Download Exercise and Blood Pressure

Exercise and Blood Pressure
Skeletal Muscle Signaling and the Heart Rate and
Blood Pressure Response to Exercise
Insight From Heart Rate Pacing During Exercise With a Trained and
a Deconditioned Muscle Group
Stefan P. Mortensen, Jesper H. Svendsen, Mads Ersbøll, Ylva Hellsten, Niels H. Secher, Bengt Saltin
Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017
Abstract—Endurance training lowers heart rate and blood pressure responses to exercise, but the mechanisms and consequences
remain unclear. To determine the role of skeletal muscle for the cardioventilatory response to exercise, 8 healthy young men
were studied before and after 5 weeks of 1-legged knee-extensor training and 2 weeks of deconditioning of the other leg
(leg cast). Hemodynamics and muscle interstitial nucleotides were determined during exercise with the (1) deconditioned
leg, (2) trained leg, and (3) trained leg with atrial pacing to the heart rate obtained with the deconditioned leg. Heart rate
was ≈15 bpm lower during exercise with the trained leg (P<0.05), but stroke volume was higher (P<0.05) and cardiac
output was similar. Arterial and central venous pressures, rate-pressure product, and ventilation were lower during exercise
with the trained leg (P<0.05), whereas pulmonary capillary wedge pressure was similar. When heart rate was controlled
by atrial pacing, stroke volume decreased (P<0.05), but cardiac output, peripheral blood flow, arterial pressures, and
pulmonary capillary wedge pressure remained unchanged. Circulating [norepinephrine], [lactate] and [K+] were lower and
interstitial [ATP] and pH were higher in the trained leg (P<0.05). The lower cardioventilatory response to exercise with
the trained leg is partly coupled to a reduced signaling from skeletal muscle likely mediated by K+, lactate, or pH, whereas
the lower cardiac afterload increases stroke volume. These results demonstrate that skeletal muscle training reduces the
cardioventilatory response to exercise without compromising O2 delivery, and it can therefore be used to reduce the load on
the heart during physical activity. (Hypertension. 2013;61:1126-1133.) Online Data Supplement
•
Key Words: cardiac output
■
exercise
■
skeletal muscle
A
difference in training status of the exercising skeletal
muscle, such as obtained by 1-legged training or immobilization, leads to a markedly lower heart rate (HR) and blood
pressure response when 1-legged exercise at the same workload is performed with the best trained leg.1,2 These observations indicate that training-induced changes in HR and blood
pressure responses to exercise are sensitive to other factors than
changes in the central circulation (ie, heart size3,4 and left ventricular function5,6) and that factors within the skeletal muscle1,7
play a role in the altered cardioventilatory response to exercise
with exercise training. However, the regulatory ­mechanisms
and consequences for the training-induced changes in central
and peripheral hemodynamics remain unclear.
During exercise, sympathetic nervous activity is increased8
by influence from a central feed forward mechanism (central
command) and contracting skeletal muscle (the exercise
pressor reflex),9 resulting in an intensity-dependent increase
in HR, ventilation, blood pressure, and vasoconstriction
in the inactive tissues.9,10 Afferent fibers located within the
■
sympathetic activity
skeletal muscles respond to mechanical distortion (group III)
and changes in the chemical environment (group IV),11 and
are thought to contribute to the cardioventilatory response
to exercise.12 Physical training attenuates the increase in
sympathetic nerve activity during exercise13 and leads to
local adaptations, such as an elevated number of capillaries
and a higher mitochondrial capacity affecting both aerobic
and anaerobic metabolism.14 Interstitial potassium (K+),15,16
pH, lactate, and adenosine have been suggested to contribute
to the exercise pressor reflex by stimulating and sensitizing
group IV fiber afferents in skeletal muscle,11 although their
individual contributions remain controversial.11,17,18 Recently,
ATP has been suggested to stimulate group IV afferents,19
and a role for ATP is supported by the tight coupling between
interstitial ATP concentrations and exercise intensity20 and
the relation between interstitial ATP and norepinephrine (NE)
concentrations during exercise.21,22
This study investigated the role of the training status of
skeletal muscles on cardiovascular responses to exercise. A
Received October 10, 2012; first decision February 7, 2013; revision accepted February 8, 2013.
From the Copenhagen Muscle Research Centre (S.P.M., N.H.S., B.S.), Department of Cardiology (J.H.S., M.E.), and Department of Anesthesia (N.H.S.),
Rigshospitalet, Copenhagen, Denmark; The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark (J.H.S.); and
Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark (Y.H.).
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.
111.00328/-/DC1.
Correspondence to Stefan P. Mortensen, Centre of Inflammation and Metabolism, Rigshospitalet, Section 7641, Blegdamsvej 9, 2100 Copenhagen,
Denmark. E-mail [email protected]
© 2013 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.111.00328
1126
Mortensen et al Cardiovascular Regulation and Muscle Training 1127
Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017
secondary aim was to evaluate whether muscle interstitial
ATP affects afferent feedback from the contracting muscle.
We measured hemodynamics and muscle interstitial nucleotides and adenosine concentrations at rest and during exercise
with a control leg, a trained leg, and a deconditioned leg. A
large difference in muscle training status within the same individual was obtained by training 1 leg for 5 weeks, while the
contralateral leg was immobilized for 2 weeks before the final
experimental day. The importance of training-induced difference in HR response to exercise was evaluated by increasing HR during exercise with the trained muscle to the same
HR as established during exercise with deconditioned leg.
Our hypothesis was that the training status of the contracting
muscles influences cardioventilatory response to exercise at a
given workload by lowering the relative exercise intensity of
skeletal muscle and sympathetic activation. Furthermore, our
hypothesis was that exercise training alters skeletal muscle
interstital ATP signaling, and thereby contributes to attenuated
cardioventilatory response to exercise.
Methods
Eight recreationally active male subjects with a mean (±SD) age of
24±4 years, body weight of 77±11 kg, height of 184±7 cm, and a
maximal oxygen uptake (Vo2max) of 47±5 mL/min per kilogram participated in the study. All subjects had a normal ECG and blood pressure and were not taking any medication. The subjects were informed
of the risks and discomforts associated with the experiments before
giving their informed consent to participate. The study was approved
by the Ethical Committee of the Capital Region of Denmark (H-12009-081) and conducted in accordance with the guidelines of the
declaration of Helsinki. No complications in connection to the invasive procedures were observed.
Experimental Protocol
The subjects completed 5 weeks of 1-legged knee-extensor exercise
(3–4 times/week) and 2 weeks of immobilization with the other leg.
The subjects were examined on 1 experimental day (experimental
protocol 1) before the training/immobilization period and on 2 experimental days (experimental protocol 1 and 2, separated by 2 days)
after the training/immobilization period (Figure S1 in the online-only
Data Supplement).
