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Control of Heart Rate by the AutonomicNervous System
STUDIES IN MAN ON THE INTERRELATION BETWEEN
BARORECEPTOR MECHANISMS AND EXERCISE
By Brian F. Robinson, Stephen E. Epstein, G. David Beiser, and
Eugene Braunwald
ABSTRACTThe control of heart rate by the autonomic nervous system was investigated
in conscious human subjects by observing the effects of /3-adrenergic blockadewith propranolol, of parasympathetic blockade with atropine, and of com-bined sympathetic and parasympathetic blockade. The increase in heart ratewith mild exercise in supine men was mediated predominantly by a decreasein parasympathetic activity; at higher levels of work, however, sympatheticstimulation also contributed to cardiac acceleration. When the response to 80°head-up tilt was compared with the response to exercise in the same subjectsupine, it appeared that the attainment of an equivalent heart rate was asso-ciated with a significantly greater degree of sympathetic activity during tiltingthan during exercise. Although heart rate was always higher at any givenpressure during exercise than it had been at rest, the changes in heart rate thatfollowed alterations in arterial pressure were found to be of similar magni-tudes at rest and during exercise; it was therefore concluded that the sensi-tivity of the baroreceptor system was not altered during exercise. Investiga-tion of the efferent pathways concerned in mediating the baroreceptor-inducedchanges in heart rate suggested that the relative roles of the sympathetic andparasympathetic systems were nearly equal in the resting state. During exer-cise, on the other hand, changes in sympathetic activity appeared to be thepredominant mechanism by which speeding and slowing of the heart wasachieved. It thus appears that baroreceptor-induced alterations in heart ratemay be mediated by increased or decreased activity of either efferent system;the ultimate balance, however, is critically dependent on the preexisting levelof background autonomic activity.
ADDITIONAL KEY WORDS propranololsympathetic nervous system tiltingheart rate control
atropinebeta-adrenergic receptors
baroreceptor reflex
• The central nervous system controls heartrate by varying the impulse traffic in sympa-thetic and parasympathetic nerve fibers ter-minating in the sinoatrial node. Although therehas been considerable interest in the mech-anisms by which the heart rate is altered inresponse to exercise, postural changes, andstimulation of the baroreceptors, the relativeroles of the two divisions of the autonomic
From the Cardiology Branch, National Heart In-stitute, Bethesda, Maryland.
Dr. Robinson is a Nuffield Medical Fellow.Accepted for publication April 4, 1966.
nervous system in mediating these changes inrate in conscious man have not been clarified.Furthermore, little information is availableconcerning the manner in which the heart rateresponse to baroreceptor stimulation is modi-fied during exercise.
In the present study, the relative roles ofthe efferent pathways which mediate the heartrate response to exercise in supine man wereinvestigated by observing the separate andcombined effects of /J-adrenergic blockadeand parasympathetic blockade on cardiacacceleration. The cardiac acceleration result-ing from head-up tilting was studied in a
400 CircmUtion Rutnb, Vol. XIX, A»t»st 1966
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CONTROL OF HEART RATE IN MAN 401
similar way, thus allowing a comparison ofthe mechanisms of speeding under conditionsof exercise and changes of posture. The sensi-tivity of the control of heart rate by thebaroreceptor system was then compared atrest and during exercise, and the efferentpathways utilized were studied by observingthe effects of the autonomic blocking agents.
MethodsFive normal volunteers and one patient (AS)
who had undergone a successful mitral commis-surotomy five months earlier were studied; theirages ranged from 19 to 28 years. All of the sub-jects were males and in good physical condition,but none was a trained athlete. All studies werecarried out in the postabsorptive state.
1. EXERCISE IN SUPINE POSITION AND CHANGE OFPOSTURE
Before any measurements were made, each sub-ject was thoroughly familiarized with the use ofthe bicycle ergometer in the supine position andwith the tilt table. In the definitive investigation,the subject was first placed on the tilt table inthe supine position and his heart rate was de-termined from the ECG for 30 sec. He was thentilted, first to 45° and then to 80° from thehorizontal, and the heart rate was recorded ineach position when the cardiotachometer andECG tracings showed that the rate was stable.Heart rate was then recorded with the subjectat rest on the bicycle ergometer in the supineposition and during the fourth minute of exerciseat each of a series of work levels which werecarried out consecutively without interveningrest periods. Oxygen uptake (Vo2) was recordedthroughout the period of exercise using a con-tinuous flow system.1 The protocol outlined abovewas repeated on three subsequent days; the car-diac sympathetic nerves were blocked on one,the parasympathetic nerves on another, and bothon the third. Stimulation of the heart throughthe sympathetic nerves and by circulatory cate-cholamines secreted by the adrenals was inhibitedby the /3-adrenergic blocking agent propranolol*given in a dose of 0.25 mg/kg iv; it has previous-ly been shown that 0.15 mg/kg reduces die effec-tiveness of infused isoproterenol at least 90%.2
Throughout this paper this is referred to as sym-pathetic blockade, although only the /3-receptorswere blocked. No untoward effects of propranololwere observed in any of the subjects at this higherdosage. Parasympathetic blockade was induced
* l-Isopropylamino-3- (1-naphthyloxy )-2-propanolhydrochloride.CircnUtion Rtsemrcb, Vol. XIX, Atgujl 1966
with 2 mg of atropine given intravenously. Com-bined sympathetic and parasympathetic blockade(double blockade) was produced by the simul-taneous administration of both drugs.
