Download Exercise training prevents the exaggerated exercise pressor reflex

J Appl Physiol 108: 1365–1375, 2010.
First published February 25, 2010; doi:10.1152/japplphysiol.01273.2009.
Exercise training prevents the exaggerated exercise pressor reflex in rats with
chronic heart failure
Han-Jun Wang, Yan-Xia Pan, Wei-Zhong Wang, Lie Gao, Matthew C. Zimmerman, Irving H. Zucker,
and Wei Wang
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
Submitted 10 November 2009; accepted in final form 23 February 2010
muscle; sympathetic nerve activity; blood pressure; decerebration
A HALLMARK OF PATIENTS SUFFERING from chronic heart failure
(CHF) is elevated sympathoexcitation and exercise intolerance
(3, 7, 50, 53). Although the mechanisms responsible for the
increase in sympathetic outflow and exercise intolerance in
CHF are not known, it has recently been suggested that this
may be due, in part, to an exaggerated exercise pressor reflex
(EPR).
The EPR is a peripheral neural reflex originating in skeletal
muscle that contributes significantly to the regulation of the
cardiovascular system during exercise. The afferent arm of this
reflex is composed of metabolically sensitive (predominantly
group IV) and mechanically sensitive (predominantly group
III) afferent fibers (4, 16, 17, 26). Evidence from animal studies
has demonstrated that increases in heart rate (HR), arterial
pressure (AP), and sympathetic nerve activity in response to
Address for reprint requests and other correspondence: W. Wang, Dept. of
Cellular and Integrative Physiology, Univ. of Nebraska Medical Center,
Omaha, NE 68198-5850 (e-mail: [email protected]).
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activation of this reflex are enhanced in rats with CHF induced
by myocardial infarction (22, 43, 44, 46). Furthermore, these
studies also suggest that an enhanced mechanical component of
this reflex (i.e., mechanoreflex) contributes to the exaggerated
EPR in CHF, whereas the cardiovascular control of the
metaboreflex is blunted (23, 47, 48). An exaggerated EPR can
potentially increase cardiovascular risk and contribute to exercise intolerance during physical activity in CHF patients. A
therapeutic strategy for preventing or slowing the progression
of the exaggerated EPR may be beneficial in CHF patients.
Accumulating studies suggest that long-term exercise training (ExT), as a nonpharmacological treatment for CHF, increases exercise capacity, reduces sympathoexcitation, and
improves cardiovascular function in CHF animals and patients
(2, 9, 11, 19, 35). However, whether ExT also improves the
exaggerated EPR function in the CHF state remains to be
determined. In the present study, we investigated the effects of
ExT on the exaggerated EPR in rats with CHF. Moreover, to
determine the mechanism by which ExT affects EPR function,
we further investigated the effects of ExT on the mechano- and
metaboreflex in sham and CHF rats.
METHODS
Experiments were performed on male Sprague-Dawley rats weighing 420 –510 g (n ⫽ 68). These experiments were approved by the
Institutional Animal Care and Use Committee of the University of
Nebraska Medical Center and carried out under the guidelines of the
National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Model of CHF
Heart failure was produced by coronary artery ligation, as previously described (8, 52). Briefly, the rat was ventilated at a rate of 60
breaths/min with 3% isoflurane during the surgical procedure. A left
thoracotomy was performed through the fifth intercostal space, the
pericardium was opened, the heart was exteriorized, and the left
anterior descending coronary artery was ligated. Sham-operated rats
were prepared in the same manner, but did not undergo coronary
artery ligation. All of the rats (n ⫽ 27) survived from the sham
surgery. However, ⬃70% of rats (i.e., 28 of total 41 rats) survived
from coronary artery ligation surgery.
In this study, the cardiac function in all experimental animals was
measured by echocardiography (VEVO 770, Visual Sonics), as previously described (52). In addition, at the end of each acute experiment, a Millar catheter (SPR 524; size, 3.5-Fr; Millar Instruments,
Houston, TX) was advanced through the carotid artery into the left
ventricle (LV) to determine LV end-diastolic pressure and LV systolic
pressure. The rats were then euthanized with an overdose of pentobarbital sodium. The hearts and lungs were removed, and the ratio of
the infarct area to whole LV minus septum was measured.
