J Appl Physiol 102: 704 –712, 2007.
First published November 2, 2006; doi:10.1152/japplphysiol.00984.2006.
Acute sympathetic vasoconstriction at rest and during dynamic exercise in
cyclists and sedentary humans
D. Walter Wray, Anthony J. Donato, Steven K. Nishiyama, and Russell S. Richardson
Department of Medicine, University of California San Diego, La Jolla, California
Submitted 5 September 2006; accepted in final form 26 October 2006
sympatholysis; limb specificity
Furthermore, very little is known about the effect of chronic
exercise training on sympathetic vasoconstriction during acute
exercise. There is accumulating evidence from both animal and
human studies supporting the attenuation of sympathetically
mediated vasoconstriction in exercising skeletal muscle (52), a
phenomenon known as “functional sympatholysis” (39). Although it has been demonstrated that sympathetic outflow to
resting muscle (36, 37) and resting norepinephrine levels (54)
are largely unchanged following aerobic exercise training,
limb- and training-specific end-organ responses to sympathetic
activation during acute exercise remain uncertain. Considering
the array of metabolic and hemodynamic adaptations that occur
as a consequence of training, it indeed seems possible that the
degree of sympatholysis may differ between exercise-trained
and sedentary individuals.
Therefore, we applied a cold-stress stimulus to examine
whether sympathetically mediated vasoconstriction at rest and
during acute exercise would differ between sedentary and
exercise-trained subjects, and whether these differences would
be global or limb specific. Specifically, we hypothesized that 1)
sympathetic vasoconstriction in response to the CPT at rest
would be attenuated in both the arms and legs of exercisetrained subjects compared with sedentary controls; 2) in sedentary subjects, acute exercise would attenuate sympathetically
mediated vasoconstriction equally in the arms and legs; and 3)
in the exercise-trained subjects, sympatholysis would be limb
specific, such that acute exercise would attenuate sympathetically mediated vasoconstriction to a greater degree in the
trained legs compared with the relatively untrained arms.
EXERCISE TRAINING IS ASSOCIATED with an improvement of many
cardiovascular and autonomic parameters, which are viewed as
beneficial adaptations to the physiological demands of the
activity. In addition to global cardiovascular improvements,
exercise training provokes limb-specific adaptations in vascular structure according to the type of exercise performed (7,
14), and even improves vascular function in nontrained limbs
(5, 8, 12, 13, 15, 21, 56). In view of the numerous previous
studies in the area, it is therefore somewhat surprising how few
human studies have specifically assessed training-induced adaptations in sympathetic control of blood flow in trained and
untrained limbs. In humans, indirect measurements of blood
flow in the arm during sympathomimetic infusion and orthostatic challenge (48) as well as cold stimuli (33) have demonstrated a similar degree of forearm vasoconstriction between
leg-trained and sedentary subjects in response to the cold
pressor test (CPT). However, to our knowledge no studies to
date have utilized ultrasound Doppler measurements to address
the impact of exercise training on limb-specific resting sympathetic vasoconstriction in humans.
Sixteen young, healthy men [8 exercise-trained cyclists, maximal
oxygen consumption (V̇O2 max) ⫽ 64 ⫾ 2 ml䡠kg⫺1 䡠min⫺1; 8 sedentary
controls, V̇O2 max ⫽ 40 ⫾ 2 ml䡠kg⫺1 䡠min⫺1] participated in the present
study. The present study was reviewed and approved by the Institutional
Review Board committee of the University of California, San Diego, and
informed consent was obtained according to the University of California,
San Diego, Human Subjects Protection Program requirements. All subjects reported to the laboratory on three separate occasions, a preliminary
visit and 2 experimental days. On the preliminary screening day, health
history and activity questionnaires were completed, maximal handgrip
and maximal knee-extensor exercise capacities were determined, and
subjects performed a maximal exercise test on a cycle ergometer to
volitional exhaustion to evaluate (V̇O2 max). On experimental days, subjects reported to the laboratory at 0900 in the fasted state for the CPT
trials. Recognizing the variability of cardiovascular responses to the CPT
(27) and the possibility of adaptation to the cold stimulus, four CPT trials
Address for reprint requests and other correspondence: D. W. Wray, Dept.
of Medicine, Physiology Div., 9500 Gilman Dr., Univ. of California San
Diego, La Jolla, CA 92093-0623 (e-mail:[email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
704
METHODS
Subjects and General Procedures
8750-7587/07 $8.00 Copyright © 2007 the American Physiological Society
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Wray DW, Donato AJ, Nishiyama SK, Richardson RS. Acute
sympathetic vasoconstriction at rest and during dynamic exercise in
cyclists and sedentary humans. J Appl Physiol 102: 704 –712, 2007. First
published November 2, 2006; doi:10.1152/japplphysiol.00984.2006.—
The impact of exercise training on sympathetic activation is not well
understood, especially across untrained and trained limbs in athletes.
