Differential control of heart rate and
sympathetic nerve activity during dynamic
exercise. Insight from intraneural recordings in
humans.
R G Victor, … , D R Seals, A L Mark
J Clin Invest.
1987;
79(2)
:508-516.
https://doi.org/10.1172/JCI112841
.
We used microelectrode recordings of muscle sympathetic nerve activity (MSNA) from the
peroneal nerve in the leg during arm exercise in conscious humans to test the concept that
central command and muscle afferent reflexes produce mass sympathetic discharge at the
onset of exercise. Nonischemic rhythmic handgrip and mild arm cycling produced graded
increases in heart rate and arterial pressure but did not increase MSNA, whereas ischemic
handgrip and moderate arm cycling dramatically increased MSNA. There was a slow onset
and offset of the MSNA responses, which suggested metaboreceptor mediation. When
forearm ischemia was continued after ischemic handgrip, MSNA remained elevated
(muscle chemoreflex stimulation) but heart rate returned to control (elimination of central
command). The major new conclusions are that: the onset of dynamic exercise does not
produce mass, uniform sympathetic discharge in humans, and muscle chemoreflexes and
central command appear to produce differential effects on sympathetic and parasympathetic
responses.
Research Article
Find the latest version:
Differential Control
of Heart Rate
and
Sympathetic Nerve
Activity
during
Dynamic Exercise
Insight from Intraneural
Recordings in Humans Ronald G. Victor,Douglas R. Seals, andAllyn L.MarkWith thetechnicalassistanceofJoan Kempf
Department ofInternal Medicine, VeteransAdministration MedicalCenter, and CardiovascularCenter, UniversityofIowa College of
Medicine; andDepartment ofExercise Science, UniversityofIowa, Iowa City, Iowa 52242
Abstract
We
used microelectrode recordings of muscle sympathetic nerveactivity (MSNA)
from the peroneal nerve in the leg during armexercise
in conscious humans to test the concept that central command andmuscleafferent
reflexes produce mass sympatheticdischarge
at the onset of exercise. Nonischemic rhythmichandgrip
and mild arm cycling produced graded increases in heart rateand arterial pressure but did not increase MSNA, whereasischemic
handgrip and moderate arm cycling dramaticallyin-creased
MSNA.
There was a slow onset and offset of the MSNA responses, which suggested metaboreceptor mediation. Whenforearm ischemia
wascontinued after ischemic handgrip, MSNAremained
elevated (muscle chemoreflex stimulation) but heart ratereturned to control (elimination of central command). Themajor
newconclusions are that: (a) the onset of dynamic exercisedoes
not produce mass, uniform sympathetic discharge in hu-mans, and (b) muscle chemoreflexes and central command appear toproduce
differential effects
onsympathetic
andparasympa-thetic
responses.Introduction
The onset
of
dynamic
exercise produces reflex changes
inefferent
autonomic
activity
thatincrease
heart rate(HR),'
cardiac output, vascularresistance,
andarterial
pressure(1-7).
Theseneurocir-culatory
responses have been attributed bothtoreflexesarising
within the
exercising
muscle(8-10),
mediatedby
chemically
sensitive and
mechanically
sensitive
muscle afferents(1 1-13),
and toneural
impulses arising
withinthe centralnervoussystem,associated
with the volitional component ofexercise,
termedcentral command
(14-17).
Apreliminaryreportof this workwaspresented atthemeetingof the AmericanSocietyfor Clinical
Investigation
inWashington, D.C.,
May, 1985,and in theYoungInvestigatorCompetition
ofthe AmericanCollege
ofCardiologyinAtlanta, March, 1986.
Addresscorrespondence toDr. Victor, Cardiology Division, Uni-versity ofTexas Health Science Center at Dallas, 5323 Harry Hines Blvd., Dallas,TX75235-9034.
Receivedforpublication24 June 1985andin
revisedform
6October 1986.1.Abbreviations usedinthispaper: HR,heartrate;
MAP,
meanarterialpressure; MSNA,
muscle-sympathetic
nerveactivity; MVC,
maximalvoluntarycontraction; RHG, rhythmic handgrip.
Tworelated tenets have greatly influenced the thinking about the
autonomic control of
thecirculation during exercise in hu-mans. The first is that the onset of dynamic exercise producesgeneralized, uniform activation of
sympathetic vasoconstrictoroutflow
aswell
astachycardia
(4, 18-20).This
postulated masssympathetic discharge is
thought to produce widespread reflexvasoconstriction, which
offsets metabolic vasodilation and helps tomaintain arterial
pressureduring rhythmic
musclecontrac-tion. The second
conceptis
that central command and muscleafferent reflexes
areredundant
controlmechanisms
thatinfluence the sameneural circuits
inbrainstem
andproduce comparableautonomic
effects (12, 21). Thus, it
has been assumed that bothmechanisms
promotesympathetic
excitation at the onset ofdy-namic exercise.
The goal of this study was to test these concepts with direct measurements
of sympathetic
nerve traffic. In contrast to theprevious studies of neurocirculatory
regulation during dynamicexercise
inhumans, which used only indirect indices of
sym-pathetic
nervousactivity,
weused
direct, microelectrode
re-cordings of
sympathetic
action
potentials (22) in conscious,
ex-ercising
humans.
Our
previous
work onstatic
exercise
in humansemphasized
the
importance of chemosensitive muscle afferents in triggering
sympathetic
excitation
innonexercising skeletal muscles during
static muscle contraction
(23).
In the presentstudies,
weper-formed
twoseries of
experiments
toexamine
the controlof
sym-pathetic
nerveactivity
and HRduring
dynamic
exercise.