8750-7587/10 $8.00 Copyright © 2010 the American Physiological Society
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Wang HJ, Pan YX, Wang WZ, Gao L, Zimmerman MC, Zucker IH,
Wang W. Exercise training prevents the exaggerated exercise pressor reflex
in rats with chronic heart failure. J Appl Physiol 108: 1365–1375, 2010. First
published February 25, 2010; doi:10.1152/japplphysiol.01273.2009.—An
exaggerated exercise pressor reflex (EPR) occurs in the chronic heart
failure (CHF) state, which contributes to exercise intolerance and
excessive sympathoexcitation during exercise. Exercise training
(ExT) improves abnormal cardiovascular reflexes in CHF. Whether
ExT can normalize the exaggerated EPR function remains to be
determined. This study was designed to investigate the effects of ExT
on the EPR and on the mechanical or metabolic components of this
reflex in sham-operated and CHF rats. The EPR was activated by
static contraction induced by electrical stimulation of L4/L5 ventral
roots. The afferent fibers associated with the mechanoreflex and
metaboreflex were activated by passive stretch and hindlimb arterial
injection of capsaicin (0.1 and 1 ␮g/kg, 0.2 ml), respectively. Heart
rate, blood pressure, and sympathoexcitatory responses during the
activation of these reflexes were compared in sham ⫹ sedentary (Sed),
sham ⫹ ExT, CHF ⫹ Sed, and CHF ⫹ ExT rats. Compared with sham ⫹
Sed rats, CHF ⫹ Sed rats exhibited exaggerated heart rate and pressor
and sympathoexcitatory responses to either static contraction or passive stretch, whereas the cardiovascular responses to injection of
capsaicin were blunted. Eight to ten weeks of ExT normalized the
exaggerated responses induced by static contraction or passive stretch
and partially improved the blunted responses due to intra-arterial
capsaicin in CHF rats. ExT had no significant effect on the EPR and
mechanoreflex and metaboreflex functions in sham rats. These findings suggest a potential therapeutic role for ExT in minimizing arterial
pressure and sympathetic outflow following activation of the EPR in
the CHF state.
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Protocol for ExT
EPR Function Evaluation
After 8 –10 wk of ExT (10 –12 wk after the coronary ligation or
sham operation), rats were used for acute experiments to evaluate the
effects of ExT on the EPR and on mechanoreflex and metaboreflex
functions. Sham-operated rats were used as control for CHF rats. Sed
rats were used as control for ExT rats. EPR function was also
evaluated in Sed rats 8 –10 wk after sham or infarction procedures.
General surgical preparation. Rats were anesthetized with isoflourane (Halocarbon Laboratories, River Edge, NY; 5% in O2). A jugular
vein and the trachea were cannulated. After tracheal cannulation, the
lungs were ventilated with an anesthetic mixture of 2–3% isoflourane
and O2. The right carotid artery was catheterized for measurement of
AP and mean AP (MAP). HR was derived from the AP pulse by using
the cardiotachometer function of the PowerLab (ADInstruments, Colorado Springs, CO). Body temperature was maintained between 37
and 38°C by a heating pad.
Decerebration. Previous studies have shown that the EPR is compromised by anesthesia, which is especially a concern in rats. However, after decerebration, the effects of anesthesia on the EPR were
largely abolished (46). Therefore, a decerebrate rat model was used in
the present studies. The decerebration procedure was performed as
described by our laboratory and others (45, 51). Briefly, rats were
placed in a stereotaxic apparatus (Stoelting, Chicago, IL) and customized spinal frame. The head and pelvis were stabilized. Before
decerebration, the lungs were ventilated with the isoflourane-oxygen
mixture. Dexamethasone (0.2 mg iv) was given to reduce brain edema
and inflammatory responses from the decerebration. The remaining
intact carotid artery was isolated and ligated to reduce bleeding during
decerebration. Subsequently, a portion of bone superior to the central
sagittal sinus was removed. The dura mater was breached and reflected. The cerebral cortex was gently aspirated to visualize the
superior and inferior colliculi. With the use of a blunt instrument, the
brain was perpendicularly sectioned precollicularly, and the transected
forebrain aspirated. The cranial vault was filled with warm agar
(37°C). After the decerebration had been completed, the lungs were
ventilated with a mixture of room air and oxygen, instead of the
anesthetic gas. A minimum recovery period of 1.25 h was employed
postdecerebration before data collection began.
Activation of the EPR, mechanoreflex, and metaboreflex. To activate both mechanically and metabolically sensitive skeletal muscle
afferent fibers, static hindlimb contraction was induced by electrical
stimulation of ventral roots. A laminectomy exposing the lower
lumbar portions of the spinal cord (L2–L6) was performed. Electrically
induced static muscle contraction of the triceps surae was performed
by stimulating the peripheral end of L4/L5 ventral roots for 30 s.
J Appl Physiol • VOL
Data Acquisition and Statistical Analysis
MAP, HR, RSNA, and muscle tension were acquired using PowerLab software. Baseline values were determined by analyzing at least
30 s of the data before muscle contraction. The peak response was
determined in the period of the greatest change from baseline. RNSA
is expressed as percentage of Max. The tension-time index (TTI) was
calculated by integrating the area between the tension trace and the
baseline level and is expressed in kilograms times seconds. Peak
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All animals were divided into four groups: sham ⫹ sedentary (Sed)
(n ⫽ 13), sham ⫹ ExT (n ⫽ 14), CHF ⫹ Sed (n ⫽ 13), and CHF ⫹
ExT (n ⫽ 15). The rats (CHF, n ⫽ 2; sham, n ⫽ 1) that were unwilling
to run steadily on the treadmill were excluded from the analysis. Rats
were treadmill trained, as described previously by us and others (32,
37). Generally, ExT was started 2 wk after coronary ligation or sham
operation. Rats ran at an initial speed of 10 m/min, 0% grade, 10 –15
min/day during the 1st wk. The speed and grade of treadmill were
gradually increased to 25 m/min and 10% grade, and the exercise
duration was increased to 60 min/day during the 2nd and 3rd wk.