2. THE BARORECEPTOR SYSTEM
The studies at rest were carried out with thesubject seated in a chair and those during exer-cise while he walked on a motor-driven treadmill.The subjects were completely familiarized withwalking on the treadmill before the study com-menced, and a speed and grade were found whichconsistently resulted in a heart rate between 90and 125 beats/min. The oxygen requirements atthis level of exercise ranged from 960 to 1,950ml/min. Arterial pressure was recorded througha short teflon catheter that had been introducedpercutaneously into the brachial artery and con-nected to a Statham P23AA pressure transducer;heart rate was determined for 30-sec periodsfrom the simultaneously recorded ECG. Increasesof arterial pressure were produced by the intra-venous infusion of phenylephrine, a pressor agentthat in the doses used is without measurabledirect cardiac effect''; the rate of administrationwas controlled by a constant speed pump.
In each experiment, the subject _was_ firststudied at rest. When mean arterial pressure andheart rate had stabilized, the arterial pressure wasraised in steps by infusing phenylephrine indoses varying from 0.05 to 0.40 mg/min, andheart rate was recorded when the pressure hadstabilized at the new level for at least 1 min. Afterdiscontinuing the phenylephrine, the subjectwalked on the treadmill at the predeterminedspeed and grade; arterial pressure and heart ratewere recorded after 5 min and again after 7 minto ensure that a steady state had been reached.The effects on heart rate of elevating arterialpressure with graded doses of phenylephrinewere then determined during exercise as at rest,but larger doses of the drug, up to 0.80 mg/min,were required to produce elevations of arterialpressure during exercise comparable to thoseachieved at rest. After discontinuing the phenyl-ephrine and allowing its effects to wear off, nitro-glycerin (0.4 mg or 0.8 mg) was given sublingual-ly while the subject was still exercising, andarterial pressure and heart rate were recorded atthe peak of the drug effect. The effects of reduc-ing arterial pressure were studied again after theheart rate had stabilized at rest. The entire studywas repeated on three subsequent days in thesame way as in the posture studies. The action ofcardiac sympathetic nerves was inhibited on oneoccasion, the parasympathetics on another, andboth on the third, utilizing the doses of blockingagents described above. The experiments wereusually completed within 45 min of administra-
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402 ROBINSON, EPSTEIN, BEISER, BRAUNWALD
tion of the blocking drug; when the study con-tinued longer, a supplemental dose (0.1 mg/kg ofpropranolol; 1 mg atropine) was given. The sub-jects were in sinus rhythm under all of the ex-perimental conditions studied.
Results and Interpretations1. RELATIVE ROLES OF PARASYMPATHETIC ANDSYMPATHETIC EFFERENTS IN THE HEART RATEA. Response to Exercise in Supine Position
Four normal subjects were investigated andall showed qualitatively similar responses(table 1); the results in one are illustratedin figure 1, left. In the control studies, carriedout with both the sympathetic and parasympa-thetic efferents intact, the heart rate at restaveraged 52/min in the four subjects and rosein an approximately linear manner with in-creasing V02. Following blockade of both sym-pathetic and parasympathetic efferents (dou-ble blockade), the resting heart rate roseabove the control level in all subjects (averageincrease of 42/min), but there was little orno further increase with mild exercise (Vo2 upto 500 ml/min); small increases in rate, aver-
aging 10/min, occurred at higher levels ofwork (Vo2 900 to 1300 ml/min). When thecardiac sympathetic system alone was blocked,the parasympathetic remaining intact, the rest-ing heart rate fell by an average of 4/min.The rate increased normally with mild exercisein every subject, but there was less speedingat the higher levels of work in three of thefour (GM, RR, and RJ: table 1, fig. 1).When the parasympathetic system was in-hibited, leaving the sympathetic intact, rest-ing heart rate increased by an average of46/min above control; cardiac accelerationin response to mild exertion was reduced andin two subjects was abolished, but the raterose normally at the higher levels of exercise.