First,
we
studied
responses torhythmic handgrip (RHG) with
andwithout
forearm
vascularocclusion
toalter themetabolic
state in theexercising muscle.
Wehypothesized
that
nonfatiguing,
nonischemic
rhythmic
contractions
wouldnottrigger
increases
in muscle
sympathetic
outflow
because theintermittent
relax-ation
would promote muscleperfusion
andwashout of
metab-olites
andthus minimize
thestimulation of
chemically
sensitive
muscle
afferents.
Toincrease
theconcentration of
muscleme-tabolites in the
vicinity
of
theafferent
nerveendings
within theexercising muscle,
wehadsubjects
perform
RHGduring
forearmarterial
occlusion with
apneumatic
cuffonthe upperarm.Wepostulated
that increased stimulation of muscle chemoreflexesduring
RHG withischemia
would promotesympathetic
exci-tation similar
tothatwhich
wehadobservedpreviously during
static exercise
that isaccompanied by
sustained increasesintissue pressure and decreases in muscle blood flow.Inthe second
series,
we used two-armcycling
to examineexercise of
alarger
musclemass atgraded
exercise intensities. Wepredicted
thatsympathetic
activation woulddevelop
and recoverslowly
atthebeginning
and end of exercise if thesym-pathetic
response weregoverned by metaboreceptors
that areinfluenced
by
thegradual
accumulation
andwashout of musclemetabolites.
Incontrast,sympathetic
excitation shouldbegin
and end
promptly
with theonsetandoffset of muscle contractionJ.Clin.Invest.
© TheAmerican
Society
forClinicalInvestigation,
Inc.ifthe response were mediated
by
either central command ormechanosensitive afferents. We also soughttodetermineifthere was athreshold work load for sympathetic neural excitation and if therewas adifference in the threshold for increases in muscle-sympathetic activityand in HR.Adissociationof HR and sym-patheticnerve responses wouldsupport theconcept that thetwo responsesaregoverned by different mechanisms.
Methods
Subjects
22 men and 3 women, ages 18-30 yr,participated in this study after providing written informedconsent. One subject participated in both seriesofexperiments. The studieswereapproved bythe institutional committeeon humaninvestigation.
Measurements
We measuredarterial pressure, HR, and efferent muscle-sympathetic nerve activity (MSNA) in the legduringrhythmic armexercise. HR (electrocardiogram), respiration (pneumograph), force of muscle
con-traction (dynograph), and MSNA (microneurography) were recorded continuouslyon aphysiologicrecorder(model 2800S;GouldInc.,Santa Clara, CA) atapaperspeed of 5 mm/s.Duringhandgrip exercise,blood pressure wasmeasured by sphygmomanometry from thenonexercising
arm. During arm cycling, systolic blood pressure was measured by sphygmomanometryfrom theleg;Korotkoff soundsweredetected with
adoppler probeplacedovertheposteriortibial artery. Arterial pressure wasmeasuredcontinuously withabrachial artery catheter(Seldinger technique) duringintravenous infusion of sodium nitroprusside.
Microelectrode
recording
ofsympathetic
nerve
activity
(microneurography)
Multiunitrecordings ofsympatheticnerveactivitywereobtained from
amusclenervefascicle in theright peronealnerveposteriortothe fibular head(22).Therecordingsweremadewith tungsten microelectrodes 200 Mumin diameter in theshaft, taperingtoanuninsulatedtipof 1-5 Mm.
Areference electrodewasinsertedsubcutaneously 1-3cmfrom the recording electrode. The electrodes wereconnectedto apreamplifier witha gain of1,000andanamplifierwithagainof 50. The neural activitywasthen fedthroughaband pass filter withabandwidth of 700-2,000 Hz. Formonitoringduring theexperiment,thefilteredneurogram wasroutedthroughanamplitude discriminatorto astorageoscilloscope andaloudspeaker. Forrecordingandanalysis,thefiltered neurogram wasfed through a resistance-capacitance integrating circuit (time constant 0.1 s)toobtaina meanvoltagedisplayof the neuralactivity.
There were three criteria foranacceptablerecordingof MSNA. First, weakelectricalstimulation (1-3 V, 0.2 ms, 1 Hz) through the electrode in the peroneal nerve elicited involuntary muscle contraction but no paresthesias. Second, tappingorstretching the muscles or tendons sup-plied by the impaled fascicle elicited afferent groups I and II mechano-receptordischarge, whereas stroking the skin in the distribution of the peroneal nerve did not evoke afferent discharge. Third, the neurogram revealed spontaneous, intermittent, pulse-synchronous bursts that in-creasedduring held expiration and phase 2 and phase 3 of a Valsalva maneuver,characteristic of MSNA (22). Evidence that such activity rep-resents efferent sympathetic nerve activity has derived from earlier studies
andincludes (a) interruption of the activity by local nerve block proximal but not distal to the recording site in the leg; (b) elimination of the activityby ganglionic blockade; and (c) conduction velocity approxi-mating 1 m/s (22). Neurograms that revealed spontaneous activity char-acteristic of cutaneous sympathetic activity were not accepted. This was
assessedusing an arousal stimulus (loud noise, skin pinch), which elicits bursts of cutaneous but not muscle-sympathetic activity. Three subjects
wereexcluded from the
protocols
because we wereunable toobtainsatisfactory
recordings
ofMSNA.Resting
nerveactivity
wasmeasuredfor 6-10min before beginning the experimental protocols to ensure that
astable baseline level of nerve activity had been obtained.
Experimental protocols (exercise interventions)
SERIES I
In 14subjectswestudied responsestoRHGusing three protocols designed
toexamine the autonomic effects of central command and muscle af-ferents both alone and in combination.