Since the 4th wk, sham and CHF rats had the same average period of
time and total workload (25 m/min, 10% grade, 60 min/day, 5
days/wk, 5–7 wk). Sed rats were used as the control. Echocardiography was performed on all rats at the completion of ExT. To assess the
effectiveness of ExT, citrate synthase (CS) activity from soleus
muscle homogenate was measured spectrophotometrically, as described previously (37). At the end of ExT, the soleus muscle and
gastrocnemius muscle were taken, frozen on dry ice, and stored at
⫺80°C until processed.
Constant-current stimulation was used at three times motor threshold
(defined as the minimum current required to produce a muscle twitch)
with a pulse duration of 0.1 ms at 40 Hz. All muscles of the hindlimb
undergoing study were denervated, except for the triceps surae
muscle.
Previous studies had reported that passive stretch, a pure mechanical stimulus, was used to selectively activate mechanically sensitive
intramuscular afferents (group III) in decerebrate rats (45, 47). Therefore, in animals in which ventral root stimulation was performed,
preferential activation of the mechanoreflex was achieved by passively stretching the triceps surae muscles using a calibrated rack and
pinion system (Harvard Apparatus). Care was taken to match the peak
tension developed in response to electrical stimulation during the
passive stretch experiments.
It has been reported that the capsaicin-sensitive receptor (transient
receptor potential vanilloid 1) is localized primarily to metabolically
sensitive afferent fibers (group IV) in skeletal muscle (48). As a result,
the exogenous chemical capsaicin can be used to preferentially activate these fibers. Therefore, in animals in which ventral root stimulation and passive stretch were performed, hindlimb arterial bolus
injections of capsaicin (0.1 or 1.0 ␮g/kg, 0.2 ml) were used to
preferentially activate the metaboreflex (48). Briefly, a catheter was
placed in the right iliac artery with its tip advanced to the abdominal
aortic bifurcation, ensuring that capsaicin was delivered to the left
hindlimb through the left iliac artery. To limit drug delivery to the left
hindlimb, the common iliac vein was reversibly ligated by a vascular
occluder (Harvard). On injection of drug, the vein was occluded for 2
min to trap the injectate in the leg (48). In the present study, ventral
root stimulation, passive stretch, and injection of capsaicin were
performed in all rats (n ⫽ 13/each group, 4 groups). The order of the
three maneuvers was randomized. The interval between two maneuvers was at least 15 min.
Recording of renal sympathetic nerve activity. To evaluate EPRevoked sympathetic activation, left renal sympathetic nerve activity
(RSNA) was recorded in decerebrated rats (n ⫽ 6/each group). RSNA
was recorded as previously described by our laboratory and others
(22, 52). In brief, the left kidney was exposed retroperitoneally
through a left flank incision. Sympathetic nerves running on or beside
the renal artery were identified. About 3 mm of the nerve were
carefully dissected free of connective tissue. A pair of flexible silver
electrodes insulated by Teflon (786500, A-M system) was hooked on
the nerve. The third electrode was placed subcutaneously, which
served as a ground electrode. Subsequently, the exposed nerve and the
electrode were embedded in Kwik-Sil gel (World Precision Instruments). Once the gel had hardened, the abdominal cavity was closed.
RSNA was amplified and filtered (bandwidth: 100 –3,000 Hz) using a
Grass P55C preamplifier. The nerve signal was monitored on an
oscilloscope. The signal from the oscilloscope was displayed on a
computer, where it was rectified, integrated, sampled (1 kHz), and
converted to a digital signal by the PowerLab data-acquisition system.
At the end of the experiment, the rat was euthanized with an overdose
of pentobarbital sodium. The maximum nerve activity (Max) occurred
1–2 min after the rat was euthanized. Background noise levels for
sympathetic nerve activity were recorded 15–20 min after the rat was
euthanized. Using the unit conversion of Powerlab Chart (AD Instruments) system, baseline nerve activity was taken as percent of Max
after the noise level was subtracted.