It thus appears that in the supine restingstate, parasympathetic restraint is the domi-nant influence on heart rate (fig. 1, Pr), andthe accelerating effects of sympathetic stimu-lation (fig. 1, Sr) are minor. The speedingof the heart in response to mild exerciseappears to result largely from withdrawal of
TABLE 1
Effects of Autonomic Blockade on Heart Rate Response to Supine Exercise
GM
RR
PY
RJ
Subject
RestExercise
RestExercise
RestExercise
RestExercise
VO,ml/mln
233455700913
271385499770
1033
259418701919
1069
234436677755
1289
ControlHR/min
597798
108
4958658191
4959727992
49657782
115
Sympatheticblockade
VOi HRml/min /min
242317509651994
299405510774
1038
343510686898
1038
229418627940
1358
5970788196
4359657583
4760708084
4454667990
Paritympath eticblockade
Vo» HRml/min /min
275355514691922
284408479745
1011
309507705877980
225425656940
1248
93101107113134
949696
110122
115112107111127
848894
110122
Doubleblockade
VOi HRml/min /min
330369515661953
292389486797
1030
290457651845
1012
244410634878
1255
85868994
104
8686868996
113108108111113
90878893
100
Control = autonomic nervous system functioning normally; double blockade = combined sympathetic and para-sympathetic blockade; Vo2 = oxygen consumption; HR = heart rate.
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CONTROL OF HEART RATE IN MAN 403
parasympathetic inhibition, since cardiac ac-celeration is essentially unimpaired by sympa-thetic blockade but tends to be inhibited byparasympathetic blockade and double block-ade. At higher levels of exercise, however,
400 600 800 1000
V02 HI I MINUTE
FIGURE 1
SUPIHE 45" JO-
POSITION
A comparison of the effects of various forms of auto-nomic blockade on the response of heart rate insubject RR to exercise when supine and to head-uptilt. The level of exercise in the control (no blockade)exercise study which would have produced a heartrate equal to that observed during the control 80°tilt is determined by interpolation (lines X and Y, seetext). Effects of parasympathetic blockade on heartrate are indicated by Pr at rest, Po during exercise,and Pt during tilting. Effects of sympathetic blockadeare indicated by Sr, Se and St.
cardiac acceleration must result in part fromsympathetic stimulation, since sympatheticblockade reduces the augmentation of heartrate in comparison to the control study. Thefinding that the increments in rate duringheavy exercise are smaller after doubleblockade than after parasympathetic blockadealone further identifies the contribution of thesympathetic system. These results were ob-tained in young healthy male adults, and itis possible that a different balance of auto-nomic effect might obtain in a different groupof subjects.
B. Response to Tilting
The heart rate rose by an average of 29/minduring the 80° head-up tilt in the controlstudy with the subjects in the unblockedstate (table 2, fig. 1). Following doubleblockade, the increase in rate induced bytilting was almost abolished and averagedonly 5/min. During parasympathetic blockade,however, heart rate increased by an averageof 36/min and during sympathetic blockadeby 17/min. Thus, in contrast to light exercisein supine position, substantial speeding couldstill occur during tilting when the parasympa-thetic system was blocked.
The results were then analyzed to charac-terize in greater detail the differences be-tween the mechanisms of cardiac speeding
TABLE 2
Effects of Autonomic Blockade on Heart Rate Response to Tilting
Subject
TUtangle
degreesControlHR/min
SympatheticblockadeHR/min
ParasympatheticblockadeHR/min
DoubleblockadeHR/min
GM
RR
PY
RJ
Mean
0458004580045800458004580
617288486179506879536680536782
576875445662465767444857485765
961141309711913411613815196113134101121137
888692899293108118114848690929697
Abbreviations as in table 1.
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404 ROBINSON, EPSTEIN, BEISER, BRAUNWALD
TABLE 3
Comparison of Effects of Sympathetic and Parasympathetic Blockade on Heart Rate Responseto Supine Exercise and Tilting
Subject
GM
RR
PY
RJ
Avg
Exercise80° tiltExercise80° tiltExercise80° tiltExercise80° tiltExercise80° tiltP
ControlHR/mln
8888797979797878
Sympatheticblockade
HR/mln
8075746278676956
AHR
- 8-13- 5-17- 1-12- 9-22- 6-16
<.O5
ParaBympatheticblockade
HR/mln
110131110134111152103132
AHR
+ 22+ 43+ 31+ 55+ 32+ 73+ 25+ 54+ 27+ 56
<.O2
AHR = change in heart rate compared to control; Avg = average change in heart rate com-pared to control. Other abbreviations as in table 1.