Experimental Protocol 1 (Before and After the
Training/Immobilization Period)
A microdialysis probe was inserted into the vastus lateralis muscle
of the experimental leg(s) under local anesthesia (lidocaine).23 The
subjects completed 10 minutes of 1-legged knee-extensions (24±4
W, ie, 35% of maximal workload (WLmax) before the training/immobilization period). Exercise with the trained and deconditioned leg
was separated by 30 minutes of rest and the order was randomized.
Muscle dialystate was collected for 10 minutes before the start of
exercise, during exercise, and during the recovery from exercise (see
Methods in the online-only Data Supplement).
Experimental Protocol 2 (After the
Intervention Period)
Three catheters were placed under local anesthesia: A 20-G catheter
was inserted into the radial artery of the nondominant arm, a catheter
(131HF7, Edwards Lifesciences, Irvine, CA) was inserted in a left
antecubital vein and advanced to the pulmonary artery under pressure
guidance. A screw-in pacing electrode (Tendril ST, St. Jude Medical,
Sylmar, CA) was inserted through the right internal jugular vein and
advanced to the right atrium under x-ray guidance, where it was fixated in the atrial wall.
After 30 minutes of supine rest the subjects performed 3 minutes
of 1-legged knee-extensor exercise with the (1) deconditioned leg
(19±2, 38±4, 56±4 W), (2) trained leg (19±2, 35±4, 56±4, 75±5
W), and (3) trained leg with HR pacing (AAI mode) to elicit the
Figure 1. Cardiac output, heart rate,
stroke volume, and blood pressures
at rest and during exercise with a
deconditioned and trained leg with
and without atrial pacing. Data are
mean±SEM. *Different from rest,
P<0.05. #Different from deconditioned
leg, P<0.05. ¤Different from trained leg
without pacing, P<0.05.
1128 Hypertension May 2013
Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017
same HR as recorded during exercise with the deconditioned leg
(38±4 and 56±4 W; Figure S2). Exercise bouts were separated by
10 minutes of seated rest, whereas the 3 trials were separated by
30 minutes of supine rest. Leg blood flow and blood samples (pulmonary and radial artery) were obtained simultaneously before and
after 2.5 minutes of exercise.
HR was obtained from an ECG, while mean arterial pressure
(MAP), mean pulmonary pressure, pulmonary capillary wedge
pressure (PCWP), and central venous pressures (CVP) were monitored with transducers positioned at the level of the heart (Pressure
Monitoring Kit, Baxter, IL). The PCWP was determined as at the end
of expiration (PCWPend exp). Left ventricular transmural filling pressure
was expressed as PCWP minus CVP.24 Pulmonary Vo2 was measured
with a metabolic system (Quark CPET system, Cosmed, Italy). CO
was calculated using the Fick equation (CO=Vo2/a-vO2 difference).
Femoral arterial blood flow was measured with an ultrasound machine (Philips Ie33, Philips Healthcare, The Netherlands) equipped
with a linear probe operating at 5 MHz. Middle cerebral artery velocity was measured by transcranial Doppler (2 MHz) through the
temporal ultrasound window at a depth of 48 to 60 mm (Multidop X,
DWL, Sipplingen, Germany). Leg mass was calculated from wholebody dual-energy x-ray absorptiometry scanning (Prodigy, General
Electrics Medical Systems, WI).
Analytical Procedures
Blood gas variables, hemoglobin, lactate, and K+ concentrations
and pH were measured using an ABL725 analyzer (Radiometer,
Copenhagen, Denmark) and corrected for central venous temperatures. Plasma catecholamines concentrations were determined with
a radioimmunoassay (LDN, Nordhorn, Germany). Interstitial ATP,
ADP, AMP, and adenosine concentrations were determined by HPLC.
Statistical Analysis
A 2-way repeated measures ANOVA was performed to test statistical significance within and between trials. After a significant F
test, pair-wise differences were identified by the Tukey honestly
significant difference post hoc procedure. The significance level
was set at P<0.05, and data are mean±SEM for 8 subjects unless
otherwise indicated.
Results
Performance
WLmax during the incremental 1-legged knee-extensor test was
67±5 W before the intervention period and increased with
exercise training to 86±6 W (P<0.05), and was lowered with
detraining to 61±4 W (P<0.05). Consequently, the relative
workload during the experiment was 31±1%, 62±1%, and
91±1% of WLmax in the detrained leg, and 22±1%, 44±1%,
65±1%, and 87±1% of WLmax in the trained leg.
Systemic Hemodynamics During Exercise With the
Trained and Deconditioned Leg
Exercise increased cardiac output (CO) in proportion to the
workload and to similar levels during exercise with the trained
and deconditioned leg (Figure 1). However, HR was lower
when exercise was performed with the trained leg at 38 W
(105±3 and 118±3 bpm with the trained and deconditioned
leg, respectively) and 58 W (118±4 and 138±6 bpm, respectively; P<0.05), whereas stroke volume (SV) was higher (56
W; P<0.05). Exercise increased radial and pulmonary arterial
blood pressures, but both pressures were lower when exercise
was performed with the trained leg (Figures 1 and 2; P<0.05).
During exercise with the trained leg, CVP was reduced
compared with baseline (P<0.05), whereas CVP did not
change during exercise with the deconditioned leg. PCWP
increased from rest to exercise, and there was no difference
between values obtained during exercise with the trained and
Figure 2. Left ventricular performance during
exercise with a deconditioned and trained leg, with
and without atrial pacing. Note that stroke volume
during exercise with the deconditioned and trained
leg was coupled to the arterial blood pressure,
whereas stroke volume was more coupled to the
left ventricular filling pressure (transmural pressure)
during atrial pacing. Data are mean±SEM.
Mortensen et al Cardiovascular Regulation and Muscle Training 1129
Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017
deconditioned leg. The left ventricular contractility index
(dP/dtmax) increased similarly during exercise with the trained
and deconditioned leg (Figure 3). The rate-pressure product increased during exercise in both conditions (P<0.05),
but was lower during exercise (at 38 and 58 W) with the
trained leg compared with the deconditioned leg (P<0.05).
Pulmonary ventilation, tidal volume, and Vco2 were higher
during exercise with the deconditioned leg (P<0.05), whereas
the ventilatory frequency was similar (Figure 4). The Ve/Vco2
ratio was lower at 38 W (P<0.05) and tended (P=0.066) to
be lower at 19 W, whereas there was no difference at 56 W.
The lower exercise induced increase in HR and MAP during
exercise with the trained compared with the detrained leg was
detectable from 10 seconds after the onset of exercise, but the
difference was larger after 30 seconds of exercise compared
with the initial 30 seconds of exercise (P<0.05; Figure S3).
There were no significant differences in blood gas variables, hemoglobin, or O2 content between trials (Table S1).