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Table 1. Hemodynamic and morphological data in sham and CHF rats following exercise training
n
Body weight, g
Heart weight, mg
Heart weight/body weight, mg/g
Wet lung weight/body weight, mg/g
MAP, mmHg
HR, beats/min
LVEDP, mmHg
LVSP, mmHg
LVESD, mm
LVEDD, mm
LVESV, ␮l
LVEDV, ␮l
EF, %
FS, %
Infarct size, %
CS, ␮mol·g⫺1·min⫺1
Sham ⫹ Sed
Sham ⫹ ExT
CHF ⫹ Sed
CHF ⫹ ExT
13
470 ⫾ 5
1514 ⫾ 27
3.2 ⫾ 0.1
5.3 ⫾ 0.6
98.1 ⫾ 5.7
368.2 ⫾ 8.4
0.8 ⫾ 0.6
126.1 ⫾ 6.5
3.9 ⫾ 0.2
7.2 ⫾ 0.4
74.8 ⫾ 4.1
335.8 ⫾ 26.2
75.7 ⫾ 2.8
45.3 ⫾ 1.9
0
19.3 ⫾ 2.3
13
438 ⫾ 6*
1533 ⫾ 21
3.5 ⫾ 0.1
5.7 ⫾ 0.5
95.1 ⫾ 4.7
361.0 ⫾ 10.1
1.4 ⫾ 0.8
120.5 ⫾ 5.9
3.6 ⫾ 0.1
6.9 ⫾ 0.4
66.1 ⫾ 3.4
329.5 ⫾ 25.6
77.3 ⫾ 3.2
46.8 ⫾ 2.3
0
29.8 ⫾ 2.9*
13
464 ⫾ 7‡
2521 ⫾ 50§‡
5.4 ⫾ 0.1§‡
9.7 ⫾ 0.8§‡
89.8 ⫾ 4.8
382.2 ⫾ 11.5
14.7 ⫾ 2.3§‡
99.2 ⫾ 5.5*‡
8.0 ⫾ 0.3§‡
10.7 ⫾ 0.3§‡
365.5 ⫾ 26.8§‡
608.0 ⫾ 27.1§‡
40.2 ⫾ 2.0§‡
25.2 ⫾ 2.4§‡
42.5 ⫾ 2.8§‡
12.8 ⫾ 1.2*‡
13
449 ⫾ 6‡
2443 ⫾ 48§‡
5.5 ⫾ 0.1§‡
9.0 ⫾ 0.6§‡
91.5 ⫾ 4.9
377.6 ⫾ 10.1
14.3 ⫾ 2.6§‡
100.2 ⫾ 5.6*‡
7.6 ⫾ 0.3§‡
10.5 ⫾ 0.3§‡
354.4 ⫾ 24.6§‡
599.7 ⫾ 28.2§‡
41.3 ⫾ 2.5§‡
27.1 ⫾ 2.1§‡
41.1 ⫾ 2.4§‡
19.1 ⫾ 1.4†‡
developed tension was calculated by subtracting the resting tension
from the peak tension and is expressed in grams. All values are
expressed as means ⫾ SE. Differences between groups were determined by a two-way ANOVA followed by the Tukey post hoc test.
P ⬍ 0.05 was considered statistically significant.
RESULTS
Evaluation of Body Weight, Organ Weight, and
Baseline Hemodynamics
Echocardiographic and hemodynamic measurements of
sham ⫹ Sed, sham ⫹ ExT, CHF ⫹ Sed, and CHF ⫹ ExT rats
are summarized in Table 1. The heart weight and lung weight-
to-body weight ratios were significantly higher in CHF rats
than those in sham rats, suggesting cardiac hypertrophy and
substantial pulmonary congestion in the CHF state. Moreover,
in rats with CHF, a gross examination revealed a dense scar in
the anterior ventricular wall. The mean infarct area was 42.5 ⫾
2.8% of the LV area. No infarcts were identified in sham rats.
Pleural fluid and ascites were also found in the CHF rats, but
none were found in the sham rats. There were no statistically
significant differences in baseline MAP and HR between the
sham and CHF rats. However, CHF rats exhibited elevated LV
end-diastolic pressure and reduced LV systolic pressure compared with sham rats. Echocardiographic data show that LV
Fig. 1. M-mode echocardiographic images from sham ⫹ sedentary (Sed) (A), sham ⫹ exercise training (ExT) (B), chronic heart failure (CHF) ⫹ Sed (C), and
CHF ⫹ ExT (D) hearts. Arrows demarcate left ventricular end-systolic diameter (LVESD) and end-diastolic diameter (LVEDD) dimensions. Notice that LVESD
and LVEDD were increased in CHF ⫹ Sed and CHF ⫹ ExT rats compared with sham ⫹ Sed and sham ⫹ ExT rats.
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Values are means ⫾ SE; n, no. of rats. Sed, sedentary; ExT, exercise training; CHF, chronic heart failure; MAP, mean arterial pressure; HR, heart rate; LVEDP,
left ventricle end-diastolic pressure; LVSP, left ventricle systolic pressure; LVESD, left ventricle end-systolic diameter; LVEDD, left ventricle end-diastolic
diameter; LVESV, left ventricle end-systolic volume; LVEDV, left ventricle end-diastolic volume; EF, ejection fraction; FS, fractional shortening; CS, citrate
synthase activity. *P ⬍ 0.05 and §P ⬍ 0.01 vs. sham ⫹ Sed. †P ⬍ 0.05 vs. CHF ⫹ Sed. ‡P ⬍ 0.01 vs. sham ⫹ ExT.