With the subject in the supine position, maximal voluntary
contrac-tion(MVC)wasdetermined before the exercise protocol using a Martin's dynamometer (Elmed, Inc., Addison, IL). Subjects performed brief, nonsustained, RHG contractions with the left hand (i.e., nondominant hand in all but onesubject)at a rateof - 40contractions/min withor
without arrested forearm circulation.
Responses to RHG alone. After a 2-min controlperiod, subjects per-formed three, 2-min bouts of RHGat 10, 30, and 50% MVC followed bya2-min recovery period. The rationale was that RHG would primarily engage central command andmechanically sensitive muscle afferents.
ResponsestoRHGduring forearm vascularocclusion. To increase the concentration of ischemic metabolites in the vicinity of the afferent
nerveendings within the exercising muscle, subjects performed RHG during forearm vascular occlusion. After control measurements, blood flowtothe left forearmwasarrested by inflation ofapneumatic cuff on the upperarm tosuprasystolic pressure (250 mmHg). Subjects then per-formed 2 min of RHGat30% MVC followed bya2-min recovery period (i.e.,relaxation withoutischemia).
Responsestomuscleischemiapost-handgrip. Subjects performed2 minofRHG during forearm ischemia with the vascular occlusion being maintained foranadditional 2 min after the cessation ofexercise. Vascular occlusionpost-handgripmaintains the stimulation of muscle chemore-flexes,while musclar relaxation eliminates central command and
me-chanicallysensitive muscle afferents.
Theorderofinterventionswasrandomized with 0-minrestperiods between interventions. During handgrip, subjectswereinstructedtorelax thenonexercising limbsandtobreatherhythmically.NoValsalva ma-neuvers wereobserved.
SERIES II
Toexamineeffects of exercise ofalargemuscle mass,westudied
re-sponsesto two-armcyclingatincreasingworkloads in six subjects.Arm
cyclingwasperformedwithsubjectsseateduprighton anelectronically brakedbicycleergometer(No.8430,cardiacstresstestingsystem; En-gineering Dynamics Corp., Lowell,MA). Aftera2-min controlperiod, subjects performed2-min boutsoftwo-armcycling (- 50rpms)at in-creasingworkloadsfrom0to80Wfollowedby2 minof recovery mea-surements.Exercise boutswereseparatedby 10-20-minrestperiodsto
allowthephysiologicvariablesto return tocontrol values andtoprevent musclefatigue. Allsixsubjectsreached40 W, fivesubjectsreached 60 W, and three subjects reached 80 Wbefore leg motion made further microneurographicmeasurementsimpossible. Two additional subjects
wereexcluded fromanalysis because of presyncopal vasodepressor re-actions in theupright position.
Subjectsalsoperformed2 minof RHG at 30 and 50% MVC in the sitting positionbeforestartingthe arm-cycling protocol to examine effects ofbody positiononresponsestoRHG.
HRandMSNA were measured simultaneously during arm cycling. The exercise protocol was repeated on a separate day to obtain
mea-surementsof systolic blood pressure by doppler-sphygmomanometry from the posterior tibial artery (along with simultaneous measurements ofHR).
After completion of the exercise protocol, each subject performed additional 2-min exerciseboutsatincreasing workloads until fatigue to determine maximum exercise capacity.
HRresponses to armcycling after atropine. To examine the sym-patheticcomponent of theHRresponse during graded arm cycling, the exerciseprotocolwasrepeatedon aseparatedayinfive of the sixsubjects whileHRwasmeasuredafterparasympatheticblockade with atropine
Comparison
of
MSNA
and
HR
responses during
intravenous
infusion ofsodium nitroprusside
In threeadditional subjects, we monitored intra-arterial pressure and compared HR and MSNA responsestoarterial baroreceptor inhibition during intravenous infusion ofsodium nitroprusside. The drug was diluted in 5% dextrose in water and infused into a peripheral vein at rates of 0.5-1.0 ug/kg per min for 2 min. The dose of nitroprusside was individ-ualized for each subjecttoproduceamaximalreduction in mean arterial pressure (MAP) of 10-15% below the baseline value. Baroreceptor in-hibition during nitroprussideprovidedaninternal control, i.e., a nonex-ercise stimulus forproducing increases in HR and MSNA.
Data
analysis
Sympatheticburstswereidentifiedbyinspectionfrom themeanvoltage neurogram and expressedasbursts per minute. The intraobserver vari-ability inidentifyingbursts is <5% while interobserver variability is
<10%(23).
Measurementsofblood pressurewereobtained duringthe lasthalf ofeachminute.Valuesfor MSNAand HR reflect themeaneither for theentireminuteorfor each30-sinterval.
Statistical analysiswasperformed using
analysis
of variance and the Bonferronimethod formultiple comparisons (24).Values of P<0.05 wereconsidered significant.Resultsareexpressedasmean±SE.Results
Exercise interventions
SERIES I
ResponsestoRHG alone (TableIandFigs. Iand 2). RHGat
10, 30, and 50% MVC produced graded increases in arterial
pressure and HR but did notincrease MSNA. For example,
during RHG at 50% MVC, MAP rose by +13±3 mmHg (P
<0.05) and HR rose by + 11±3
beats/min
(P < 0.05), but MSNAdidnotchange (AMSNA=- 1±3bursts/min,
P>0.10).Basal MSNA wassignificantly increased (P <0.05) from
19±1
bursts/min
sittingto28±4bursts/min
supine. However,the MAP, HR, and MSNAresponsesto RHGat 30 and 50%
MVCwerecomparable in both positions(Table I).