Therefore, in eight sedentary subjects (maximal oxygen consumption ⫽
40 ⫾ 2 ml䡠kg⫺1 䡠min⫺1) and eight competitive cyclists (maximal oxygen
consumption⫽ 64 ⫾ 2 ml䡠kg⫺1 䡠min⫺1), we evaluated heart rate, blood
pressure, blood flow, vascular conductance, and vascular resistance in the
leg and arm during acute sympathetic stimulation [cold pressor test
(CPT)]. The CPT was also performed during dynamic leg (knee extensor)
or arm (handgrip) exercise at 50% of maximal work rate (WRmax) with
measurements in the exercising limb. At rest, the CPT decreased vascular
conductance similarly in the leg and arm of sedentary subjects (⫺33 ⫾
8% leg, ⫺38 ⫾ 6% arm) and cyclists (⫺34 ⫾ 4% leg, ⫺31 ⫾ 9% arm),
and during exercise CPT-induced vasoconstriction was blunted (i.e.,
sympatholysis) in both the leg and arm of both groups. However, the
magnitude of sympatholysis was significantly different between the arm
and leg of the sedentary group (⫺47 ⫾ 11% arm, ⫺25 ⫾ 8% leg), and
it was less in the arm of cyclists (⫺28 ⫾ 11%) than sedentary controls.
Taken together, these data provide evidence that sympathetically mediated vasoconstriction is expressed equally and globally at rest in both
sedentary and trained individuals, with a differential pattern of vasoconstriction during acute exercise according to limb and exercise training
status.
705
SYMPATHETIC VASOCONSTRICTION AND EXERCISE TRAINING
were performed over 2 experimental days (2 trials each day) with a
counterbalanced design: 1) CPT at rest with blood flow measurements
made in the right arm, 2) CPT during handgrip exercise with blood flow
measurements made in the right (exercising) arm, 3) CPT at rest with
measurements made in the left leg, and 4) CPT during knee-extensor
exercise with measurements made in the left (exercising) leg. Each CPT
was preceded by at least 30 min of supine rest. For all CPT trials,
sympathetic activation was accomplished through immersion of the foot
in an ice-water slurry (1–3°C), which has been well documented as a
potent reflex stimulus capable of increasing muscle sympathetic nerve
activity (31, 44, 45) and plasma norepinephrine levels in both arm and leg
(18) without significantly elevating plasma epinephrine (2, 20, 28).
and 3 of the CPT and saved to the GE Logiq 7 hard drive for offline
image and waveform analysis.
Arterial blood pressure and heart rate. Arterial blood pressure was
measured on the left wrist using automated radial tonometry (Medwave Vasotrac APM205A, BioPac Systems, Goleta, CA), with one
measurement every 10 –15 s. Heart rate was recorded from a standard
three-lead ECG, an integral component of the Doppler system (Logiq
7, GE Medical Systems).
Vascular resistance and conductance. Vascular resistance and
conductance were calculated as:
Exercise Modalities
Conductance (ml䡠min⫺1 䡠mmHg⫺1) ⫽ blood flow/mean arterial pressure
Single-leg knee-extensor exercise was performed as described
previously (1, 40, 56). Briefly, the ergometer was adjusted so that
contraction of the quadriceps muscles turned a flywheel producing an
⬇90 –170° arc of the lower leg, and tension was incremented by
increasing friction on a belt surrounding the flywheel. Each subject
completed a one-leg maximal work rate (WRmax) test to volitional
exhaustion on the preliminary visit, and this WRmax value was used to
calculate an individual work rate of 50% WRmax for dynamic (1 Hz)
knee-extensor exercise.