Radial and pulmonary arterial lactate and K+ concentrations
were higher during exercise with the deconditioned leg (at
38 and 56 W; P<0.05), whereas pulmonary arterial pH was
lower (at 19 and 38 W; P<0.05). Plasma NE concentrations increased during exercise in all 3 trials, but was lower
during exercise with the trained leg at 56 W (P<0.05) and
tended (P=0.057) to be lower at 38 W. Plasma epinephrine
concentrations increased during exercise with the trained
Figure 3. Left ventricular contractility index (dP/dtmax), arterial
plasma norepinephrine (NE), and rate-pressure product at rest
and during exercise with a deconditioned and trained leg, with
and without atrial pacing. Data are mean±SEM. *Different from
rest, P<0.05. #Different from deconditioned leg, P<0.05.
leg at 75 W only (P<0.05), but there was no difference
between trials.
Effect of Atrial Pacing on Systemic Hemodynamics
During Exercise With a Trained Leg
Atrial pacing during exercise with the trained leg increased
HR to similar values as during exercise with the deconditioned
leg (123±5 [pace] and 119±3 [deconditioned] bpm at 38 W
and 141±7 [pace] and 138±6 [deconditioned] bpm at 58 W).
CO, SV, CVP, pulmonary arterial, and diastolic blood pressures were similar during the pacing trial and during exercise
with the deconditioned leg, whereas systolic blood pressure
and MAP were lower.
Compared with exercise with the trained leg without pacing,
CO during the pacing trial was similar because of a parallel
decrease in SV (P<0.05). Mean arterial and pulmonary
pressures, CVP, PCWP, dP/dtmax, and the rate-pressure product
were also unchanged, but atrial pacing lowered the systolic
pressure (P<0.05). Atrial pacing did not alter any blood gas
variables.
Figure 4. Pulmonary ventilation, respiration frequency, and
tidal volume at rest and during exercise with a deconditioned
and trained leg with and without atrial pacing. Data are
mean±SEM.*Different from rest, P<0.05. #Different from
deconditioned leg, P<0.05.
1130 Hypertension May 2013
Effect of Exercise With a Trained or Deconditioned
Leg on Peripheral Hemodynamics
Leg blood flow was lower during exercise with the trained leg
­compared with exercise with the deconditioned leg at 38 W
(P<0.05) and tended (P=0.063) also to be lower at 56 W,
whereas there was no difference in leg vascular conductance
between the 2 legs (Figure S4). Middle cerebral artery Vmean
increased during exercise at 19 W with both the trained and
deconditioned leg, whereas it only tended to increase (P=0.062–
0.070) at higher workloads. There was no difference in middle
cerebral artery Vmean or cerebral conductance index between when
exercise was performed with the trained or deconditioned leg.
Muscle Interstitial Nucleotide and Adenosine
Concentrations
Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017
Muscle interstitial ATP, ADP, AMP, and adenosine concen­
trations were similar in the 3 conditions at rest and increased
during exercise, and returned to baseline concentrations in
the recovery period (Figure 5 and Table S2; P<0.001). The
ATP concentration was, however, lower during exercise
with the deconditioned muscle compared with exercise with
the control and trained muscles (P<0.05), whereas ADP,
AMP, and adenosine concentrations were similar. The total
interstitial nucleotide/nucleoside concentration was higher in
the trained muscle compared with the deconditioned muscle
(P<0.05). In the nonexercising muscle, ATP, ADP, AMP, and
adenosine concentrations did not change from resting values
during exercise with the contralateral leg. Arterial and femoral
venous blood pressure, HR, and rate-pressure product from
this experimental day are presented in Table S3.
Discussion
Several findings in this study support an important role of the
training status of contracting skeletal muscles for the central
hemodynamic response to exercise. First, HR was lower during
exercise with the trained leg, whereas CO remained unaltered
because of a parallel increase in SV. Second, arterial, pulmonary, and central venous pressures were lower during exercise with the trained leg, whereas PCWP was similar. Third,
plasma NE concentrations were lower during exercise with
the trained leg. Fourth, interstitial ATP and venous pH were
higher during exercise with the trained leg, whereas mixed
Figure 5. Interstitiel ATP and adenosine concentrations at
rest and during exercise and the recovery from exercise in the
control, trained, and deconditioned muscle. Data are mean±SEM.
*Different from rest P<0.001. §Different from control leg,
P<0.001. ¤Different from trained leg, P<0.05.
venous lactate and K+ concentrations were lower. Collectively,
these results demonstrate that the central response to exercise
is tightly coupled to the training status of the contracting
skeletal muscle and the relative workload performed and that
these changes can occur independently of adaptations within
the central circulation and without compromising CO and O2
delivery. Reduced afferent feedback from contracting skeletal
muscle resulting in a lower sympathetic nerve activity in the
trained state seems to play an important role for the attenuated
HR and blood pressure response to exercise. Altered lactate
and K+ concentrations and pH, but not interstitial nucleotides
and adenosine, can contribute to the training-induced attenuated sympathetic activation.
Central Response to Exercise With a Trained and
Deconditioned Leg
To differentiate between the contribution of local and central
adaptations for the training-induced lowering of HR, we used
a set-up that created a large difference in the training status of
the leg muscles within the same central circulation. We found
that HR, blood pressure, and ventilation were lower when the
trained leg was exercising at the same workload, suggesting
lower activation of the sympathetic nervous system as confirmed by the attenuated NE response during exercise with the
trained leg.13 These differences were related to the changes
within the skeletal muscle that result in an increased WLmax,
because the responses were similar when expressed at the
same relative workload (Figure 6). Changes in HR and blood
pressure during exercise are tightly coupled to improvements
in Vo2max and thus relative exercise intensity.4 Here, we demonstrate that similar changes in SV, MAP, and HR can occur
independent of the central adaptations to exercise training (ie,
an increase in Vo2max, maximal CO, heart size, left ventricular
function, and blood volume).3,4 Importantly, the attenuated HR
and MAP response to exercise did not affect CO, because of a
parallel reverse change in SV. The unaltered CO during exercise with a trained and detrained muscle is consistent with the
tight coupling between O2 delivery and metabolic demand,25
but the regulatory mechanisms increasing SV when HR is
reduced in the trained state have been unclear. In the trained
leg, the higher SV seems to be coupled to a lower cardiac
afterload (arterial pressure) during exercise at a given workload, because the left ventricular contractility index and filling pressures were similar when exercise was performed with
the trained and deconditioned leg at the same workload. The
similar contractility index suggests that myocardial force production during exercise with the trained leg relies on cardiac
filing (Frank-Starling mechanism) or altered cardiac cycle
length (interval–force relationship).26 Consequently, the ratepressure product was lower during exercise with the trained
leg, indicating that the myocardial oxygen consumption was
reduced by ≈20% during exercise with the trained leg, despite
a similar CO.27
To evaluate the importance of the lower HR response to
exercise with the trained leg, HR was increased by atrial pacing during exercise with the trained leg to elicit the same HR
as during exercise with the deconditioned leg. The increase in
HR did not change CO or arterial pressures, suggesting that
the attenuated HR response with exercise training is not of
Mortensen et al Cardiovascular Regulation and Muscle Training 1131
Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017
Figure 6. Heart rate, blood pressure, and ventilation at rest and
during exercise with a deconditioned and trained leg with and
without atrial pacing plotted against the relative workload of the
leg. Data are mean±SEM. *Different from rest, P<0.05. ¤Different
from trained leg without pacing, P<0.05.