ResponsestoRHG during arrestedforearm circulation(Table IIand Figs. I and 2). During forearmvascular occlusion, RHG
at 30% MVC producedan augmentedpressor response anda
striking increase in MSNA (Fig. 2). However, the increase in sympathetic activity didnotbegin with theonsetof muscle
con-traction. TheMSNA didnotchange during the firstminute, but
increased markedly over control values (from 20±2 to 36±2
bursts/min,
P <0.05) during the second minute of ischemic handgrip (Table II).Table
LResponses to RHG
MAP HR MSNA
Supine Sitting Supine Sitting Supine Sitting
mmHg mmHg beats/min beats/min bursts/min bursts/min
Controlperiod
lst
min 90±1 61±1 18±12ndmin 92±1 64±1 18±1
RHG at 10% MVC
1st min 93±1* 64±1 15±1
2nd min 94±1* 64±1 16±1
Recoveryperiod
1st min 92±1 61±1 20±1
2nd min 91±1 62±1 18±1
Controlperiod
1st min 94±1 95±4 63±1 64±5 19±1 29±4
2nd min 95±1 95±4 63±1 63±6 19±1 27±3
RHGat30% MVC
1st min 98±1* 100±5* 67±1* 68±6 17±1 23±4
2nd min 101±1* 102±5* 68±1* 66±6 18±1 26±3
Recoveryperiod
1st min 96±1 96±4 62±1 61±6 21±1 28±3
2nd min 94±1 95±4 63±1 62±6 21±1 30±4
Controlperiod
1st min 94±1 94±5 63±1 61±2 19±1 25±4
2nd min 94±1 92±6 64±1 59±3 20±1 27±4
RHGat50% MVC
1st min 102±1* 103±8* 74±1* 71±3* 18±1 23±5
2nd min 107±1* 108±7* 75±1* 72±3* 18±1 23±5
Recoveryperiod
1st min 96±1 93±5 65±1 58±2 20±1 29±6
2nd min 94±1 92±5 64±1 58±1 20±1 29±4
Entriesaremean±SE for 6
subjects
at10%MVC,
14subjects
at30%MVC,and 9subjectsat50% MVC in the supine position and for 6 subjectsTable II. Responses
to RHGduring
Forearm Vascular OcclusionMAP HR MSNA
mmHg beats/min bursts/min
Controlperiod
lstmin 95±1 64±1 19±2
2nd min 95±1 65±1 20±2
RHG at30% MVC during vascularocclusion
1st min 105±1* 74±1* 17±2
2nd min 115±1* 77±1* 36±2*
Recoveryperiod
1st min 96±1 63±1 26±2*
2nd min 96±1 63±1 23±2
Controlperiod
1st min 95±2 62±1 19±2
2nd min 94±2 62±1 18±2
RHGat30% MVCduring vascularocclusion
1st min 104±2* 70±1* 20±2
2nd min 117±2* 73±1* 33±2*
Vascularocclusion post-RHG
1st min 113±2* 64±1 38±2*
2nd min 115±2* 62±1 39±2*
Recoveryperiod
1st min 96±2 65±1 24±2
2nd min 94±2 62±1 21±2
Entriesaremean±SE for 9subjectsinthe first sequence and for 12 subjectsin thesecond sequence.
* P<0.05vs.controlvalues.
Responses
tomuscle
ischemia
post-handgrip (Table
IIand
Fig.
1).
Whenforearm
circulatory
arrestwasmaintained after thecessation of RHG,
HRreturned
promptly
tocontrolvalues,
but MAP
and
MSNA remainedsignificantly (P
<0.05)
elevated. Indeed, MSNAtended
tobe higher during post-handgrip
muscleischemia
thanduring
the second minute of RHG.Three
subjects
experienced pain in the forearm during
vas-cular occlusion andmostsubjects experienced
mildparesthesias.
However, there was no
correlation between pain
and thein-creased
MSNA
produced by forearm ischemia during
orafter
RHG.
The
moststriking increases in MSNA
occurredin four
subjects
whoexperienced
nopain.
SERIES 2
Responses to two-arm cycling (Table III and Figs. 3, 4, and 5).
Mild
armcycling
at0,
10, and 20Whad no effect on MSNA butproduced graded increases
in HR and MAP. For example,during
armcycling at 20 W,HRincreased by 24 beats/min over controlvalves in session Aand by 22 beats/min in session B andsystolic
blood pressure rose by 25 mmHg but MSNA did notchange (Table III).Incontrast, MSNAincreased markedly during heavier
ex-ercise. Cycling
at 40 and 60 W increased MSNA by 69±16% and121±29% respectively over control valves (P < 0.05).Atworkloads that produced significant increases in
sym-pathetic
nerveactivity (e.g., 40 W), there was a temporal dis-sociation between responses of HR and MSNA (Fig. 4). HR roseA
MAP (mmHg)
ECG
93 106 95
Peroneal
Neurogram I
(MSNA)
Force toll,rrIt,,r 11 r I )
(% MVC) O
Control Rhythmic Recovery
Hndgrip
(30%MVC) iOs
B
MAP (mmHg) 94 115 94
ECG .. .. .
Peroneal
Neurogram
Force . r -_
(%MVC) oL _
Control Rhythmic Recovery Hatndgrnp
(30% MVC) i1n
plus
Vasular
Occlusion
C
125 123 95
ECG . . ...