during exercise and tilting. The level of Vo2
during exercise which would have producedthe same degree of cardiac acceleration asthat actually observed during the 80° tilt wasdetermined by interpolation (fig. 1, lines Xand Y). The effect of sympathetic and para-sympathetic blockade on the heart rate atthis level of Voo was then estimated bydetermining the intercepts of line Y with theappropriate heart rate-Vc>2 relationship. Theeffects of autonomic blockade could then becompared under conditions of exercise andtilting which had identical effects upon theheart rate when the autonomic nervous systemwas functioning normally. If the mechanismof speeding had been identical during exerciseand tilting, then the effects of autonomicblockade should also have been similar. Infact, the responses to sympathetic and toparasympathetic blockade were consistentlydifferent during the two interventions (fig. 1,table 3). During exercise, parasympatheticblockade increased heart rate by an averageof 27/min (fig. 1, Pe), but the increase duringtilting (Pt) was more than twice as greatand averaged 56/min (P<.02). Similarly,during exercise, sympathetic blockade de-creased the heart rate by an average of only6/min (Se), whereas the decrease duringtilting (St) was significantly greater (P < .05),averaging I6/min. It is thus apparent thatachievement of the same heart rate involved
a different balance of autonomic activity,depending on whether the stimulus was pro-vided by exercise in supine position or bytilting. Exercise resulted in a greater degreeof parasympathetic withdrawal than did tiltingas is shown by the lesser degree of speedinginduced by atropine during exercise. Converse-ly, exercise produced a smaller degree ofsympathetic stimulation than did tilting, asis shown by the lesser degree of slowinginduced by /3- adrenergic blockade. Thus, thecardiac acceleration in response to mild supineexercise in these subjects appeared to dependpredominantly on parasympathetic withdraw-al, whereas that produced by tilting involveda relatively greater degree of sympatheticstimulation.
2. EFFECTS OF EXERCISE ON CONTROL OF HEART RATEBY THE BARORECEPTOR MECHANISM
In these experiments, changes in heart ratewere related to the changes in mean arterialpressure with which they were associated.It is appreciated that the use of mean arterialpressure as an index of baroreceptor stimula-tion ignores the passible influence of alterationsin pulse pressure; however, since mean pres-sure and pulse pressure always changed in thesame direction, the basic pattern of the resultsis unaffected by the fact that mean arterialpressure alone was considered. Although therelation between heart rate and mean arterialpressure was not a linear one, it was never-
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CONTROL OF HEART RATE IN MAN 405
theless found useful to express the results interms of average values when making broadcomparisons between different conditions.
At rest, graded elevations of mean arterialpressure in the six subjects studied causedprogressive decreases in heart rate, while re-ductions of pressure uniformly resulted inincreases of heart rate (table 4, fig. 2). Onthe average, a change of 40 mm Hg in meanarterial pressure was associated with an in-verse change in rate of 50/min. During exer-cise, the heart rate was always higher atany given arterial pressure than it was atrest, but the absolute magnitude of changesin rate that followed alterations in pressurewere similar to those observed at rest (fig.2);on the average, a change of 37 mm Hg inmean arterial pressure was associated with achange in rate of 42/min. One subject (GM)was studied at rest in both the sitting andstanding positions, as well as at two levelsof exercise; the relation between heart rateand mean arterial pressure could be expressedby four similar curves, each increase in stressleading to a further upward displacement ofthe entire curve (fig. 3).
60 70 13080 90 100 110
UEAN ARTERIAL PRESSURE
FIGURE 2
Relation between heart rate and mean arterial pressurein subject RR sitting at rest and during exercise inupright position. Arrows identify the baseline observa-tions made before phenylephrine or nitroglycerinwas given to modify arterial pressure. Slopes of thelines relating heart rate to mean arterial pressure aresimilar at rest and during exercise, but the heart rateis always greater at any given arterial pressure duringexercise than it is at rest.
140
120
100
40
"1 1 T 1 I 1 1 1—
o Enron Wj -1140 ml/Hit
• titn'ot fCj • 9S0 ml /Hit
A SHtiif Rill
A Slllitf Rill
50 60 70 60 90 100 120 M0 160 ISO
UEAN ARTERIAL PRESSURE » K |
FIGURE 3
Relation between heart rate and mean arterial pres-sure in subject GM studied at rest, in the sitting andstanding positions and at two levels of exercise inupright position. Arrows identify the baseline observa-tions before arterial pressure was altered. Relationsbetween heart rate and mean arterial pressure aresimilar under all four conditions, but the curve isdisplaced upward with the change from sitting tostanding, and there is further upward displacementat each of the two levels of exercise.