Handgrip exercise was also performed, as described previously (10,
57). The handgrip exercise protocol was designed with a concerted
effort to modify the traditional static handgrip model to be more
dynamic (including pilot work assessing perceived effort) to facilitate
matching of arm and leg exercise modalities. A single maximal
voluntary contraction (MVC) was established for each subject using a
hydraulic handgrip dynamometer with an analog output (Rolyan
Ability One, Germantown, WI), and this MVC value was used to
calculate an individual work rate of 50% MVC for dynamic (0.5 Hz)
handgrip exercise. During the handgrip exercise, subjects were instructed to squeeze the dynamometer as quickly as possible, which
limited the isometric contraction phase to ⬍20% of the 2-s duty cycle.
Both arm and leg exercise was performed for 5– 6 min to achieve
steady-state blood flow conditions before the CPT commenced.
Both vascular resistance and conductance were calculated to allow
the most comprehensive evaluation of the degree of vasoconstriction
under various conditions. Others have concluded that resistance is the
more appropriate calculation when changes in blood pressure are
greater than changes in blood flow (such as the resting CPT), whereas
conductance best describes vasoconstriction when blood flow changes
dramatically (such as rest vs. exercise comparisons) (3, 24). The
magnitude of sympatholysis was calculated as:
Ultrasound Doppler. The ultrasound Doppler system (Logiq 7, GE
Medical Systems, Milwaukee, WI) was equipped with two linear
array transducers operating at an imaging frequency of 7– 8 MHz (leg)
and 10 MHz (arm). Vessel diameter was determined at a perpendicular angle along the central axis of the scanned area, where the best
spatial resolution was achieved. The common femoral artery of the
left leg was insonated distal to the inguinal ligament, ⬃2–3 cm
proximal to the bifurcation. The brachial artery of the right arm was
insonated approximately midway between the antecubital and axillary
regions, medial to the biceps brachii muscle. The blood velocity
profile was obtained using the same transducers with a Doppler
frequency of 4.0 –5.0 MHz, operated in the high-pulsed repetitionfrequency mode (2–25 kHz) with a sample volume depth of 1.5–3.5
cm. In duplex mode, real-time ultrasound imaging and pulse-wave
velocity profile were viewed simultaneously. All blood velocity measurements were obtained with the probe appropriately positioned to
maintain an insonation angle of 60° or less. The sample volume was
maximized according to vessel size and centered, verified by real-time
ultrasound visualization of the vessel. Using artery diameter and mean
blood velocity (Vmean), blood flow was calculated as:
Blood flow (ml/min) ⫽ Vmean␲ 䡠 (vessel diameter/2)2 䡠 60
At all sample points, arterial diameter and angle-corrected, timeand space-averaged, and intensity-weighted Vmean values were calculated using commercially available software (Logiq 7, GE Medical
Systems). Two digital ultrasound recordings and velocity spectra
segments of 20 –30 s were recorded at rest and during minutes 1, 2,
J Appl Physiol • VOL
Vascular conductance at rest [percent change (%⌬)]
⫺ vascular conductance during exercise (%⌬).
This index of functional sympatholysis reflects the ability of
muscle contractions to blunt the vasoconstrictor response observed
under resting and exercise conditions (9).
Tissue volume measurements. Forearm and thigh circumferences
(at three sites: distal end, proximal end, and one-third distal-toproximal end) and length were measured to calculate tissue volume
(19). Additionally, central and dorsal skinfold measurements were
taken to assess subcutaneous fat and allow an estimation of muscle
volume for the thigh and forearm (19). Muscle mass of the complete
forearm was then calculated from this anthropometrically measured
muscle volume by multiplying by the density of muscle (1.06 g/cm3).
On the basis of both an excellent agreement (⫾5%) and a high
correlation (r2 ⫽ 0.83) between this method and dual-energy X-ray
absorptiometry (Explorer, Hologic, Waltham, MA) documented in our
laboratory (10), we applied the following regression equation:
Forearm muscle mass (kg) 䡠 1.155 ⫺ 0.24
⫽ forearm muscle mass (kg)
Thigh muscle volume was converted to quadriceps muscle mass
with the use of the following equation:
Thigh muscle volume (liters) 䡠 0.307 ⫹ 0.353 ⫽ thigh muscle mass.