H"rt
bemln me
_~~~~~~~~Oytrn_uuo O.Sn!4NoO
ocutur Font- lOtS
Occinoon tiundOrro
Figure 1. Recordings ofMSNA from one subject during three experi-mental interventions vs. rhythmichandgripat 30% of MVC. Data rep-resent the last 30 s of each
2-mmn
measurement period. (a) RHG alone did notincrease MSNA. (b) RHG during forearm vascular occlusion produced a striking increase in MSNA. (c) During maintenance of forearmvascular occlusion (muscle ischemia) after cessation of isch-emic handgrip, HR returned to control but MSNA remained elevated.most rapidly in the first30sof arm cycling(64±5to94±4 beats/
min,
P < 0.05) and showed little additional increase between the first and second minutes of exercise at 40 W(97±6to100±9 beats/min,PR > 0.10). Incontrast, MSNAdidnot increase sig-nificantly from control in the first 30sofcyclingat 40 W(from 31±5to34±6bursts/mmn;
F>0.1) butincreasedto41±6 bursts/min
atthe end of the firstminuteofcycling
(P < 0.05 vs.control) and increased further to54±10bursts/mmn
after the secondmin (P < 0.05 vs. firstminute).Fig.
5 depicts therelationship between changes in HR andMSNA for RHG at 10-50% MVC (both supine and
upright)
and armcyclingat
0-80iW.
During RHGandduring
armcycling at low workloads, HR increased by up to 25 beats/mm but MSNAdid
not increase. In contrast,during armn
cycling athigher workloads, whichincreased HRby>
25beats/min,
MSNA in-creased in proportion to the increases in HR.AMAP (mmHg)
10% 30% 50% 30%
- MVC j MVC
No Occl. during
Occl.
A HR
(beats/min)
18 r
9
0
A MSNA (bursts/min)
24
rP=NS
10%30%660%~ 30%o
L. MVC _j MVc
NoOccl. during OCClr
12
o
-4
Figure 2. Effects of forearm vascular occlusion (muscle ischemia) on re-sponsesduring the second minute of RHG. Valuesare
mean±SE
for 6subjects at 10% MVC, 14 subjects at 30% MVC, and 9 subjectsat50% MVC. Duringnonischemic handgrip at 10, 30,
and
50% MVC(clear bars), MAP and HR increased in proportion to intensity of contrac-tion, but MSNA did not increase. In contrast,during muscle ischemia RHG at only 30% MVC (solid bars)10% 30% 50% 30% produced anaugmented pressor
re-L.
MVC .J MVC sponse and astriking increase inNoOcci. during
OCCI MSNA.
HRfrom 63±5to119±10
beats/min
(P<0.05) and significantly decreased thepercentincreaseinheartduring all intensities ofarmcycling. Most importantly,atropineprevented the matching between exercise intensity and HR during mild cycling because heartincreased consistently by only 6-8%overcontrol values during mild exerciseateither0, 10,or20 W. Incontrast,there
was a significant increase (P< 0.05)inthe magnitude of HR
responseafter atropine duringarmcyclingasthe work loadwas
increased from 20to40Wand from40to60 W.
Responses to intravenous
infusion of
sodiumnitroprusside
(Table
IVand Fig. 7). Nitroprusside
infusionproduced
pro-gressive decreases in arterialpressureandprogressive increases
in HR and MSNA. The HR and MSNA responses to
nitro-prusside infusion followed parallel time-courses without alag intheonsetof the MSNAresponse.
Discussion
Thisstudy providesthe first direct measurements ofsympathetic
nerve traffic during dynamic exercise in humans. The major newconclusionsarethat central commandappearstoinitiate parasympatheticwithdrawal andtachycardiaattheonsetof
ex-ercise, whereasmuscle chemoreflex activation is importantin producing parallel activation of sympatheticoutflowtothe
non-exercising skeletal muscles and the heart(sinus node) during dynamic exercise. Animportant corollary is that the onset of
Peroneal
Neurogram
(MSNA)
200_ Heart Rate
(beats/min)
Posterior Tibial
Artery Systolic 150 170
Pressure (mmHg)
Control 20watts
rhythmic musclecontraction does notproducemass,uniform
sympathetic discharge in humans because themuscle
chemo-reflex isnotengaged
during
theinitialstageof mildormoderatedynamicexercise.
Differential control ofsympathetic
and parasympathetic re-sponsesby central command and
muscle chemoreflexes.HRand MSNAresponses weredissociated duringeachofseveraldifferent exercise interventions. The observations providestrongevidence thatthetworesponses areregulatedatleast inpartbydifferent mechanisms.Themoststriking example of this dissociationoccurred dur-ing gradedarmcycling when the increases in MSNA lagged
con-siderably behind the increases in HR, withrespecttobothtime
course and exerciseintensity. Thiscannotbe explained by an inherent lag insympatheticvs.parasympatheticresponsiveness because arterial baroreceptor deactivation during vasodilator infusion producedparallel increases in HR and MSNA without
anydelay in theonsetofthe MSNAvs.HRresponse.
Thelag in theonsetof sympathoexcitation in nonexercising muscleduring moderate and heavy contractions of large muscles andduring ischemic contraction of small musclessuggests
me-taboreceptor mediation. Mense and Stahnke (27) and Kaufman
etal.(28) have identified populations ofgroupIVmuscle
affer-entsincatsthat areactivated predominately orexclusively by ischemic rather than nonischemic contractions. During ischemic exercise, impulse activityintheseafferentsexhibitedadelayin
04*~4v
10s
188
40watts
225
60watts
Arm Cycling
Figure 3.RecordingofMSNA in theleg duringtwo-armcyclingatmild, moderate,andheavylevelsofintensity.Datarepresentthe last 25 sof each2-minmeasurementperiod.Mild exerciseat20Whadnoeffectonsympatheticneuralactivitybutproduceda25beat/minincrease inheart
rateanda20mmHgrise insystolicbloodpressure. In thissubject,the thresholdworkload forsympatheticactivation was 40W.