major regulatory consequence and that the difference in blood
pressure was not directly coupled to the lower HR. Instead,
the lower SV during atrial pacing was related to a reduction
in ventricular filling pressure, suggesting that an unaltered
venous return was the mechanism by which CO was maintained during the pacing trial. The similar CO and blood pressure levels with and without atrial pacing is in agreement with
observations in resting and exercising humans28 and dogs.29
Collectively, these observations suggest that CO and O2 delivery are regulated mainly by peripheral O2 demand28,30 and that
the regulation can occur independently of the lower sympathetic activation and consequently HR, blood pressure, and
ventilatory response to exercise in the trained state. The lower
HR during exercise in the trained state is paralleled by a higher
SV that occurs secondary to the reduced cardiac afterload.
Skeletal Muscle Signaling Mechanisms
The tight coupling between the relative load on the skeletal
muscles and cardioventilatory response demonstrates that
the training status of the skeletal muscles was driving these
changes, but the underlying signaling mechanisms are likely
to include several factors. First, exercise with the trained
leg was associated with lower mixed venous K+ and lactate
concentrations and a higher pH. Interstitial lactate concentrations increase with exercise intensity16 and blockade of
acid sensitive ion channels attenuates the pressor response
in cats.31 In support of a role of K+ and pH for the exercise
pressor reflex, a relationship between K+ concentrations and
MAP15 and between muscle pH and sympathetic activity has
been reported.32 Second, differences in central command
are also likely to have contributed to the observed change in
responses due to differences in the relative exercise intensity
between the 2 legs10 and consequently increased motor unit
recruitment and perceived exertion. Third, differences in circulating substances released from skeletal muscle may also
have contributed by stimulating peripheral chemoreceptors.
Also, the higher pH and lower Pco2 levels may have contributed to the lower ventilation during exercise with the trained
leg. Last, increased venous distension coupled to the higher
femoral venous blood pressures in the exercising detrained leg
may also have contributed by increasing afferent signaling.33
Although the relative contribution of each of these variables is
unclear, the difference in HR and MAP during exercise with
the 2 exercising legs was delayed such that it was larger after
30 seconds of exercise compared with at the onset of exercise. Group IV afferent fibers show a 5- to 15-second delay in
response from the onset of exercise reflecting their activation
by metabolic substances.10,12 Altered afferent feedback therefore seems to account for part of the observed differences in
cardioventilatory response.
The increase in muscle interstitial ATP concentrations during exercise was markedly lower in the deconditioned muscle.
The lower interstitial ATP concentrations but higher MAP,
HR, and plasma NE concentration during exercise with the
deconditioned leg suggest that ATP alone or in synergy with
other substances34 is not an obligatory mediator of the traininginduced changes in afferent signaling. ATP is released from
contracting skeletal muscle cells35 as well as from endothelial
cells in response to mechanical stress.36 The lower increase in
total adenine nucleotides and adenosine in the deconditioned
leg suggests that deconditioning lowered the release of ATP
into the interstitial space rather than a lower resynthesis of
ATP in the interstitial space from its breakdown products.
ATP can override sympathetic vasoconstrictor activity
(functional sympatholysis) in a similar manner as exercise.37,38
In the same subjects, we have found a coupling between the
muscle training status and the degree of functional sympatholysis during exercise.39 The sympatholytic properties of
ATP are not affected by the training status of the skeletal
muscles.23,39 The lower interstitial ATP concentrations and
impaired functional sympatholysis in the deconditioned leg
is in agreement with the observation that interstital ATP concentrations and the degree of functional sympatholysis during
exercise is lower in sedentary elderly compared with young
and trained elderly.23 Taken together, the coupling between
changes in interstitial ATP levels and the degree of functional
sympatholysis during exercise observations open up for the
possibility that the interstitial ATP plays a role in mediating functional sympatholysis during exercise, and thereby
contributes by optimizing the blood flow distribution within
the contracting muscle and the lowering of leg blood flow
with exercise training.23,40,41 Although the physiological role
1132 Hypertension May 2013
of ATP-sensitive P2Y2 receptors on smooth muscle cells of
human skeletal muscle42 remain undisclosed, the presence of
these receptors and the relatively high interstitial ATP levels as
compared with plasma ATP levels43 suggest a functional role
of interstitial ATP in the regulation of the vascular tone.
Conclusion
Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017
The lower HR, blood pressure, and ventilatory responses to
exercise at a given workload with a trained skeletal muscle
suggest that factors within the contracting skeletal muscle
contribute to a lower sympathetic activation during exercise.
Changes in skeletal muscle lactate and K+ concentrations and
pH are likely to contribute to these changes by altering afferent feedback, whereas the markedly lower interstitial ATP
concentrations during exercise with the previously immobilized leg suggest that interstitial ATP contributes to blood flow
regulation in other ways than by simulating muscle afferents.
The similar CO and O2 delivery, despite an 8% to 14% lower
HR and blood pressure during exercise with the trained leg,
suggest that adaptations within the skeletal muscles can result
in ≈20% lower myocardial work during exercise without compromising O2 delivery and aerobic metabolism.
Perspective
In cardiovascular diseases associated with an impaired muscle
perfusion, the exercise pressor reflex is augmented44 and physical inactivity is therefore likely to aggravate the sympathetic
response to exercise. In chronic heart failure, excessive ventilation coupled to increased skeletal muscle signaling impairs
exercise tolerance.45,46 Previous studies have demonstrated
that single leg training can improve peak leg Vo2 and exercise
capacity in patients, and single leg training is a well-tolerated
exercise model.47–49 Exercise training with 1 leg at a time can
therefore be a useful intervention to lower the blood pressure,
HR, and ventilatory response during exercise, improve skeletal muscle tissue perfusion and metabolism and, consequently,
lower the load on the heart during daily physical activities
while avoiding the acute strain on the central circulation associated with whole-body exercise.
Acknowledgments
The skilful technical assistance of Karina Olsen is gratefully
acknowledged.
Sources of Funding
This study was supported by a grant from the Lundbeck foundation. Dr Mortensen was supported by a grant from the Danish Heart
Foundation and The Danish Council for Independent ResearchMedical Sciences.
Disclosures
None.
References
1. Kanstrup IL, Marving J, Høilund-Carlsen PF, Saltin B. Left ventricular
response upon exercise with trained and detrained leg muscles. Scand J
Med Sci Sports. 1991;1:112–118.