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end-systolic diameter, LV end-diastolic diameter, LV endsystolic volume, and LV end-dastolic volume were increased,
whereas ejection fraction and fractional shortening were attenuated in CHF rats compared with sham rats (Fig. 1 and Table 1),
indicating decreased cardiac function in CHF rats. After ExT,
indexes of cardiac function were not significantly different
between CHF ⫹ Sed and CHF ⫹ ExT rats, indicating that ExT
did not improve cardiac function in CHF rats. ExT did not
significantly affect MAP and HR in sham and CHF rats.
However, CS activity, an important marker of skeletal muscle
aerobic metabolism, increased by 54% in the soleus muscle of
sham ⫹ ExT rats and by 49% in CHF ⫹ ExT rats compared
with their respective controls (Table 1). Nonetheless, the CS
activity in CHF ⫹ ExT rats was still lower than in sham ⫹ ExT
rats (Table 1).
Effects of ExT on HR, AP, and Sympathoexcitatory
Responses to Static Contraction in Sham and CHF Rats
Fig. 2. Original record showing the exercise pressor reflex (EPR) control of blood pressure, heart
rate (HR), and renal sympathetic nerve activity
(RSNA) in response to static contraction induced
by electrical stimulation of L4/L5 ventral roots in
sham ⫹ Sed (A), sham ⫹ ExT (B), CHF ⫹ Sed
(C), and CHF ⫹ ExT (D) rats. In the HR panel,
the arrows point to artifacts. ABP, arterial blood
pressure; MAP, mean arterial pressure; Max,
maximum RSNA; BPM, beats/min.
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In the four groups of rats (n ⫽ 13/group), static contraction
was induced by electrical stimulation of the L4/L5 ventral roots.
Stimulation elicited increases in MAP and HR. Representative
recordings from a rat in each of the four groups are shown in
Fig. 2. Mean data are shown in Fig. 3. Compared with sham ⫹
Sed rats, CHF ⫹ Sed rats exhibited greater pressor and HR
responses to a 30-s static contraction (Fig. 3, A and B). The
exaggerated responses in CHF ⫹ Sed rats were attenuated in
CHF ⫹ ExT rats. Although ExT trended to decrease MAP and
HR responses to static contraction in sham rats, it did not reach
statistical significance.
In 6 of 13 rats in each group, RSNA responses to 30-s static
contraction were compared among the four groups to investigate the effect of ExT on EPR-evoked sympathoexcitation in
sham and CHF rats. Figure 4 is a representative figure showing
measurements of baseline RSNA, maximum RSNA (Max), and
noise level in four groups. Baseline RSNA was expressed as
percentage of Max after subtracting the noise level. As we
expected, baseline RSNA in CHF ⫹ Sed was significantly
increased compared with sham ⫹ Sed rats (42.8 ⫾ 2.4 vs. 26.3 ⫾
3.1% of Max, P ⬍ 0.05). ExT in CHF significantly attenuated the
basal RSNA (29.8 ⫾ 2.7% of Max).
During 30-s static contraction, RSNA was immediately increased at the onset of muscle contraction and then returned to
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Fig. 3. Mean data showing the effects of ExT on pressor (A), HR
(B), and sympathoexcitatory (D) responses to a 30-s static contraction in sham and CHF rats. C: both baseline and contractioninduced RSNA were compared in sham ⫹ Sed, sham ⫹ ExT,
CHF ⫹ Sed, and CHF ⫹ ExT rats. Values are means ⫾ SE. *P ⬍
0.05 vs. sham ⫹ Sed and sham ⫹ ExT. †P ⬍ 0.05 vs. baseline
RSNA. #P ⬍ 0.05 vs. CHF ⫹ Sed.
in CHF ⫹ ExT rats (Fig. 3D), indicating that ExT reduced the
exaggerated sympathoexcitation during muscle stimulation in
CHF rats. ExT also trended to decrease RSNA responses to static
contraction in sham rats, but it did not reach statistic significance.
Fig. 4. Original record showing blood pressure and
RSNA responses to euthanasia with an overdose of
pentobarbital sodium in sham ⫹ Sed (A), sham ⫹ ExT
(B), CHF ⫹ Sed (C), and CHF ⫹ ExT (D) rats. In each
rat, arrow a points to basal RSNA, arrow b points to
maximum RSNA, and arrow c points to noise level. The
Max occurred 1–2 min after the rat was euthanized.
Baseline nerve activity was taken as percentage of Max
after the noise level was subtracted. Notice that maximum RSNA is close in all 4 rats, whereas the CHF rat
had a higher basal RSNA level than other rats.