30r
15
Table III. HR,Arterial Pressure,andSympathetic Nerve ResponsestoArmCycling
Session A
HR MSNA
Control period Exerciseperiod Recoveryperiod Controlperiod Exerciseperiod Recoveryperiod Exercise
intensity Istmin 2nd min Istmin 2nd min Istmin 2nd min Istmin 2nd min Istmin 2nd min Istmin 2ndmin
W beats/min beats/min beats/min beats/min beats/min beats/min bursts/min bursts/min bursts/min bursts/min bursts/min bursts/min
74±7* 74±6* 62±6 61±5 81±6* 79±6* 63±6 60±5 84±5* 87±7* 65±7 61±6 96±5* 101±9* 76±9 64±8 104±4* llO±5*t 78±3* 61±2
28±6 33±3 31±5
33±5
29±4
32±5 31±3 28±4 28±5 27±3
28±5 27±5 32±3 30±4 30±4 30±4 32±3 30±3 31±6 33±8 33±5 31±6
38±6
49±1I**
38±7 32±551±12* 67±15*t 40±7* 31±5
Posterior tibialartery systolicpressure
Controlperiod Exerciseperiod Recoveryperiod Controlperiod Exerciseperiod Recoveryperiod
Exercise
intensity 1st min 2nd min Istmin 2nd min 1stmin 2nd min 1stmin 2nd min 1stmin 2nd min Istmin 2nd min W beats/min beats/min beats/min beats/min beats/min beats/min mmHg mmHg mmHg mmHg mmHg mmHg
0 59±4 61±4 73±5* 70+5* 56±5 58±4 166±8 165±8 179±8* 178±7* 168±8 170±7
10 60±3 61±4 79±5* 76±5* 57±4 58±4 167±8 167±8 184±7* 187±7* 172±7 170±6
20 60±4 59±4 84±5* 82±6* 59±4 58±4 165±7 167±8 186±7* 191±5* 175±7 170±7
40 58±4 61±4 91+6* 94+6* 65±6 59±4 168±8 167±8 200±6* 208±5*t 184±8* 180±8*
60 57±3 59±4 105±7* 109±7* 72±4* 58±3 162±5 164±8 212±7* 223±4*t 192±7* 185±10*
Entriesaremean±SEfor sixsubjectsat0-40 W andfivesubjectsat60 Wduringtwoseparateexperimental
sessions,
A(simultaneous
measure-mentsof HR and MSNA) andB(simultaneousmeasurementsof HR andposterior
tibialarterysystolic
pressure).HRresponsestoexercisewhere comparable in sessionsAand B. * P<0.05vs.controlvalues. t P<0.052ndvs.1stmin of exercise.theonsetof the excitatoryresponsein the first minute of muscle
contraction, increased progressively
during
the second minute of exercise,wasmaintainedatahigh level during postcontractionischemia,
anddecreased
graduallyduring
relaxation without ischemia (27). The strikingsimilarity
between the behavior of thesegroupIVafferents incatsand the MSNAresponsesduring80
MSNA
(bursts/ 40 min)
0 120 Heart
Rate
6
(beats!/6 min)
0
0 1020304.0 01.02.03040 0 1.0203040
FExefc-seA Exercise.q FExercseI
Time(min)
Figure4.Comparison of sympatheticnerve(MSNA) andHR re-sponsesduring 2 min ofarmcyclingat(A) 0, (B) 20, and (C)40 W. Valuesaremean±SE for six subjects. Mildexerciseat0and 20 W produced rapid, graded increases inHRbut hadnoeffectof
sympa-thetictraffic. Duringmoreintense exerciseat40 W, sympathetic activ-ityincreasedsignificantly;however,the neuralresponsedeveloped
moreslowly than the chronotropicresponse.
ischemic
contractions inhumans
supports the viewthat
che-mosensitive muscle afferents areimportant
in the control ofMSNA during dynamic
exercise inhumans.
Our
findings
areconsistent with previoushemodynamic
ob-servations,whichsuggestthattheneurocirculatory adjustments
tomild
dynamic
exerciseare notdependent
uponmuscle che-moreflexes(29, 30). In humans,
elimination of muscleafferent
input with selectivesensorynerve
block
did not attenuatetheincreases
in arterialpressureand HRduring mild, nonischemic
400r
0 0
0
300
MSNA 200 (% Control)
100
0
0 o
Q
0
*
U*
0o
0
0 10 20 30 40 50 60 70
AHeart Rate(beats/min)
Figure5. Relationship betweenthe HR and sympatheticnerve
re-sponsestoRHGat(filled circles 10-50% MVC) for19 subjectsand to
armcycling (open circles)at0-80Wfor6subjects.MSNA is
ex-pressedas apercentageof the controlvalues. During RHGandarm
cyclingatlowworkloads,HRincreasedbyupto25beats/minbut MSNA didnotincrease.Incontrast,duringarmcyclingathigher workloads, which increasedHR by>25beats/min,MSNAincreased in proportiontotheincreasesin HR.
64±5 63±5 63±5 64±5 60±3
0 63±6
10 63±5
20 62±5
40 63±5
60 60±2
Session B HR
160
Heart Rate (beats/min)80
0
I____
0 10 20 40 60 0 10 20 40 60
Exercise Intensity(watts)
Figure 6. HR in the control state (open bars) and during the second minuteof graded arm cycling (open bars) before (A) and after (B) atro-pine(0.04 mg/kg i.v.). Data are mean±SE for five subjects. Percent changes in HR from controltothe secondminute of exercise are also shown.Before atropine, HR responses were matched to the intensity of the exercise (P<0.05vs.responseat0load). When the parasympa-thetic component of the HR responsetoexercise was markedly atten-uatedafter atropine,gradedarmcycling began to produce graded
in-creasesin HR (P<0.05vs.responseat0 load)oncesubjectsattained
aworkload of 40 W.
exercise (29).