2. Saltin B, Nazar K, Costill DL, Stein E, Jansson E, Essén B, Gollnick D.
The nature of the training response; peripheral and central adaptations of
one-legged exercise. Acta Physiol Scand. 1976;96:289–305.
3. Ekblom B. Effect of physical training on oxygen transport system in man.
Acta Physiol Scand Suppl. 1968;328:1–45.
4. Saltin B, Blomqvist G, Mitchell JH, Johnson RL Jr, Wildenthal K, Chapman
CB. Response to exercise after bed rest and after training. Circulation.
1968;38:VII1–78.
5. Levine BD, Lane LD, Buckey JC, Friedman DB, Blomqvist CG. Left
ventricular pressure-volume and Frank-Starling relations in endurance
athletes. Implications for orthostatic tolerance and exercise performance.
Circulation. 1991;84:1016–1023.
6. Pelliccia A, Culasso F, Di Paolo FM, Maron BJ. Physiologic left ventricular cavity dilatation in elite athletes. Ann Intern Med. 1999;130:23–31.
7. Clausen JP. Circulatory adjustments to dynamic exercise and effect of
physical training in normal subjects and in patients with coronary artery
disease. Prog Cardiovasc Dis. 1976;18:459–495.
8. Alam M, Smirk FH. Observations in man upon a blood pressure raising
reflex arising from the voluntary muscles. J Physiol (Lond). 1937;89:
372–383.
9. Mitchell JH, Kaufman MP, Iwamoto GA. The exercise pressor reflex: its
cardiovascular effects, afferent mechanisms, and central pathways. Annu
Rev Physiol. 1983;45:229–242.
10. Williamson JW, Fadel PJ, Mitchell JH. New insights into central cardiovascular control during exercise in humans: a central command update.
Exp Physiol. 2006;91:51–58.
11. Kaufman MP, Rybicki KJ. Discharge properties of group III and IV muscle afferents: their responses to mechanical and metabolic stimuli. Circ
Res. 1987;61(4 pt 2):I60–I65.
12. Amann M, Blain GM, Proctor LT, Sebranek JJ, Pegelow DF, Dempsey JA.
Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans. J Appl Physiol. 2010;109:
966–976.
13. Ray CA. Sympathetic adaptations to one-legged training. J Appl Physiol.
1999;86:1583–1587.
14. Blomqvist CG, Saltin B. Cardiovascular adaptations to physical training.
Annu Rev Physiol. 1983;45:169–189.
15. Fallentin N, Jensen BR, Byström S, Sjøgaard G. Role of potassium in the
reflex regulation of blood pressure during static exercise in man. J Physiol
(Lond). 1992;451:643–651.
16. MacLean DA, Imadojemu VA, Sinoway LI. Interstitial pH, K(+), lactate,
and phosphate determined with MSNA during exercise in humans. Am
J Physiol Regul Integr Comp Physiol. 2000;278:R563–R571.
17. Vissing J, MacLean DA, Vissing SF, Sander M, Saltin B, Haller RG. The
exercise metaboreflex is maintained in the absence of muscle acidosis:
insights from muscle microdialysis in humans with McArdle’s disease.
J Physiol (Lond). 2001;537(pt 2):641–649.
18. Cui J, Leuenberger UA, Blaha C, Yoder J, Gao Z, Sinoway LI. Local adenosine receptor blockade accentuates the sympathetic responses to fatiguing exercise. Am J Physiol Heart Circ Physiol. 2010;298:H2130–H2137.
19. Hanna RL, Hayes SG, Kaufman MP. alpha,beta-Methylene ATP elicits
a reflex pressor response arising from muscle in decerebrate cats. J Appl
Physiol. 2002;93:834–841.
20. Hellsten Y, Maclean D, Rådegran G, Saltin B, Bangsbo J. Adenosine concentrations in the interstitium of resting and contracting human skeletal
muscle. Circulation. 1998;98:6–8.
21. Li J, King NC, Sinoway LI. Interstitial ATP and norepinephrine concentrations in active muscle. Circulation. 2005;111:2748–2751.
22. Mortensen SP, González-Alonso J, Nielsen JJ, Saltin B, Hellsten Y. Muscle
interstitial ATP and norepinephrine concentrations in the human leg during exercise and ATP infusion. J Appl Physiol. 2009;107:1757–1762.
23. Mortensen SP, Nyberg M, Winding K, Saltin B. Lifelong physical activity
preserves functional sympatholysis and purinergic signalling in the ageing
human leg. J Physiol (Lond). 2012;590(pt 23):6227–6236.
24. Belenkie I, Smith ER, Tyberg JV. Ventricular interaction: from bench to
bedside. Ann Med. 2001;33:236–241.
25.Andersen P, Saltin B. Maximal perfusion of skeletal muscle in man.
J Physiol (Lond). 1985;366:233–249.
26.Seed WA, Walker JM. Review: Relation between beat interval and
force of the heartbeat and its clinical implications. Cardiovasc Res.
1988;22:303–314.
27.Nelson RR, Gobel FL, Jorgensen CR, Wang K, Wang Y, Taylor HL.
Hemodynamic predictors of myocardial oxygen consumption during
static and dynamic exercise. Circulation. 1974;50:1179–1189.
28. Bada AA, Svendsen JH, Secher NH, Saltin B, Mortensen SP. Peripheral
vasodilation determines cardiac output in exercising humans: insight from
atrial pacing. J Physiol. 2012;590:2051–2060.
29. White S, Patrick T, Higgins CB, Vatner SF, Franklin D, Braunwald E.
Effects of altering ventricular rate on blood flow distribution in conscious
dogs. Am J Physiol. 1971;221:1402–1407.
Mortensen et al Cardiovascular Regulation and Muscle Training 1133
Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017
30.Guyton AC. Regulation of cardiac output. N Engl J Med. 1967;277:
805–812.
31. Hayes SG, McCord JL, Rainier J, Liu Z, Kaufman MP. Role played by
acid-sensitive ion channels in evoking the exercise pressor reflex. Am J
Physiol Heart Circ Physiol. 2008;295:H1720–H1725.
32. Victor RG, Bertocci LA, Pryor SL, Nunnally RL. Sympathetic nerve discharge is coupled to muscle cell pH during exercise in humans. J Clin
Invest. 1988;82:1301–1305.
33. Cui J, McQuillan P, Moradkhan R, Pagana C, Sinoway LI. Sympathetic
responses during saline infusion into the veins of an occluded limb.
J Physiol (Lond). 2009;587(pt 14):3619–3628.
34. Light AR, Hughen RW, Zhang J, Rainier J, Liu Z, Lee J. Dorsal root
ganglion neurons innervating skeletal muscle respond to physiological
combinations of protons, ATP, and lactate mediated by ASIC, P2X, and
TRPV1. J Neurophysiol. 2008;100:1184–1201.