This anthropometrically determined quadriceps muscle mass, previously revealed to correlate highly with muscle mass assessed by
computer tomography (r2 ⫽ 0.86), was then corrected on the basis of
this relationship with the following equation (35):
Muscle mass (anthropometric; kg) 䡠 0.924 ⫺ 0.292
⫽ quadriceps muscle mass (kg)
It should be noted that these calculations do not remove the volume
occupied by bone.
Data Analyses and Statistics
For each ultrasound Doppler segment, Vmean was averaged across
the first and last half of the recorded clip (20 s), and diameter
measurements (1–3 per segment) were evaluated during diastole and
during the relaxation phase of the duty cycle during exercise, as
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Measurements
Resistance (mmHg 䡠 ml⫺1 䡠 min) ⫽ mean arterial pressure/blood flow
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SYMPATHETIC VASOCONSTRICTION AND EXERCISE TRAINING
Table 1. Subject characteristics at rest
Sedentary
Age, yr
Height, cm
Weight, kg
Maximal O2 consumption,
ml 䡠 kg⫺1min⫺1
Heart rate, beats/min
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
Mean arterial pressure, mmHg
Brachial artery diameter, cm
Common femoral artery diameter, cm
Maximal handgrip, kg
Maximal knee extensor, W
Handgrip 50% WRmax, kg
Knee extensor 50% WRmax, W
Forearm muscle mass, kg
Quadriceps muscle mass, kg
Cyclists
22⫾1
175⫾2
74⫾3
24⫾1
179⫾2
71⫾3
40⫾2
61⫾2
118⫾4
69⫾4
86⫾3
0.44⫾0.01
0.93⫾0.01
52⫾3
45⫾4
26⫾1
23⫾2
0.81⫾0.04
2.19⫾0.1
64⫾2*
54⫾2*
113⫾4
64⫾4
80⫾4
0.46⫾0.01
1.00⫾0.02*
50⫾3
82⫾7*
25⫾1
40⫾3*
0.86⫾0.04
2.46⫾0.1*
CPT Responses at Rest
During the resting CPT with measurements in the arm,
increases in heart rate and blood pressure were observed in
both groups (Table 2). Arm blood flow decreased significantly
only in the sedentary group (Fig. 2, Table 2), although vascular
conductance was reduced (Fig. 3, Table 2) and resistance
increased (Fig. 4, Table 2) to a similar degree in both cyclists
and sedentary subjects. During the resting CPT with measurements in the leg, heart rat, blood pressure, and vascular resistance increased in both groups, while blood flow and vascular
conductance decreased to a similar degree in both groups (Figs.
2, 3, 4, Table 2).
CPT Responses During Exercise
described previously (10, 56). Data during the CPT were analyzed
both in 1-min segments and averaged across the 3-min of the test.
Two-way ANOVA and repeated-measures ANOVA were used to
compare differences between limbs and groups, with the Bonferroni
test used for post hoc analysis when a significant main effect was
found. All group data are expressed as means ⫾ SE. Significance was
established at P ⬍ 0.05.
RESULTS
Subject characteristics for both groups are presented in
Table 1, and hemodynamic responses to the CPT at rest and
During handgrip exercise, heart rate increased similarly in
both groups, but remained significantly lower in cyclists than
sedentary controls during steady-state exercise (Table 2). Exercising arm blood flow, vascular conductance, and vascular
resistance were similar between groups (Table 2, Figs. 2, 3, and
4). When the CPT was applied during arm exercise, increased
heart rate and blood pressure were observed in both groups,
arm blood flow increased significantly (⬇31%) in the sedentary group, and arm blood flow in the cyclist was unchanged
(Table 2).