Indogs,
moderate decreases in muscle
perfusion
that would
potentiate
muscle chemoreflexes did
not accentuatethe
arterial
pressureand
HR responsestomild
dynamic
exer-cise
(30).
The
presentstudy
supportsprevious
reportsthat the
chron-otropic
responsesduring
the initial
stagesof
exercise
aredue
towithdrawal
of vagal
tone(6, 7, 31). The small residual increases
in HR
during
mild
armexercise
after
atropine
weremostlikely
due
toincomplete
muscarinic blockade
(limited by
the central
neural
side-effects
of
atropine
in human
subjects).
Because theparasympathetically
mediated
tachycardia
began promptly
atthe
onsetofexercise,
wesuggestthat this autonomic
adjustment
is mediated
by central command rather than
by
muscle
che-moreflexes.
Our data also
suggestthat there is
acomparable lag
in the
activation
of
sympathetic
drive
tothe sinus node and
tothe
nonexercising
skeletal muscles
during
graded
exercise in humans.
This relative
delay in the onset of sympathetic activation com-paredwith
the rapid onset of parasympathetic withdrawal isconsistent with
theview that muscle chemoreflexes are importantin
the control of sympathetic outflow to the heart as well asskeletal
muscle. However, we cannot exclude the possibility thatthe
onsetof sympathoexcitation
during dynamic exercise is also relatedin
part to acritical
level of central command and/ormechanosensitive
muscle afferent discharge.Mechanisms of
exercise pressor responses. Themechanisms
responsible
for
these increases in arterial pressure duringexercise appear todiffer
depending
uponthe
intensity
of the exercise and
the
presence orabsence
of
muscleischemia.
During mild exercise
thatdid
not produce musclesympa-thetic
activation,
arterial
pressureincreasedin proportion
toex-ercise
intensity and
in
parallelwith
the graded increases in HR.Thus,
it is likely
that the pressor response to mildexercise ismediated importantly
byconcomitant increases in HR andcar-diac
output.However,
becausethere is increasing
evidence thatregional
sympathetic
responses can behighly differentiated
(22, 32, 33), we cannotexclude the possibility that sympathetic activation in vascular beds other than that in skeletal muscle might alsocon-tribute
tothe
pressor responsein the early
stageof
exercise. Wespeculate that the
promptforearm
vasoconstrictor
responses,which
have been reported at the onset of leg exercise, areme-diated by
increased sympathetic outflow
to skin rather thanmuscle.
Becauseskin sympathetic activity, unlike
musclesym-pathetic activity,
is extremely responsive
toarousal stimuli
(22), cutaneousvasoconstriction
atthe
onsetof exercise probably
represents
anarousal
response.
Inaddition, previous studies
in-dicate that the
onsetof exercise is accompanied by
vasoconstric-tion
in the renal and splanchnic beds (4). Sympathetic activation
in the skin and viscera during exercise
may bemediated
bymechanisms
other thanmuscle
chemoreflexes.
During exercise that increased
MSNA,reflex
sympatheticactivation appeared
tohave
animportant influence
on the ex-ercisepressor response.The
striking increase in
MSNA duringischemic
handgrip
wasassociated with
a markedlyaugmentedTable
IV.ResponsestoIntravenousInfusion of
SodiumNitroprusside
Controlperiod Nitroprussideinfusion Recovery period
60s 120s 30s 60s 90s 120s 60s 120s
SubjectI
MAP(mmHg) 123 128 125 117 115 113 107 117
HR(beatsperminute) 76 76 76 86 92 102 106 84
MSNA
(bursts
perminute)
26 16 28 50 60 64 54 22 Subject2MAP(mmHg) 79 78 73 73 71 71 74 77
HR
(beats
perminute) 48 46 48 52 62 64 50 44MSNA(burstsper minute) 16 14 18 28 38 40 22 14
Subject3
MAP(mmHg) 90 89 83 83 83 82 85 94
HR(beatsperminute) 54 54 60 60 62 60 70 54
MSNA(burstsper
minute)
32 24 40 40 42 44 50 18Mean±SE
MAP(mmHg) 97±13 98±15 94±16 91±13 90±13 89±13 89±10 96±12
HR(beatsperminute) 59±9 59±9 61±8 66±10 72±10 75±13 75±16 61±12
MSNA(burstsperminute) 25±5 18±3 29±6 39±6 47±7 49±7 42±10 18±2
A
250 Arterial
Pressure 125 _
(mmHg) _
200 _ HeartRate
(Pbeots/min) 1_
PeronealI
Neurogrom
(MSNA)
B
Mean Arterial Pressure
(mmHg)
Heart
Rate
(bpm)
MSNA (bursts/mir
Figure
7.ceptorinh travenous
ing
ofartethetic acti
Nitroprus!
withoutattothe HR
nseinar
primaril3
rather th4,
at
only
3( thannonexercise ]
Mech
rhythmic
musclea presumal However
nonische
though
n ficient ccnotexclu
ferents
mrather
thInfluc
barorecel
hibitsan(
soconstri One reas
supine
pactivation
afferents.
increase
pulmona
Rhyt)
staticmu
increases in MAP than does rhythmic contraction, even when thetwoforms of exercise are performed to equivalent increases
in
oxygenconsumption (37-39).