35. Cunha RA, Sebastião AM. Adenosine and adenine nucleotides are independently released from both the nerve terminals and the muscle fibres
upon electrical stimulation of the innervated skeletal muscle of the frog.
Pflugers Arch. 1993;424:503–510.
36.Burnstock G. Release of vasoactive substances from endothelial cells
by shear stress and purinergic mechanosensory transduction. J Anat.
1999;194 (pt 3):335–342.
37. Remensnyder JP, Mitchell JH, Sarnoff SJ. Functional sympatholysis during muscular activity. Observations on influence of carotid sinus on oxygen uptake. Circ Res. 1962;11:370–380.
38. Rosenmeier JB, Hansen J, González-Alonso J. Circulating ATP-induced
vasodilatation overrides sympathetic vasoconstrictor activity in human
skeletal muscle. J Physiol (Lond). 2004;558(pt 1):351–365.
39. Mortensen SP, Mørkeberg J, Thaning P, Hellsten Y, Saltin B. Two weeks
of muscle immobilization impairs functional sympatholysis but increases
exercise hyperemia and the vasodilatory responsiveness to infused ATP.
Am J Physiol Heart Circ Physiol. 2012;302:H2074–H2082.
40. Kalliokoski KK, Oikonen V, Takala TO, Sipilä H, Knuuti J, Nuutila P.
Enhanced oxygen extraction and reduced flow heterogeneity in exercising muscle in endurance-trained men. Am J Physiol Endocrinol Metab.
2001;280:E1015–E1021.
41. Saltin B, Mortensen SP. Inefficient functional sympatholysis is an overlooked cause of malperfusion in contracting skeletal muscle. J Physiol
(Lond). 2012;590(pt 24):6269–6275.
42.Mortensen SP, González-Alonso J, Bune LT, Saltin B, Pilegaard H,
Hellsten Y. ATP-induced vasodilation and purinergic receptors in the
human leg: roles of nitric oxide, prostaglandins, and adenosine. Am
J Physiol Regul Integr Comp Physiol. 2009;296:R1140–R1148.
43. Hellsten Y, Nyberg M, Mortensen SP. Contribution of intravascular versus
interstitial purines and nitric oxide in the regulation of exercise hyperaemia in humans. J Physiol (Lond). 2012;590(pt 20):5015–5023.
44. Khan MH, Sinoway LI. Muscle reflex control of sympathetic nerve activity
in heart failure: the role of exercise conditioning. Heart Fail Rev. 2000;5:
87–100.
45. Olson TP, Joyner MJ, Dietz NM, Eisenach JH, Curry TB, Johnson BD.
Effects of respiratory muscle work on blood flow distribution during exercise in heart failure. J Physiol (Lond). 2010;588(pt 13):2487–2501.
46.Olson TP, Joyner MJ, Johnson BD. Influence of locomotor muscle
metaboreceptor stimulation on the ventilatory response to exercise in
heart failure. Circ Heart Fail. 2010;3:212–219.
47. Magnusson G, Gordon A, Kaijser L, Sylvén C, Isberg B, Karpakka J,
Saltin B. High intensity knee extensor training, in patients with chronic
heart failure. Eur Heart J.. 1996;17:1048–1055.
48.Tyni-Lenné R, Gordon A, Jensen-Urstad M, Dencker K, Jansson E,
Sylvén C. Aerobic training involving a minor muscle mass shows greater
efficiency than training involving a major muscle mass in chronic heart
failure patients. J Card Fail. 1999;5:300–307.
49. Dolmage TE, Goldstein RS. Effects of one-legged exercise training of
patients with COPD. Chest. 2008;133:370–376.
Novelty and Significance
What Is New?
Summary
• A local difference in the training status of the contracting muscle alters
the heart rate and blood pressure response to exercise independently of
the central circulation
Local adaptations in skeletal muscle with exercise training can
lower the heart rate, blood pressure, and ventilatory response to
exercise without compromising tissue oxygen delivery.
What Is Relevant?
• Small muscle mass exercise training can lower the strain on the heart
during daily physical activity
Skeletal Muscle Signaling and the Heart Rate and Blood Pressure Response to Exercise:
Insight From Heart Rate Pacing During Exercise With a Trained and a Deconditioned
Muscle Group
Stefan P. Mortensen, Jesper H. Svendsen, Mads Ersbøll, Ylva Hellsten, Niels H. Secher and
Bengt Saltin
Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017
Hypertension. 2013;61:1126-1133; originally published online March 11, 2013;
doi: 10.1161/HYPERTENSIONAHA.111.00328
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/61/5/1126
Data Supplement (unedited) at:
http://hyper.ahajournals.org/content/suppl/2013/03/11/HYPERTENSIONAHA.111.00328.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/
ONLINE SUPPLEMENT
Skeletal muscle signaling and the heart rate and blood pressure response to exercise:
insight from heart rate pacing during exercise with a trained and a deconditioned muscle group
Stefan P. Mortensen1, Jesper H. Svendsen2,3, Mads Ersbøll2,
Ylva Hellsten4, Niels H. Secher1,5, Bengt Saltin1
1
The Copenhagen Muscle Research Centre, Rigshospitalet, Denmark,
2
Department of Cardiology, Rigshospitalet, Denmark
3
The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
4
Department of Exercise and Sport Sciences, University of Copenhagen
5
Department of Anesthesia, Rigshospitalet, Denmark
Correspondence to:
Stefan P. Mortensen, DMSC
The Copenhagen Muscle Research Centre and Centre of Inflammation and Metabolism
Rigshospitalet, Section 7641
Blegdamsvej 9, DK-2100 Copenhagen, Denmark
Phone +45 61717040
Fax +45 35457634
E-mail [email protected]
Expanded online methods and results section
Training and immobilization period
On the first visit to the laboratory, the subjects became accustomed to one-legged knee-extensor
exercise and an incremental test was performed to exhaustion to determine the maximal workload
(WLmax) for each leg. The training was randomized between the right and left leg and included a 5
min warm-up followed by 10 intervals of two minute exercise duration separated by a one minute of
recovery. The workload was adjusted such that the subjects were exhausted upon completion of
each training session. During the first training session the mean workload was 42±5 W and during
the last session it was 80±7 W. After three weeks of training, the contralateral leg was immobilized
using a lightweight fiber cast from above the malleoli to below the groin. The day before the first
experimental day, the cast was removed and the leg was passively moved to confirm full range of
motion.
Atrial pacing (experimental protocol 2)
Atrial pacing was performed in the AAI mode. In the AAI mode, the pacemaker withholds pacing when it
senses an intrinsic atrial electrical activation. If the pacing rate is higher than the intrinsic rate a pacing
stimulus will be delivered and this impulse will be conducted to the ventricles through the normal conduction
system, ensuring normal physiologic activation and relaxation of the ventricles.