180
160 -
140 -
120 -
100 -
60 -
60 -
40
1REST
- \
_
A
A
1
1
\ !
1 1 1 1
0 CcnlnlA Pamjmpalhtlic Bhettdi ~• S/mfttiitic BlKlliiA DttUt Blutidi -
>—
40 60 80 100 120 140
MEAN ARTERIAL PRESSURE a n
160 180
FIGURE 4
Effects of varying types of autonomic blockade onthe relation between heart rate and mean arterialpressure in subject RR sitting at rest. Arrows denotethe baseline observations before arterial pressurewas modified under each circumstance. Heart ratecontinues to show some inverse variation in responseto changes in mean arterial pressure when eitherdivision of the autonomic was blocked. When bothdivisions were blocked, changes in rate were almostcompletely prevented.
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406 ROBINSON, EPSTEIN, BEISER, BRAUNWALD
TABLE 4
Effects of Autonomic Blockade on Heart Rate Response to Changes in Arterial Pressure
GM
RR
PY
RJ
JW
Subject
Rest
ExerciseV o 2 = 960
Rest
ExerciseVo2 = 1430
Rest
ExerciseVo2 = 1950
Rest
ExerciseVo2 = 1406
Rest
BP
N
BP
BNBP
N
BP
BN
BP
N
BP
BNBP
N
BP
BN
BP
Control
MAPmmHg HR/mln
8395
11248
858896
104
65879498
11378
86879195
110
727583909598
1037671818590
10478718391
10511875709398
110120977575808898
715850
104
11811610694
1467062554892
1101081019286
13814454474038366980
12311610910614615655514443769897949290
108130136757265
Sympathetic blockade
MAPmmHg
7585
10068668490
110121
6296
104
8175848792
103
797573839195
72
8487
10010990708592
105
76758495
1051158784
HR/min
676349677396868378
965646
627088868380
869495494338
63
95948885
100102464439
5164847978787888
Paruympatheticblockade
MAP mm Hi HR/mln
951321387565829997
127
599097
127
6660738388
100
68
7587
112
60
84100128
65618192
126
48
6297
1121225250
1109496
108132131118116108
139118106103
126137141134120119
178
140120116
141
165142136
163181110
94101
114
120104105114128142
Double blockade
HAP mm Hi HR/min
8298
14260
6383
112
5291
113
67657797
126
7670628083
105118
57
697589
107675558
103122
58527892
1051187774
(Table 4, continued on
87848884
10210098
1048988
8392
1009790
103108118999999
101
97
120120115109121126849391
8791
101989696
104110
next page.)
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CONTROL OF HEART RATE IN MAN 407
3. RELATIVE ROLES OF PARASYMPATHETIC ANDSYMPATHETIC EFFERENT* IN MEDIATING BARORECEPTOR-INDUCED ALTERATIONS IN RATE
A. Rest
In the 4 subjects studied, a change of 41mm Hg in arterial pressure in the unblockedstate was associated on average with changein rate of 49/min (table 4, fig. 4). Followingdouble blockade, the heart rate at rest re-mained essentially constant when arterial pres-sure was altered (fig. 4), a change of 65 mmHg in mean arterial pressure being associatedwith an inverse change in heart rate of only7/min; autonomic stimuli resulting fromchanges in pressure would therefore appearto have been effectively inhibited by thedrugs used. When the parasympathetic systemalone was blocked, substantial changes inheart rate occurred in response to changesin arterial pressure, but tended to be lessthan during the control period; on the aver-age, a change of 63 mm Hg in mean arterialpressure was associated with a change in heartrate of 29/min. During parasympathetic block-ade, when rate was controlled primarily bythe sympathetic system, the heart not onlyspeeded when arterial pressure was reducedbelow control, but also slowed as the pressurewas elevated; this indicates that in a resting,
sitting subject the heart rate can be changedreflexly by either increase or decrease in theactivity of the sympathetic nervous system.
When the sympathetic system alone wasblocked, the heart rate continued to vary in-versely with arterial pressure, a change of 29mm Hg being associated with an averagechange in heart rate of 25/min. During sympa-thetic blockade, when rate was controlledprimarily by the parasympathetic system, ratecould not only be slowed by an intensificationof vagal restraint as pressure was elevated,but could also be speeded by a decrease invagal activity when pressure was decreasedbelow control.