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baseline in 5–10 s (Fig. 2). Compared with sham ⫹ Sed and sham ⫹
ExT rats, CHF ⫹ Sed rats exhibited a larger RSNA response to
static contraction (Fig. 3, C and D). However, the enhanced
RSNA response to static contraction was significantly attenuated
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Effect of ExT on Mechanoreflex in Sham and CHF Rats
As shown in Figs. 5 and 6, passive stretch, a purely
mechanical stimulus, elicited increases in MAP, HR, and
RSNA in the four groups of rats. Compared with sham ⫹
Sed and sham ⫹ ExT rats, CHF ⫹ Sed rats exhibited greater
pressor, HR, and RSNA responses to passive stretch, which
were attenuated in CHF ⫹ ExT rats (Fig. 6). There was no
significant difference in MAP, HR, and RSNA responses to
passive stretch between sham ⫹ ExT and sham ⫹ Sed rats
(Fig. 6).
Effect of ExT on Metaboreflex in Sham and CHF Rats
Muscle Tension Produced by Static Contraction or
Passive Stretch
In the present study, muscle peak developed tension induced
by static contraction or passive stretch ranged from 650 to 800
g in all groups. There was no significant difference in TTI
during either static contraction or passive stretch between
groups (Table 2).
DISCUSSION
The primary findings of the present study demonstrated 1) that
ExT attenuated the exaggerated EPR, as well as the excessive
sympathoexcitation during static contraction in CHF rats; 2) that
ExT normalized the enhanced mechanoreflex function in CHF
rats; and 3) that ExT partially improved the blunted metaboreflex
function in CHF rats.
Fig. 5. Original record of the mechanoreflex
control of blood pressure, HR, and RSNA in
response to passive stretch in sham ⫹ Sed (A),
sham ⫹ ExT (B), CHF ⫹ Sed (C), and CHF ⫹
ExT (D) rats. In the HR and RSNA panels, the
arrows point to artifacts.
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In the present study, the metaboreflex was activated by
hindlimb arterial injection of capsaicin (0.1 or 1.0 ␮g/kg, 0.2
ml). As shown in Fig. 7, injection of capsaicin (1.0 ␮g/kg, 0.2
ml) increased MAP, HR, and RSNA in sham ⫹ Sed rats,
whereas these responses to injection of capsaicin were significantly blunted in CHF ⫹ Sed rats (Figs. 7 and 8). ExT
partially restored the blunted cardiovascular responses to injection of capsaicin (1.0 ␮g/kg, 0.2 ml; Fig. 7) in CHF rats.
There was no significant difference in MAP, HR, and RSNA
responses to injection of capsaicin between sham ⫹ ExT and
sham ⫹ Sed rats (Fig. 8).
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Fig. 6. Mean data showing the effects of ExT on pressor
(A), HR (B), and sympathoexcitatory (D) responses to
passive stretch in sham and CHF rats. C: both baseline
and stretch-induced RSNA were compared in sham ⫹
Sed, sham ⫹ ExT, CHF ⫹ Sed, and CHF ⫹ ExT rats.
Values are means ⫾ SE. *P ⬍ 0.05 vs. sham ⫹ Sed and
sham ⫹ ExT. †P ⬍ 0.05 vs. baseline RSNA. #P ⬍ 0.05
vs. CHF ⫹ Sed.
Traditionally ExT was considered contraindicated for CHF
patients. However, over the past decade, numerous clinical
trials and small randomized studies have demonstrated that
long-term regular exercise is safe in stable CHF patients and
increases the quality of life as well as survival (1, 18, 31, 54).
The beneficial effects of ExT include improved autonomic
balance, reduced neurohumoral activation, an increase in exercise capacity, and ameliorated myopathy in CHF patients and
animals (34, 41, 42). Furthermore, Piepoli et al. (38) first
reported that 6-wk forearm training improved the abnormal
exercise-evoked ventilation and cardiovascular responses in
CHF patients, suggesting a beneficial effect of ExT on the
abnormal muscle reflex function in CHF patients. However,
due to intrinsic limitations of human research, the study of
Piepoli et al. could not exclude the possibility that ExT plays a
beneficial role by affecting central command, a mechanism
whereby a volitional signal from the motor cortex or subcortical nuclei, responsible for recruiting motor units, activates
cardiovascular activity during exercise (6, 10). However, in
animal experiments, this limitation can be largely resolved by
1) using a decerebrate model to remove the cortical structures
from which central command originates; and 2) electrical
stimulation of the peripheral end of ventral roots to induce
nonvolitional contraction. In the present study, by using a
decerebrate rat model, we first observed that ExT improved the
exaggerated EPR function, as well as excessive sympathoexcitation during static contraction in CHF rats. Interestingly, we
noticed that, although ExT tended to attenuate EPR function in
sham rats, the effect did not reach statistic significance.