The comparatively greaterpressor responseto
nonfatiguing static
vs.rhythmic
contraction has been attributed traditionally to two factors. First, during staticexercise,
sustained increases in intramuscular pressure causes passive(i.e.,
nonreflex) increases in vascular resistance___________________________________ because of mechanical hindrance to blood flow withinthe
con-Control Sodium(1,.g/kgNitroprussideInfusion
permin i.v.) tracted muscle(39,40). Second,
it
has beenproposed thatreflex
125 vasoconstriction is offset by greater metabolic vasodilatation
during dynamicthanduringstatic exercise(39-41). An
impor-100 _ tant feature of this studyis the suggestionthat theaugmented
pressor responsetostatic vs.rhythmiccontraction isexplained
75 in part bya difference in reflex rather than mechanical
mech-100 - anismsin these two modes of exercise (41).
In a
previous study (23),
we found that statichandgrip
at 7530%
MVCproduced
anaverage increase inMAPof 18mmHg
50 t I I andincreased MSNA from
21±3
to33±4
bursts/min.
Incon-50 trast, we found in this study that RHG at 30% MVC increased
F_ mean pressureby only 7 mmHg and did notincrease MSNA.
25 3 A
major
factorin thediscrepancy
between the pressor responsesto thesetwo forms of exercise may be that static contraction
0 produces chemoreflex-mediated increases in MSNA, whereas
Control 430s 60s 90s 120s
Nitroprusside 11111*
rhythmic contraction
doesnot.Theevidence for this postulateInfusion isthat RHG at 30% MVC
during
arrested forearmcirculationComparison
of MSNA andHRresponsestoarterial barore- increased MAPby
20mmHg
andincreased MSNA from 20±2 ibitionduringdecreasesinarterialpressureproduced byin- to36±2
bursts/min.
These responses toischemicrhythmic con-infusion of sodiumnitroprusside.
(A)Acontinuous record- traction are comparable to those seen during static handgrip, rialpressure,HR(cardiotachometer),
and musclesympa- which causes sustained increases in tissue pressure.vity
inonesubject. (B) Average responses
inthreesubjects.
Clinicalimplications.
Thesefindings
inhealthy subjects
side infusion
produced parallel
increases in MSNA andHR wouldpredict
thatsympathetic
nerveresponsestodynamic
ex-nylagin theonsetof thesympathetic
nerveresponserelative ercise should be augmented in patients with cardiovasculardis-response. orders that impair perfusion of the exercising muscles. When
patients
with unilateral
iliofemoral
stenosis andintermittent
terial pressure. This
augmentation appeared
tobe due claudicationperformed rhythmic leg exercise,
increases inaortic yto an increase insympathetic
vasoconstrictor tone pressure were much greaterduring
contraction of the poorlyanHR
(and
cardiacoutput)
becauseischemic
handgrip
perfusedleg
thanduring
contraction of the wellperfused
leg )%MVC
produced
asignificantly larger
pressor responsebefore
theonsetof ischemic
pain (42).
Inaddition,
peripheral
ischemic
handgrip
at50% MVCeventhough
thesetwo vasoconstrictor responsestodynamic
exercise inconscious dogsinterventions
produced
comparable
increases in HR. weremarkedly
enhanced when oxygendelivery
tothe exercising anosensitivemuscle
afferents.
Inanesthetized cats, mild
muscleswasimpaired by
heartblock, anemia,
orcongestive
heart
-contractions activate mechanosensitive group III failure
(7).
ifferents
andproduce
a reflex pressor response that isIn
conclusion,
the presentstudy challenges
twotraditionalbly
mediated
by
increased
sympathetic
outflow
(34).
conceptsof
cardiovascular
regulation during dynamic
exercise. r,in conscious humans MSNAdid
notincrease
during
First, during
theinitiation of
dynamic
exercise in humans
theremic
RHGcontractions
orduring
mild
armcycling.
Al-is
aconcomitant
delay
in the
onsetof sympathetic activation
tonild
rhythmic
contraction
doesnotappeartobeasuf-
nonexercising
skeletal muscle andtothe heart. This
challengesndition
toreflexly
increase
MSNA inhumans,
we can-the
conceptof
masssympathetic discharge
atthe onset of ex-ide thepossibility
thatmechanosensitive thinfiber
af-ercise. Second, this study documents the complexity in
thecon-iay contribute
tosympathetic regulation during
intense
trol of HR, arterial
pressure, and MSNA during dynamicex-an
mild
rhythmic
contractions.
ercise. Although
both central neural and peripheral reflexmech-ence
ofbody
position
and low pressure
cardiopulmonary
anisms contribute to the maintenance of arterial pressure during
ptors.
Activation of
cardiopulmonary
baroreceptors
in-dynamic exercise,
the data suggest that central command and dunloading
of these receptors augmentsthereflex va- muscle chemoreflexes do not exert comparable effects on sym-ictor responsestomuscleafferent stimulation
(35, 36). pathetic and parasympathetic responses.;on
why
MSNA did not increaseduring
RHG in theposition might
be thatcardiopulmonary
baroreceptor
Acknowledgments
n inhibited the excitatory influence from the muscle
We thank Dr. B. Gunnar
Wallin
foradvice andsupportand Dr. Jere Thisexplanation is unlikelybecause MSNA did notH.
Mitchell
forhisadvice and thoughtfulcomments. We also thankduring
RHG ateither 30 or50%MVC whencardio- Christine Sinkey for technical assistance and Sara Jedlicka and Cynthia tryreceptors
wereunloaded in theupright
position.
Lawson for secretarial assistance.hmicvs. static exercise.
During nonfatiguing
exercise,
Thiswork wassupported by aClinical
Investigator Award (HLO1362)
(NHLBI) and by research grants HL24962 and HL14388 from the
NHLBI and by researchfunds from the Veterans Administration.
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