Table 2. Hemodynamic responses to the cold pressor test (3-min average) at rest and during exercise
Sedentary
Baseline
Blood flow, ml/min
Rest arm
Rest leg
Ex arm
Ex leg
MAP, mmHg
Rest arm
Rest leg
Ex arm
Ex leg
HR, beats/min
Rest arm
Rest leg
Ex arm
Ex leg
VC, ml 䡠 min⫺1 䡠 mmHg⫺1
Rest arm
Rest leg
Ex arm
Ex leg
VR, mmHg 䡠 ml⫺1 䡠 min
Rest arm
Rest leg
Ex arm
Ex leg
CPT
Cyclists
% Change
Baseline
CPT
% Change
62⫾8†
304⫾21†
334⫾39
2,953⫾316†
49⫾5
251⫾50*
363⫾62
2,898⫾283
⫺16⫾4
⫺16⫾9
⫹8⫾8
⫺2⫾7
104⫾5*
117⫾8*
109⫾6*
121⫾6*
⫹23⫾3
⫹28⫾5
⫹16⫾3
⫹16⫾3
93⫾12
386⫾45
296⫾44
1,943⫾117
68⫾8*
285⫾27*
350⫾39*
2,037⫾185
⫺23⫾8
⫺20⫾9
⫹31⫾12
⫹3⫾4
86⫾4
88⫾4
96⫾4
97⫾4
107⫾6*
107⫾7*
112⫾3*
111⫾4*
⫹20⫾4
⫹19⫾4
⫹16⫾2
⫹13⫾4
59⫾2
61⫾2
72⫾3
91⫾2
74⫾3*
69⫾1*
80⫾4*
98⫾3*
⫹27⫾6
⫹15⫾4
⫹9⫾3
⫹12⫾3
54⫾2†
54⫾2†
64⫾3†
89⫾4
57⫾2†
61⫾4*
70⫾5*
95⫾4
⫹8⫾4
⫹13⫾8
⫹11⫾6
⫹8⫾5
1.13⫾0.2
4.34⫾0.4
3.15⫾0.5
20⫾1
0.65⫾0.1*
2.79⫾0.4*
3.15⫾0.3
18⫾2
⫺38⫾6
⫺33⫾8
⫹13⫾11
⫺9⫾4
0.76⫾0.1
3.42⫾0.3
3.45⫾0.2
29⫾4†
0.48⫾0.1*
2.27⫾0.3*
3.24⫾0.4
25⫾3
⫺31⫾9
⫺34⫾4
⫺7⫾8
⫺12⫾7
1.07⫾0.2
0.25⫾0.03
0.41⫾0.07
0.05⫾0.01
1.99⫾0.3*
0.47⫾0.08*
0.36⫾0.04
0.06⫾0.00
⫹99⫾24
⫹93⫾27
⫺3⫾9
⫹12⫾4
1.50⫾0.2
0.31⫾0.03
0.30⫾0.02
0.04⫾0.01
2.52⫾0.4*
0.54⫾0.1*
0.35⫾0.04
0.05⫾0.01
⫹79⫾27
⫹77⫾20
⫹15⫾11
⫹22⫾14
85⫾3
91⫾5
95⫾6
105⫾5
Values are means ⫾ SE. CPT, cold pressor test (3-min average); MAP, mean arterial blood pressure; HR, heart rate; VC, vascular conductance; VR, vascular
resistance; Ex, exercise. *Significantly different from baseline (pre-CPT), P⬍0.05. †Significant difference between sedentary and cyclist groups. P⬍0.05.
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Values are means ⫾ SE. WRmax, maximal work rate. *Significant difference
between sedentary and cyclist groups, P⬍0.05.
during exercise are provided in Table 2. The physiological
response to the CPT over time is inherently variable. Thus, to
most accurately describe the measured responses, data are
presented in 10-s intervals (Fig. 1, n ⫽ 1), 1-min segment
(Figs. 2–5, all subjects), and the 3-min average response (text,
Table 2, Figs. 2–5, all subjects).
SYMPATHETIC VASOCONSTRICTION AND EXERCISE TRAINING
707
whereas leg blood flow was unchanged in both groups (Table
2, Fig. 2).
Magnitude of Sympatholysis
The percent change in vascular conductance during the
resting and exercising CPT was distinct between limbs and
groups (Fig. 3). To more comprehensively quantify these
changes, the difference in vascular conductance between rest
and exercise, or “magnitude of sympatholysis” (9), was calculated and is summarized in Fig. 5. In sedentary subjects, a
greater sympatholysis (i.e., metabolic blunting of sympathetic
vasoconstriction) was seen in the arm compared with the leg.
The sympatholytic response was similar between limbs in the
cyclists, with significantly less sympatholysis in the arm of
cyclists compared with sedentary subjects.