B. Ex«rcb«
In the four subjects in whom the effectsof autonomic blockade on the response tobaroreceptor stimulation were studied duringexercise in upright position, an average changein arterial pressure of 40 mm Hg was associatedwith a change in heart rate of 52/min duringthe control studies (table 4, fig. 5). In thesame subjects, parasympathetic blockadecaused only a slight impairment of the rateresponse, an average change in arterial pres-sure of 60 mm Hg being associated with a
Subject
N
BP
BNBP
N
BP
BN
MAP mm
11680759196
120807566738067607475857065
TABLE 4 continuedControl Sympathetic blockade
H i HR/min MAP mm Hg HR/mli
568896
10510394
10010681695098
11394856895
103
P a raiy mpa th et i cblockade Double blockade
AS
Exercise
Rest
Exercise
MAP = mean arterial pressure; B = baseline; P = phenylephrine given in increasing doses; N = nitroglycerine.Other abbreviations as in table 1.
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408 ROBINSON, EPSTEIN, BEISER, BRAUNWALD
200
180 -
160
5 140 -
120 -
100 -
60
1EXERCISE
s1
1
A
5 A
, \ A
V1
1 1 1 1
O CMIIII
A Parts/apsfielic Bleckodt ~
• Sjmptlktlic Bhcksdi
A Dot bit Blictnit —
^A^__
1 1 1
-
40 60 80 100 120 140
MEAN ARTERIAL PRESSURE mre
160 180
FIGURE 5
Effects of varying types of autonomic blockade onthe relation between heart rate and mean arterialpressure during exercise in subject RR. Arrows denotethe baseline observations for each. Response of heartrate to alterations of arterial pressure is only slightlyreduced after parasympathetic blockade, but it ismarkedly impaired following sympathetic blockadeand double blockade.
change in rate of 43/min. This finding suggeststhat during exercise the alterations in rate asa consequence of changing arterial pressuretook place largely as a result of variationsin sympathetic activity. This conclusion issupported by the finding that when the sympa-thetic system alone was blocked, the heartrate response to changes in arterial pressurewas much impaired, a change of 40 mm Hgbeing associated with an average change inrate of only 15/min. Moreover, when sympa-thetic blockade was added to parasympatheticblockade, the rate response that had beenobserved during parasympathetic blockadealone was markedly attenuated; during doubleblockade a change in pressure of 55 mm Hgwas associated with an average change in rateof 15/min.
At the levels of exercise employed, changesin the degree of sympathetic stimulation ofthe heart thus appeared to play a moreimportant role in mediating baroreceptor in-duced increases and decreases in heart ratethan did changes in parasympathetic activity.At rest, on the other hand, the roles of the
sympathetic and parasympathetic systems inmediating baroreceptor reflexes appeared tobe more nearly equal.
Discussion
Interest in the mechanism of exercise-in-duced tachycardia dates to 1914 when Gasserand Meek observed in the dog that aftervagotomy little augmentation of heart rateoccurred during exercise, although stellateganglionectomy did not greatly impair therate response.4 Bruce et al., on the other hand,studying anesthetized dogs, observed that thecardioacceleration produced by electrically in-duced muscular contraction was abolished notonly by vagotomy, but also by excision ofthe upper thoracic sympathetic ganglia.6
Donald and Shepherd, however, reported thateven after total cardiac denervation, animalsexhibited a large, though subnormal increasein heart rate during running.8 Relatively littleinformation is available concerning the rela-tive roles of the two components of the auto-nomic nervous system in effecting the tachy-cardia of exercise in man. S. Robinson et al.7
observed that at maximal levels of exerciseatropine did not elevate heart rate, suggestingthat vagal restraint is normally totally with-drawn at this level of activity. It is generallyagreed that sympathetic blockade lowers theheart rate during exercise, a finding whichsuggests that sympathetic stimulation contrib-utes to cardiac acceleration.2' 8"10 No informa-tion is available, however, on the interplaybetween the two divisions of the autonomicnervous system during exercise, and the rela-tive importance of each at varying levels ofexercise has not previously been defined.
In the present investigation we examinedthe response to exercise in the supine position,since only in this way could the effects ofexercise be separated from the effects of theupright position with its associated alterationsin the background of autonomic activity. Theresults, presented schematically in figure 6,indicate that the speeding of heart rate atrelatively mild exercise (Vo2 up to 500 ml/min) is effected primarily by a withdrawalof parasympathetic restraint on the sinoatrial
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CONTROL OF HEART RATE IN MAN 409
Para s/epctki lie Bfecktde
\
\ -
\ „COM! rol
Ti
Sympathetic Blocked*
REST MAX ¥0
FIGURE 6
Schematic diagram showing the relative contributionsof the sympathetic and parasympathetic systems tocardioacceleration at various levels of exercise. Brokenlines are extrapolations based on published'- ? andunpublished data. Comparisons are between control(no blockade) state and parasympathetic or sympa-thetic blockade.
node. At higher levels of work, further with-drawal of parasympathetic restraint occurs, butincreases in sympathetic activity becomeprogressively more important in acceleratingthe cardiac rate. This interpretation is de-rived from a comparison of the rate responsesat varying levels of exercise in the control studywith those observed after either sympatheticor parasympathetic blockade; comparison ofthe rate response after blocking one divisionof the autonomic with the response afterdouble blockade leads to a similar conclusion(fig-7).