Measurements
Microdialysis (experimental protocol 1)
The microdialysis probes were perfused at a rate of 5 µl min-1 with ringer acetate and to determine the
relative exchange of nuclotides and adenosine across the membrane, a small amount (2.7 nM) of [2-3H]ATP
was added to the perfusate for calculation of probe recovery. The molecular probe recovery (PR) was
calculated as [PR=(dpminfusate-dpmdialysate/dpminfusate], where dpm denotes disintegrations per minute (Scheller
& Kolb, 1991; Jansson et al 1994). The [2-3H]ATP activity (in dpm) was measured on a liquid scintillation
counter (Tri-Carb 2000; Copenhagen) after addition of the perfusate to 3 ml of Ultima Gold scintillation
liquid (Perkin Elmer). After collection of samples, the microdialysate was weighed, and the actual flow rate
was calculated to estimate any loss of fluid or abnormal decrease in perfusion rate.
Femoral arterial blood flow (experimental protocol 2)
Femoral arterial blood flow (LBF) was measured with ultrasound Doppler (Philips Ie33, Philips
Healthcare, The Netherlands) equipped with a probe operating an imaging frequency of 9 MHz and
Doppler frequency of 5.0 MHz. The site of blood velocity measurements in the common femoral artery was
distal to the inguinal ligament but above the bifurcation into the superficial and profound femoral branch to
avoid turbulence from the bifurcation. All recordings were obtained at the lowest possible insonation angle
and always below 60°. The sample volume maximized according to the width of the vessel, and kept clear of
the vessel walls. A low-velocity filter (velocities <1.8 m/s) rejected noises caused by turbulence at the
vascular wall. Doppler tracings and B-mode images were recorded continuously and doppler tracings were
averaged over 8 heart cycles. The arterial diameter of was determined after each doppler recording and
averaged over three cardiac cycles. Arterial diameter measures were assessed during the systole from arterial
B-mode images with the transducer parallel to the vessel.
Cardiac output (experimental protocol 2)
Q was calculated using the Fick principle (Q=VO2/a-vO2 difference). Pulmonary VO2 was measured online
(Quark CPET system, Cosmed, Italy). Pulmonary arterial blood samples were withdrawn over 20 seconds
and the measured VO2 values were averaged for the same time period. Heart rate (HR) was obtained from a
3-lead electrocardiogram.
Blood pressures (experimental protocol 2)
Radial arterial mean (MAP), systolic (SBP) and diastolic (DBP) blood pressure, mean pulmonary (PAP),
pulmonary capillary wedge pressure (PCWP) and central venous pressures (CVP) were monitored with
transducers positioned at the level of the heart (Pressure Monitoring Kit, Baxter) and connected to a
hemodynamic monitor (Dialogue 2000, Danica Elektronic, Copenhagen, Denmark). Determination of PCWP
was performed immediately after blood sampling.
Calculations (experimental protocol 2)
Stroke volume (SV) and systemic vascular conductance (SVC) was calculated as the quotient of Q (ml)
divided by HR and MAP, respectively. The left ventricular contractility index dP/dtmax was calculated as the
peak systolic value of the first derivative of the arterial pressure curve over 20 cardiac cycles. The ratepressure rate was calculated by multiplying HR by the systolic blood pressure.
Table S1 Blood gas variables, O2 content, plasma lactate and pH at rest and during exercise
Rest
Blood
variable
PO2
(mmHg)
ra
pa
Hemoglobin
(g/L)
ra
pa
O2
saturation
(%)
ra
pa
O2 content
(ml/L)
ra
pa
PCO2
(mmHg)
ra
pa
pH
ra
pa
Lactate
(mmol/L)
ra
pa
Potassium
(mmol/L)
ra
pa
Deconditioned
Trained
19±2 watts
Trained
before pace
trial
Deconditioned
Trained
38±3 watts
Deconditioned
Trained
56±4 watts
Trained
with HR
pacing
Deconditioned
Trained
75±5 watts
Trained
with HR
pacing
Trained
103±2
99±3
101±1
108±3#
102±2
107±3#
100±2
104±2
108±3
105±2
106±3
106±3
43±2
46±4
43±1
38±2
38±4
36±3*
35±2*
34±1*
32±2*
33±2*
33±1*
32±2*
143±4
143±4
143±3
142±3
146±3
145±3
146±5
146±5
147±3*
145±4
148±4
150±4*
148±3*
147±3*
150±3*
150±3*
154±3
154±4*
150±3*
150±3*
152±3*
151±4*
151±4*
152±3*
98.0±0.1
97.8±0.2
97.8±0.1
98.2±0.1
97.9±0.1
98.3±0.1
97.7±0.2
97.9±0.1
98.1±0.1
98.1±0.1
98.0±0.1
98.0±0.2
72.1±1.2
72.6±0.8
72.0±1.2
59.1±1.7*
58.9±1.2*
55.1±1.8*
54.8±1.9*
53.2±1.5*
48.3±2.6*
48.9±0.9*
50.1±1.7*
46.0±1.8*
190±6
140±4
190±4
140±3
195±5
141±4
195±6
117±5*
195±5*
116±5*
198±5*
112±4*
197±4*
109±5*
200±4
108±4*
206±4*
101±7*
200±4*
99±4*
40±1
46±1
37±2
43±2
40±0
44±1
41±1
51±1*#
40±1
48±2*
39±1
54±1*
41±1*
51±1*
40±1
50±2*
38±1
55±1*
39±1
54±2*
39±1
52±1*
38±2
55±2*
7.40±0.01
7.37±0.01
7.42±0.01
7.41±0.02
7.38±0.01
7.39±0.03
7.39±0.00
7.33±0.01*#
7.41±0.00
7.37±0.01*
7.39±0.00
7.32±0.00*#
7.40±0.00
7.35±0.00*
7.38±0.00
7.33±0.01*
7.39±0.01
7.31±0.00*
7.39±0.01*
7.32±0.00*
7.38±0.01
7.31±0.01*
7.39±0.01
7.30±0.01*
202±4*
103±5*
199±5*
94±6*
1.3±0.2
1.6±0.3
1.6±0.1
2.5±0.2*
1.8±0.3
3.2±0.3*#
2.2±0.3
2.9±0.5
4.2±0.5*#