DISCUSSION
During leg (knee-extensor) exercise, heart rate was similar
between groups, and exercising leg blood flow and leg vascular
conductance were higher in the cyclists than sedentary controls, attributable to the higher absolute work rate in cyclists
(Table 2). When the CPT was applied during leg exercise,
increases in both heart rate and blood pressure were observed,
Fig. 2. Absolute blood flow values before (Pre)
and during a 3-min CPT at rest (black bars) and
during exercise at 50% of maximal work rate
(WRmax; gray bars) in the leg (top) and arm
(bottom) of sedentary and cyclist groups. For all
CPT trials, sympathetic activation was accomplished through immersion of the foot in ice
water. Values are means ⫾ SE. *Significantly
different from pre-CPT value, P ⬍ 0.05. ‡Significant difference between sedentary and cyclist
groups, P ⬍ 0.05.
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Fig. 1. Typical dynamic response to the cold pressor test (CPT; immersion of
the foot in ice water) at rest in the arm of a representative subject from the
cyclist group. bpm, beats/min.
The present study has provided several new findings regarding the impact of exercise training on sympathetically mediated
vasoconstriction at rest, and the blunting of this response
during acute exercise. Despite lower resting limb blood flow in
the cyclists, a similar vasoconstriction was observed in both the
arm and leg of the two groups in response to the CPT. Thus,
contrary to our stated hypotheses, vasoconstriction in response
to the CPT at rest was not affected by exercise training status
and was not limb specific. However, during acute exercise,
sympathetic vasoconstriction was blunted in the arms and legs
of both groups, and the magnitude of this sympatholysis was
significantly less in the arm of the cyclists compared with
sedentary controls. Taken together, these data provide evidence
that sympathetically mediated vasoconstriction is expressed
equally and globally at rest, with a differential pattern of
vasoconstriction during acute exercise according to training
708
SYMPATHETIC VASOCONSTRICTION AND EXERCISE TRAINING
Fig. 3. Changes in calculated vascular conductance from
pre-CPT values during a 3-min CPT at rest (solid black
bars) and during exercise at 50% of WRmax (solid gray
bars) in leg (top) and arm (bottom) trials in sedentary and
cyclist groups. Also shown is the 3-min average (avg)
response for the CPT at rest (hatched black bars) and
exercise (hatched gray bars). For all CPT trials, sympathetic activation was accomplished through immersion of
the foot in ice water. Values are means ⫾ SE. %⌬, Percent
change. *Significantly different from resting CPT trial,
P ⬍ 0.05.
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on June 18, 2017
Fig. 4. Changes in calculated vascular resistance from pre-CPT values during a 3-min
CPT at rest (solid black bars) and during
exercise at 50% of WRmax (solid gray bars) in
leg (top) and arm (bottom) trials in sedentary
and cyclist groups. Also shown is the 3-min
average response for the CPT at rest (hatched
black bars) and exercise (hatched gray bars).
For all CPT trials, sympathetic activation was
accomplished through immersion of the foot
in ice water. Values are means ⫾ SE. *Significantly different from resting CPT trial, P ⬍
0.05.
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SYMPATHETIC VASOCONSTRICTION AND EXERCISE TRAINING
709
status and perhaps training modality. This unique alteration in
exercising hemodynamic control between trained and untrained limbs exemplifies the systemic impact of limb-specific
exercise training, and teleologically it may represent an adaptation that optimizes the distribution of blood flow to meet
limb-specific demand in these individuals during exercise.
Limb Specificity and Sympathetic Vasoconstriction at Rest
In the present study, the CPT was utilized to activate skin
thermonociceptors, which subsequently provoked a profound
reflex increase in sympathetic nerve activity (25), with subsequent changes in heart rate, arterial blood pressure, and blood
flow. The typical cardiovascular response to the CPT in the
resting arm of a cyclist is illustrated in Fig. 1.
Expression of sympathetic activation in response to the CPT
has been well documented, with others demonstrating a robust
(⬎300%) increase in muscle sympathetic nerve activity (32,
44) that does not differ according to fitness (45) or between
limbs (42, 46). Similarly, the CPT elevates venous norepinephrine levels 40 – 60% to a similar degree in both arms and legs
(18) and does not differ between athletes and sedentary individuals (6, 16). These similarities in sympathetic activation
between limbs and fitness levels thus set the stage to explore
the end-organ translation of sympathetic activation into vasoconstriction, which to our knowledge has not been investigated
with ultrasound Doppler methodologies.