J Appl Physiol • VOL
The mechanism(s) by which ExT improves the exaggerated
EPR function remains unclear. Both central and peripheral
(muscle afferent) mechanisms may be involved in this process
in the CHF state. In the present study, ExT also attenuated the
exaggerated sympathoexcitation at rest in CHF rats, which was
consistent with the findings of Gao et al. (9) and Liu et al. (24),
who demonstrated that ExT normalizes the elevated RSNA in
rabbits with pacing-induced CHF. Futhermore, Gao et al.
reported that the beneficial effects of ExT on the excessive
sympathoexcitation in CHF state is at least partially mediated
by affecting central neural structures, such as the rostral ventrolateral medulla (9). Mueller and Hasser (33) also reported
that alterations in neurotransmission at the level of the nucleus
tractus solitarius contribute importantly to regulation of HR
and sympathetic nerve activity in ExT rats. Based on these
findings, it is reasonable to speculate that ExT may normalize
the exaggerated EPR, in part, via a central mechanism.
Another possibility is that ExT may attenuate the exaggerated EPR by affecting muscle afferent pathways. Previous
studies (5, 25) have shown that peripheral skeletal myopathy
develops in CHF (e.g., muscle atrophy, decreased peripheral
blood flow, fiber-type transformation, and reduced oxidative
capacity), which can be reversed by ExT (11, 13). Iwamoto and
Botterman (14) have reported that contraction of fast-twitch
fiber (type II) evoked a larger pressor response to static
contraction compared with slow-twitch fiber (type I) contraction, suggesting that type II fiber contraction may activate a
larger number of muscle afferent receptors. In the CHF state, a
muscle fiber-type shift from type I to type II could cause an
exaggerated EPR. Since muscle fiber-type transformation in
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Effect of ExT on the Exaggerated EPR in CHF State
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Fig. 7. Original record of the metaboreflex control of blood pressure, HR, and RSNA in response to hindlimb arterial injection of capsaicin
(1.0 ␮g/kg, 0.2 ml) in sham ⫹ Sed (A), sham ⫹
ExT (B), CHF ⫹ Sed (C), and CHF ⫹ ExT (D)
rats. In the HR panel, the arrows point to artifacts. Capsaicin was injected during the horizontal bar.
CHF can be reversed by ExT (11, 13), the improvement of
abnormal fiber-type shift by ExT may subsequently affect
muscle afferent function, and eventually ameliorate the exaggerated EPR function in the CHF state. However, the hypothesis above remains to be tested.
Effect of ExT on the Abnormal Mechano- and Metaboreflex
Function in CHF Rats
Previous studies have established that there is an exaggerated EPR in CHF patients and animals (43, 46). Futhermore,
studies by Mostoufi-Moab et al. (30) and Middlekauff et al.
(27, 29) provide evidence that the mechanical component of
the EPR (mechanoreflex) is enhanced in CHF patients. Using a
decerebrate rat model, the studies of Smith et al. (47) and Li et
al. (23). reported consistent findings that the mechanoreflex is
elevated in CHF rats, which contributes to the exaggerated
EPR function in CHF (23, 47). Based on the finding that ExT
normalizes the exaggerated EPR function in the CHF state, it
was important to determine whether the mechanoreflex is
primarily affected by ExT. In the present study, we found that,
J Appl Physiol • VOL
compared with sham rats, CHF rats had an exaggerated mechanoreflex-evoked pressor and sympathoexcitatory response,
which confirmed the findings of Smith et al. (47) and Li et al.
(23). However, the exaggerated mechanoreflex function seen in
CHF was prevented by 8 –10 wk of ExT in the present study.
In addition, the response to contraction and stretch was characterized by pressor and sympathetic responses that were brief
at the onset of contraction or stretch and dissipated well before
the end of stimulation, a classical characteristic of mechanoreflex activation. It is highly possible that a 30-s static contraction predominantly activates the mechanical component of
EPR, as does passive stretch. This also may explain why ExT
had similar effects between EPR and mechanoreflex induced
by stretch in the present study. Therefore, the findings above
suggest that ExT may partially alter EPR function by affecting
the mechanoreflex in CHF rats.
The role of the metaboreflex in the exaggerated EPR function remains controversial. Based on measurements of ventilation, the studies of Piepoli et al. (39, 40) showed that CHF
patients had an overactive metaboreflex compared with control
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EXERCISE TRAINING AND EXERCISE PRESSOR REFLEX
1373
Fig. 8. Mean data showing the effects of ExT on pressor (A),
HR (B), and sympathoexcitatory (D) responses to arterial injection of capsaicin (0.1 or 1.0 ␮g/kg, 0.2 ml) in sham and CHF
rats. C: both baseline and capsaicin-induced RSNA were compared in sham ⫹ Sed, sham ⫹ ExT, CHF ⫹ Sed, and CHF ⫹
ExT rats. Values are means ⫾ SE. *P ⬍ 0.05 vs. sham ⫹ Sed
and sham ⫹ ExT. †P ⬍ 0.05 vs. baseline RSNA. #P ⬍ 0.05 vs.