The possibility cannot be excluded thatinterference with the activity of one divisionof the autonomic nervous system might leadto compensatory changes in the other thatwould obscure to some extent the relativecontribution of each of the two components.Interpretation of the results could also becomplicated if the degree of blockade ofeither system was incomplete. This did notappear to be the case in the present experi-ments, however, since heart rate was con-stant, or increased only slightly at the higherlevels of exercise during double blockade. Itmust be borne in mind that the autonomicnervous system is probably not the only mech-
CircuUium Rti—rcb, Vol. XIX, August 1966
anism concerned in speeding the heart dur-ing severe exertion. As already mentioned, theheart rate of dogs continues to increase sub-stantially during heavy exercise even aftercomplete cardiac denervatdon,6 and the in-creases in rate seen in man during maximumexertion after double blockade (our labora-tory, unpublished observations) may be dueat least partly to nonautonomic influences.
In contrast to the mechanism of speedingduring mild exercise, the increase in heartrate induced by upright tilting involved asignificantly greater degree of sympatheticstimulation. This finding is relevant to theunderlying mechanism responsible for thetachycardia of exercise. It has been suggestedthat this tachycardia is mediated primarilythrough the baroreceptor system.11'12 Sincearterial pressure does not normally fall in manduring exercise, this hypothesis in its simp-lest form appears to be untenable. It could beargued, however, that the baroreceptor sys-tem is 'reset' during exercise and-responds asif the blood pressure were reduced. If thiswere the case, it might be expected that thetachycardia of exercise would be mediatedby a balance of autonomic activity similar tothat observed during tilting. The observation
ic Bltcktdt
REST MAX V 0 ,
FIGURE 7
Schematic diagram showing the relative contributionsof the sympathetic and parasympathetic systems tocardioacceleration at various levels of exercise. Brokenlines are extrapolations based on published'-7 andunpublished data. Comparisons are between doubleblocked state and parasympathetic or sympatheticblockade alone.
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410 ROBINSON, EPSTEIN, BEISER, BRAUNWALD
that the mechanisms of speeding are in factquite different suggests that the speeding ofthe heart during exercise is not mediatedprimarily through the baroreceptor system,but depends, at least partly, on some othermechanism.
Interest in the control of heart rate by thebaroreceptor system dates back to the workof Marey, who in 1859 demonstrated the in-verse relation between arterial pressure andheart rate.18 Subsequent attempts to definethe mechanisms involved in the efferent limbof this reflex more precisely have yielded con-flicting results. Several investigations carriedout in experimental animals demonstrated areciprocal relation between the sympatheticand parasympathetic nervous systems in re-sponse to changes in arterial pressure.14"10
However, on the basis of studies carried outin this laboratory, primarily on anesthetizeddogs, it was concluded that when arterialpressure rises above control, the slowing ofheart rate results from an increase in para-sympathetic restraint, while when pressurefalls below control levels, the resultant- in-crease in heart rate is mediated primarily bythe sympathetic nervous system.3 The resultsof the present investigation seem to resolvethis apparent discrepancy. One of the majordifferences in the experimental conditions be-tween the investigations in which a reciprocalrelation was demonstrated and the study inwhich it was not was the level of backgroundsympathetic tone present. It has been demon-strated in this study that the backgroundautonomic activity existing prior to the in-duced change in arterial pressure profoundlyinfluences the results. In the sitting position,sympathetic activity is apparently of sufficientmagnitude to permit slight cardiac slowingby withdrawal of sympathetic stimulation aspressure is raised. In contrast, in the supineposition sympathetic activity appears to beminimal, since slowing does not occur con-sistently when arterial pressure is elevatedafter parasympathetic blockade.8 On the otherhand, during exercise in the upright position,when sympathetic activity is at a much higherlevel and parasympathetic activity is lessened,
cardiac slowing consequent upon increases inarterial pressure results predominantly fromreduction in sympathetic tone; increase inparasympathetic activity plays a relativelyminor role.