Others have recognized vascular limb specificity in response
to orthostasis (17), and sympathomimetics (34), whereas our
group (56, 57) and others (29, 30, 41) have identified marked
J Appl Physiol • VOL
differences in vascular reactivity between limbs. In a recent
study, Jacob et al. (18) evaluated adrenergic receptor sensitivity (change in vascular resistance) following sympathomimetic
drug infusion (phenylephrine and isoproterenol) and the CPT
in the arm and leg of younger, normally active volunteers. This
study reported a similar increase in local norepinephrine spillover in the arms and legs following the CPT, but interestingly
the calculated vascular resistance increased in the arm but
decreased in the leg, suggesting a limb-specific end-organ
response. However, during adrenergic drug infusions in the
same subjects the arm demonstrated a greater sensitivity to
phenylephrine and a lesser sensitivity to isoproterenol compared with the leg, suggesting that adrenergic-receptor differences cannot explain the paradoxical leg response. This study
thus provides convincing evidence for similar sympathetic
activation between limbs, but it provides no explanation for the
dissociation between sympathetic activation and its functional
correlate in the leg.
Despite these limb-specific differences in other experimental
paradigms, in the present study we observed similar changes in
vascular conductance and resistance in the arms and legs of
both cyclists and sedentary controls in response to the CPT at
rest (Table 2, Figs. 2 and 3). The reasons for the disparity
between the present data and those of Jacob et al. (18) may be
attributed to methodological differences (venous plethysmography vs. ultrasound Doppler in the present study) or age
(24 –50 yr vs. 19 –22 yr in the present study). These data thus
support the concept that sympathetically mediated vasoconstriction provoked by the CPT is expressed systemically at rest
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Fig. 5. “Magnitude of sympatholysis” in the
leg and arm of sedentary and cyclist groups,
i.e., the calculated difference in vascular conductance changes between rest and exercise to
the CPT. Data are reported for minutes 1, 2,
and 3 (solid gray bars) as well as the 3-min
average response (hatched gray bars). For all
CPT trials, sympathetic activation was accomplished through immersion of the foot in ice
water. Values are means ⫾ SE. *Significantly
different from leg, P ⬍ 0.05. ‡Significant
difference between sedentary and cyclist
groups, P ⬍ 0.05.
710
SYMPATHETIC VASOCONSTRICTION AND EXERCISE TRAINING
in the peripheral circulation (38), with no apparent selectivity
of this response between limbs.
Exercise Training and Sympathetic Vasoconstriction at Rest
Sympathetic Vasoconstriction During Acute Exercise
Although sympathetic activation is fully expressed in resting
muscle, recent studies indicate that this response may be
blunted in the exercising limb, an event know as functional
sympatholysis (52). In further support of this concept, we
observed smaller changes in both arm and leg vasoconstriction
during acute exercise compared with the resting CPT (Fig. 4).
These data extend recent observations by Koch et al. (22) that
leg blood flow did not change when the CPT was applied to
young subjects during upright cycling, although this study did
not include a resting CPT trial for comparison. In another study
involving cystic fibrosis patients and healthy controls, a 2-min
CPT was applied at rest and during handgrip exercise at 5–15%
of WRmax, but no sympatholysis was observed in the exercising forearm compared with rest (43). Again, the discrepancy
between these previous findings and the current data may be
due to methodological differences; for example, the present
protocol utilized a higher work rate in the arm (50% WRmax),
which is significant considering the suggested intensity-dependant nature of sympatholysis (4, 55). Thus, to our knowledge,
this is the first report of a blunted sympathetic vasoconstriction
in response to the CPT during limb-specific exercise in humans.