CHF ⫹ Sed.
Effect of ExT on Cardiac Function
Table 2. Tension-time indexes for either static contraction
or passive stretch in sham ⫹ Sed, sham ⫹ ExT, CHF ⫹
Sed, and CHF ⫹ ExT rats
Tension-Time Index, kg ⫻ s
Group
n
Contraction
Stretch
Sham ⫹ Sed
Sham ⫹ ExT
CHF ⫹ Sed
CHF ⫹ ExT
13
13
13
13
15.6 ⫾ 2.4
16.3 ⫾ 2.8
15.1 ⫾ 2.2
15.8 ⫾ 2.7
15.3 ⫾ 2.9
15.9 ⫾ 2.6
15.7 ⫾ 2.5
15.5 ⫾ 2.7
Values are means ⫾ SE; n, no. of rats. There were no significant differences
(P ⬎ 0.05) between means in any one group.
J Appl Physiol • VOL
nephrine, indicating that the muscle metaboreflex-induced
sympathoexcitation is augmented but not decreased in CHF.
Therefore, the controversial conclusions that the metaboreflex
is blunted or exaggerated in CHF may be partially due to
different measurements of physiological parameters, such as
ventilation, blood pressure, and sympathetic nerve activity.
Different approaches used to activate the metaboreflex in these
studies may also contribute to the dispute about the blunted or
enhanced metaboreflex in CHF state. Here, following the
studies of Smith et al. (48), we confirmed their findings that the
pressor response to hindlimb administration of capsaicin was
blunted in CHF rats. Furthermore, we also found that ExT
slightly but significantly improved the blunted metaboreflex
activated by capsaicin in CHF rats. However, compared with
the effect of ExT on the exaggerated mechanoreflex in CHF
rats, the effects of ExT on blunted metaboreflex control of
blood pressure and sympathetic nerve activity were less. The
underlying mechanisms by which ExT affect the mechanoreflex and metaboreflex functions in CHF state remain to be
clarified.
In the present study, to evaluate the efficiency of ExT, we
measured the CS activity in skeletal muscle in all groups. The
data showed that ExT increased CS activity in skeletal muscle
in both sham and CHF rats, indicating the efficiency of ExT in
all groups. Although ExT modulated the exaggerated EPR as
well as excessive sympathoexcitation at rest and during exercise in the CHF state, ExT did not improve the decreased
cardiac function in CHF rats, indicating that the beneficial
effect of ExT on the exaggerated EPR was not mediated by an
improvement in cardiac function. In addition, previous studies
have reported that ExT improves skeletal myopathy in the CHF
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subjects. However, based on measurements of blood pressure
or sympathoexcitatory responses to postcontraction circulatory
arrest (an isolated activator of the muscle metaboreflex), the
studies of Sterns et al. (49), Negrão et al. (36), and Middlekauff
et al. (28) showed that the metaboreflex control of blood
pressure and sympathetic nerve activity was reduced in patients
with CHF (New York Heart Association classes II to IV),
indicating that metaboreflex function is blunted rather than
exaggerated in CHF patients. In animal experiments, the studies of Smith et al. (47, 48) and Li et al. (23) reported that the
pressor response to hindlimb injection of capsaicin (an exogenous metabolite to activate metaboreflex) was attenuated in
CHF rats, supporting the fact that the metaboreflex control of
cardiovascular function was blunted in CHF. However, by
activating the muscle metaboreflex via a reduction of blood
flow to the exercising muscles (hindlimbs) during dynamic
exercise in conscious dogs, Hammond and colleagues (12)
demonstrated that muscle metaboreflex activation in CHF
induces augmented HR response, exaggerated peripheral vasoconstriction, and secretion of renin, vasopressin, and norepi-
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EXERCISE TRAINING AND EXERCISE PRESSOR REFLEX
state and increases exercise performance (2, 11, 15, 19).
Interestingly, in this study, we found that TTI during static
contraction was not increased by ExT in sham and CHF rats.
Limitations
Summary
In conclusion, we have shown that ExT improves the exaggerated EPR, as well as the excessive sympathoexcitation
during static contraction in CHF rats. The beneficial effect of
ExT on the exaggerated EPR may be due to the normalization
of the enhanced mechanical component of EPR in CHF.
Finally, we also found that ExT partially improved the blunted
metaboreflex control of AP and RSNA in CHF rats. These
findings suggest that ExT, as a nonpharmacological therapeutic
strategy, has potential clinical value in reducing the elevated
sympathetic tone at rest and during exercise in the CHF state.
GRANTS
This work was supported by grant from National Heart, Lung, and Blood
Institute (PO1 H62222). H.-J. Wang was supported by a postdoctoral fellowship from American Heart Association.
DISCLOSURES
No conflicts of interest are declared by the author(s).
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