3.4±0.4*
3.4±0.4*
4.8±0.5*
1.2±0.2
1.5±0.3
1.6±0.1
2.2±0.3*
1.7±0.3
3.0±0.3*#
2.1±0.3
2.7±0.5
4.4±0.5*#
3.4±0.5*
3.2±0.4*
5.1±0.7*
3.8±0.1
3.8±0.1
3.8±0.0
4.2±0.1*#
4.0±0.1*
4.5±0.1*#
4.1±0.1*
4.3±0.1*
4.7±0.1*#
4.5±0.1*
4.5±0.1*
4.6±0.1*
3.8±0.1
3.7±0.1
3.7±0.1
4.1±0.2*
3.9±0.1*
4.4±0.1*#
4.0±0.1*
4.2±0.2*
4.8±0.1*#
4.3±0.2*
4.3±0.2*
4.7±0.2*
RA: radial artery, PA: pulmonary artery. * different from rest, P<0.05, # different from trained muscle, P<0.05
Table S2 Interstitial nucleotides and adenosine at rest and during exercise
Nucleotide Control leg exercise (24±4 W)
Rest
ATP
(µmol/L)
ADP
(µmol/L)
AMP
(µmol/L)
Adenosine (µmol/L)
Control muscle
Exercise
Recovery
Deconditioned leg exercising (24±4 W)
Deconditioned muscle
Rest
Exercise
Recovery
Rest
Trained leg exercising (24±4 W)
Trained muscle
Exercise Recovery
Rest
Trained muscle
Exercise
Recovery
Deconditioned muscle
Rest
Exercise Recovery
0.3±0.2 3.9±1.2*
0.3±0.2
0.1±0.1 1.3±0.2*¤#
0.0±0.0
0.2±0.2 0.2±0.1
0.2±0.2
0.1±0.1 4.2±0.9*
0.4±0.2
0.1±0.1 0.2±0.1
0.1±0.0
0.1±0.0 3.7±1.3*
0.4±0.2
0.2±0.1 3.5±1.1*
0.1±0.0
0.3±0.2 0.4±0.1
0.3±0.2
0.2±0.0 4.7±1.1*
2.0±2.0
0.1±0.1 0.2±0.1
0.0±0.0
0.8±0.5 7.4±2.8*
1.4±0.5
1.0±0.4 11.3±4.1*
0.7±0.2
1.1±0.5 1.3±0.3
1.3±0.7
0.8±0.3 14.3±4.0*
1.2±0.3
0.7±0.3 1.0±0.6
0.3±0.2
0.2±0.1 1.4±0.3*
Total adenines (µmol/L) 1.4±0.6 16.5±5.2*
0.3±0.1
0.4±0.1 1.2±0.2*
0.3±0.1
0.2±0.0 0.4±0.1
0.2±0.0
0.3±0.1 1.0±0.3*
0.2±0.0
0.3±0.1 0.4±0.1
0.4±0.1
2.4±0.7
1.7±0.4 17.3±5.2*#
1.2±0.2
1.8±0.8 2.2±0.4
2.0±1.1
1.4±0.4 24.1±4.9*¤
2.3±1.3
1.0±0.4 1.8±0.6
0.8±0.2
* different from rest, P<0.05, ¤ different from control muscle, P<0.05 # different from trained muscle, P<0.05
Table S3 Arterial blood pressure, heart rate and rate-pressure product
Hemodynamic variable
Mean arterial pressure (mmHg)
Systolic pressure(mmHg)
Diastolic pressure (mmHg)
Femoral venous pressure (mmHg)
Heart rate (beats/min)
Rate-pressure product
Rest
94±2
127±2
78±1
71±2
Control leg exercising
Exercise
Recovery
106±3*
92±2
141±4*
123±6
84±2
77±2
91±3*
73±2
(beats/mmHg/sec)
8977±213 12913±598*
Hemodynamic variable
Change from rest to exercise
Control
Deconditioned Trained
Mean arterial pressure (mmHg)
Systolic blood pressure(mmHg)
Diastolic blood pressure (mmHg)
Femoral venous pressure (mmHg)
Heart rate (beats/min)
Rate-pressure product
(beats/mmHg/sec)
8901±473
12±3
15±3
6±3
20±2
13±2#
15±3
7±2
3.8±1.5#
24±3#
4±2¤
7±3
3±2
2.1±0.4
14±3
3936±567
4502±670#
2290±457
Deconditioned leg exercising
Rest
Exercise
Recovery
94±3
107±3*#
100±2
128±5
142±6*
131±4
76±3
83±3*
82±3
6.0±1.1
9.7±1.4*#
6.7±1.3
69±1
93±3*#
73±4
8787±417 13289±1020*#
9669±811
* different from rest, P<0.05, ¤ different from control muscle, P<0.05 # different from trained muscle, P<0.05.
Rest
98±2
128±5
78±3
6.2±1.1
71±3
Trained leg exercising
Exercise
Recovery
103±3¤
98±3
135±4
132±5
80±3
77±3
8.3±1.3*
6.0±1.7
85±2*
70±4
9295±687 11585±537*
9337±744
Figure
F
S1. Experimenta
E
al design. Sub
bjects completed an expeerimental dayy (experimen
ntal protocol 1)
before
b
a fivee week exerciise training period
p
of onee leg and two experimentaal days (expeerimental
protocol
p
1 an
nd 2) after th
he training period.
Three
T
weeks into the training period, th
he other leg w
was deconditio
oned (full leg cast). To enssure full rangee of
motion,
m
the cast was removed the day before
b
the firsst experimentaal day and paassive leg movvement was
performed.
p
A knee-brace (Don-Joy)
(
waas applied at a fixed positio
on (30°) until the second experimental dday.
Figure
F
S2. Experimenta
E
al protocol 2 (experimenttal day 3).
Subjects perfformed one-leegged knee ex
xtensor exerciise with the deconditioned
d
leg, trained leg
l and traineed
leg
l with atriaal pacing to th
he same heart rate observedd during exerccise with the deconditioned leg. The
workloads
w
weere selected based
b
on the peak
p
workloadd of the traineed leg. Red arrrows indicatee when bloodd
samples weree obtained. See text for detaails.
Figure S3 Difference in heart rate and blood pressure response between exercise with
a deconditioned and trained leg.
Difference in exercise
induced in
heart rate (betas/min)
35
§
30
25
§
20
15
10
5
Difference in exercise
induced increse in
blood pressure (mmHg)
0
20
§
15
§
10
5
0
0
20
40
60
Time (seconds)
§ different from < 30 seconds of execise, P<0.05
80
100
Figure S4
***
#
4
**
Deconditioned leg
Trained leg
Trained leg with HR pacing
2
MCA Vmean
(cm/s)
***
6
0
Leg vascular conductance
(ml/min/mmHg)
80
*
70
**
60
50
40
1.0
80
*
60
***
40
CVCi
(cm/s/mmHg)
Leg blood flow
(L/min)
8
***
**
20
0.8
0.6
0.4
0.2
0.0
0
0
20
40
60
80
100
0
20
Workload (W)
40
60
80
Workload (W)
Online figure 4 Leg blood flow, leg vascular conductance, middle cerebral artery mean blood
velocity (MCA Vmean) and cerebral conductance index (CVCi) at rest and during exercise with
a deconditioned and trained leg with and without atrial pacing.
* different from rest, P<0.05, # different from deconditioned leg, P<0.05
100