The observations on the effects of exerciseon the relation between arterial pressure andheart rate (figs. 2 and 3) are relevant to thequestion of the sensitivity of the baroreceptormechanism under differing conditions. It hasbeen suggested that the baroreceptor reflexesare suppressed during static muscular exer-cise.17 On the other hand, Bevegard andShepherd18 recently observed similar de-creases in heart rate at rest and during exer-cise when the baroreceptors were stimulatedby application of subatmospheric pressure tothe neck. Our findings are in accord withtheirs and indicate further that similar re-sponses occur at rest and during exercisewhen arterial pressure is decreased. It thusappears that the sensitivity of the barorecep-tor system to induced changes of pressuredoes not undergo any substantial alterationin the transition from rest to exercise: at anygiven level of arterial pressure, the heart rateduring exercise is higher than at rest, butwhen arterial pressure is changed, the mag-nitude of the alteration in heart rate is similarunder both conditions.
Since the baroreceptor system remains ac-tive during exercise, it undoubtedly continuesto play a modifying role in determining theheart rate, and presumably it also influencesthe level of inotropic stimulation of the myo-cardium. It might therefore be expected thatif the level of cardiac stimulation becameexcessive, the resultant increase in output andarterial pressure would lead to a reflex reduc-tion in sympathetic stimulation of the heartwhich would tend to lower the rate andcontractile state to more appropriate levels.In this way, the baroreceptor system mightbe visualized as providing the feedback neces-sary for adjusting the cardiac performanceduring exercise so that the output was pre-cisely adjusted to the fall in peripheral re-sistance, and so to the metabolic demand.Thus, even though the primary drive to in-
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CONTROL OF HEART RATE IN MAN 411
creased cardiac activity during exercise aroseby some mechanism that was quite indepen-dent, the baroreceptor system might still beof crucial importance in determining the finallevel of cardiac stimulation attained.
AcknowledgmentWe would like to thank Mrs. Frankie Hayes for
her expert nursing assistance. Dr. A. Sahagian-Edwards of Ayerst Laboratories, Inc., New York,kindly supplied the propranolol (Inderal; ICI).
References1. KAHLER, R. L., THOMPSON, R. H., BUSKTRK, E.
R., FRYE, R. L., AND BRAUNWALD, E.: Studieson digitalis: VI. Reduction of the oxygen debtafter exercise with digoxin in cardiac patientswithout heart failure. Circulation 27: 397,1963.
2. EPSTEIN, S. E., ROBINSON, B. F., KAHLER, R. L.,AND BRAUNWALD, E.: Effects of beta-adrenergicblockade on the cardiac response to maximaland submaximal exercise in man. J. Clin. In-vest. 44: 1745, 1965.
3. GLJCK, G., AND BRAUNWALD, E.: Relative rolesof the sympathetic and parasympathetic ner-vous systems in the reflex control of heart rate.Circulation Res. 16: 363, 1965.
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7. ROBINSON, S., PEARCY, M., BRUECKMAN, F. R.,NICHOLAS, J. R., AND MILLER, D. I.: Effectsof atropine on heart rate and oxygen intake in
working man. J. Appl. Physiol. 5: 508, 1953.8. BISHOP, J. M., AND SECEL, N.: The circulatory
effects of intravenous pronethalol in man atrest and during exercise in the supine and up-right position. J. Physiol. (London) 169: 112,1963.
9. CHAMBERLAIN, D. A., AND HOWARD, J.: Thehemodynamic effects of /3-sympathetic block-ade. Brit. Heart J. 26: 213, 1964.
10. SCHRODER, C , AND WERKO, L.: Hemodynamicstudies and clinical experience with nethalide,a beta-adrenergic blocking agent. Am. J. Car-diol. 15: 58, 1965.
11. WARNER, H. R., TOPHAM, W. S., NICHOLES,K. K.: The role of peripheral resistance incontrolling cardiac output during exercise.Ann. N. Y. Acad. Sci. 115: 669, 1964.
12. TOPHAM, W. S., AND WARNER, H. R.: Effect oncardiac output of brachiocephalic constric-tion during rest and exercise. Physiologist 8:289, 1965.
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18. BEVEGARD, B. S., AND SHEPHERD, J. T.: Circu-latory effects of stimulating the carotid arterialstretch receptors in man at rest and duringexercise. J. Clin. Invest. 45: 132, 1966.
CircnUtion Rtiircb, Vol. XIX, Angus! 1966
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BRAUNWALDBRIAN F. ROBINSON, STEPHEN E. EPSTEIN, G. David BEISER and EUGENE
Interrelation Between Baroreceptor Mechanisms and ExerciseControl of Heart Rate by the Autonomic Nervous System: Studies in Man on the
Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1966 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research
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