Sympatholysis and Exercise Training
Others have reported that exercise training results in a
reduction in muscle sympathetic nerve activity during acute
J Appl Physiol • VOL
Experimental Considerations
Several limitations must be considered when evaluating the
findings from the present study. The CPT is inherently variable, and it may evoke different afferent pain responses depending on the tolerance and sensitivity of the subject. In
addition, the possibility exists for adaptation when multiple
CPT tests are performed. To address these issues, by design
each subject served as his or her own control, a lengthy
recovery time was included in the protocol, and the order of the
CPT trials was counterbalanced to minimize any possible
ordering effect. Similar increases in mean arterial pressure
between the four trials confirm that the stimulus was comparable across tests and groups (see Table 2). It is noteworthy that
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Although several cross-sectional (45, 51) and longitudinal
(36, 47) studies have suggested that regular exercise training
does not significantly change resting MSNA, we hypothesized
that the actual expression of sympathetic activity would be
lessened due to limb-specific, training-induced changes in
end-organ (i.e., ␣-adrenoreceptor) function. Animal data are
equivocal regarding the effect of exercise training on limb
␣-adrenergic responsiveness. In rats, longitudinal training studies have demonstrated decreased sensitivity to sympathomimetics in the trained muscle (53) and no change (11) or
decreased sensitivity (50) in isolated arterial segments. In
addition, in situ studies have reported enhanced adrenergic
vasoconstriction in the untrained spinotrapezius muscle of the
exercise-trained rat (23). In humans, to our knowledge only
two studies have assessed the effect of exercise training on
␣-adrenoreceptor-mediated vasoconstriction. Smith et al. (48)
observed similar changes in arm blood flow (venous plethysmography) and arterial blood pressure in sedentary and endurance-trained subjects in response to both sympathomimetic
infusion and orthostatic challenge. Similarly, O’Sullivan et al.
(33) demonstrated a similar degree of vasoconstriction in the
forearm of trained and sedentary subjects in response to a
2-min CPT. Thus, the present findings utilizing ultrasound
Doppler measurements in both the arm and leg extend these
earlier findings, demonstrating that chronic exercise training
does not alter resting sympathetically mediated vasoconstriction to either trained or untrained limbs in young, healthy
subjects (Figs. 2 and 3, Table 2).
knee-extensor (36) and handgrip (49) exercise, a response that
appears to be limited to the trained limb (47). Thus one focus
of the present study was to identify potential limb-specific
responses to sympathetic vasoconstriction within both sedentary and exercise-trained subjects during acute exercise. These
comparisons are made with recognition of the caveat that
handgrip and knee-extensor exercise may produce different
metabolic stress in the exercising tissue. However, the similar
increases in mean arterial pressure from rest to exercise in the
arm and leg of both groups (Table 2) suggest that these
exercise modalities, although certainly not identical, may be
comparable.
Although leg blood flow and vascular conductance were
significantly higher in cyclists than sedentary subjects during
knee-extensor exercise (due to the higher absolute work rate),
the CPT during exercise did not cause significant change in
absolute leg vascular conductance in either group (Table 2).
These responses resulted in a similar calculated magnitude of
sympatholysis between sedentary (⫺24 ⫾ 8%) and cyclists
(⫺22 ⫾ 9%) (Fig. 5). In contrast to the leg, the magnitude of
vasoconstriction in the arm during exercise compared with rest
differed according to training status. In both the sedentary and
cyclist groups, absolute arm vascular conductance was significantly reduced during the resting CPT and unchanged during
the exercising CPT (Table 2). However, when these vascular
conductance changes are expressed as percent changes, the
magnitude of sympatholysis in the arm was significantly
greater in the sedentary group (⫺47 ⫾ 11%) than in the
cyclists (⫺28 ⫾ 11%) (Fig. 5).
From these results, it appears that vasoconstriction in the
arm of the cyclists is somewhat less inhibited (i.e., more
sympathetic vasoconstriction during exercise) than the sedentary group during exercise. We speculate that this response
may be due to increased ␣-adrenergic sensitivity, similar to
animal data demonstrating increased adrenergic vasoconstriction in the untrained (spinotrapezius) skeletal muscle of treadmill trained rats (23). Conceptually, this observed decrease in
arm sympatholysis compared with the sedentary group may
represent a training adaptation related to end-organ sensitivity
designed to ensure optimal distribution of blood flow to the
exercising legs, and it may serve to prevent possible overperfusion of the arm and potential blood flow “steal” from the
legs. However, further studies with measurements at multiple
exercise intensities are needed to determine the mechanism
responsible for this intriguing response in the relatively untrained limb of competitive cyclists.
SYMPATHETIC VASOCONSTRICTION AND EXERCISE TRAINING
ACKNOWLEDGMENTS
We express our gratitude to all subjects who participated in the study.
GRANTS
This study was funded in part by National Heart, Lung, and Blood Institute
Grant HL-17731; the Stein Institute for Research on Aging; the University of
California San Diego Clinical Research Feasibility Fund; and Tobacco-Related
Disease Research Program Grant 15RT-0100.
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