers of
the brain. In addition, a lower level of excitation of cardiorespiratory and locomotor centers of the brain for a given absolute
workload during exercise has been also documented.31 It seems
unlikely that the reduction in MSNA after training is associated with the improvement in arterial baroreflex sensitivity,
because further analysis in the present study showed no
significant correlation between the absolute changes in
baroreflex control of MSNA and the changes in baseline
MSNA in hypertensive patients (r⫽0.28, P value not significant, and r⫽0.38, P value not significant, respectively).
Confirming previous studies dealing with exercise training
and hypertension,14 the present investigation clearly demonstrates that regular moderate dynamic exercise reduces systolic, diastolic, and mean BP in humans with high BP.
Surprising was the fact that BP did not reach normal levels
after exercise training. These findings raise the possibility
that vascular changes caused by hypertension32,33 were not
fully reversed by our exercise regimen. It is possible that a
4-month period of exercise training may be insufficient to
reverse vascular structural alterations, which might explain
the failure to completely normalize BP in our study. The
decrease in both MSNA and BP after training could suggest
a cause and effect relationship between these 2 parameters.
However, the present results seem to be insufficient to
support this concept. Despite the significant correlation between the changes in MSNA and the changes in BP (r⫽0.62;
P⬍0.01), this association is weakened when only exercisetrained hypertensive patients are taken into consideration
(Figure 4).
Both the decrease in resting HR and the improvement in
peak oxygen uptake in the exercise-trained hypertensive
patients and in normotensive control subjects clearly demonstrate the effectiveness of our exercise regimen. Resting
bradycardia and increase in peak oxygen uptake are considered 2 important markers of exercise training adaptation in
humans.34,35
Perspectives
The changes in baroreflex sensitivity and MSNA caused by
exercise training have clinical implications. Previous observations demonstrated that reduction in baroreflex sensitivity
is an independent risk factor for sudden death after acute
myocardial infarction.36 Thus, it is reasonable to expect that
the improvement in baroreflex sensitivity plays a protective
role in hypertensive patients. In fact, the increase in baroreflex control of HR after regular exercise was associated with
increased survival after a 10-year follow-up in patients with
uncomplicated myocardial infarction.37 The sympathoinhibition after exercise training may improve prognosis in humans
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June 2007
with hypertension. In preliminary studies, we found that
increased MSNA was associated with mortality in heart
failure patients.38 Finally, moderate dynamic exercise training
is a unique nonpharmacological therapy for the treatment of
human hypertension.
In conclusion, regular exercise restores baroreflex control
of sympathetic nerve activity and HR in patients with
hypertension. In addition, this nonpharmacological therapy
provokes neurovascular inhibition and reduction in BP levels
in human hypertension.
16.
17.
18.
19.
Sources of Funding
This study was supported by Fundação de Amparo à Pesquisa do
Estado de São Paulo, São Paulo-SP (FAPESP, 01/00009-0 and
2005/59740-7) and in part by Fundação Zerbini, São Paulo-SP.
C.E.N. (304304/2004-2), M.U.P.B.R. (305159/2005-4), and I.C.T.
(306931/2006-0) were supported by Conselho Nacional de Pesquisa
(CNPq), and M.C.L. was supported by Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior (CAPES).
Disclosures
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21.
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23.
None.
24.
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