@TCNAL
Vol.
OF APPLIED PHYSIOLOGY 38, No. 2, February 2975. P~inled
in U.S.A.
acceleration in man b y a muscle-heart reflex Cardiac
A. P. HOLLANDER Ijepar
AND
tmen t of Physiology,
elicited
L. N. BOUMAN
University
of
Amsterdam,Amsterdm, The lV&erlands
HOLEANDER, A. P., AND L.N. BOUMAN. Curdiac acceleration in man atropine. Coote et al. (8) mentioned the existence of an elicited by a muscle-heart reJex. J. Appl. Physiol. 38(2): 272-278. CLexercise reflex” in cats that was unchanged after cutting 1975.-The shortening of the R-R interval in response to volunboth vagal nerves. tary and electrically induced isometric muscle contractions of short The present experiments were undertaken in the first duration was investigated in 15 volunteers. In some of those explace to decide between peripheral or the central origin of periments the elect of vagal blockade was also studied. The results the impulse that accelerates the heart at the onset of exercise. show: I) a lag time between the start of the contraction and the In series 1 the lag time between the onset of arm contracfollowing decrease in R-R interval duration of 550 milliseconds; 2) tions and cardiac acceleration is compared to the lag time a similar R-R interval response due to voluntary and electrically between leg contractions and cardiac acceleration. induced contractions of the same force; 3) no shortening of the R-K interval when the skin is stimulated without ensuing muscular In series 2 the effect on heart rate was studied of arm contraction; 4) a complete disappearance of the response to isomuscle contractions that were elicited by electrical stimulametric contractions during vagal blockade. A difference in lag tion. time between the onset of arm contraction and cardiac acceleraThe second objective was to clear the efferent way of the tion and the onset of leg contraction and cardiac acceleration could cardiac accelerating system at the onset of exercise b’y pharnot be demonstrated. Most of the results give strong evidence to the macological blockade (series 3). existence of a muscle-heart reflex in man, involved in the instantaneous cardiac acceleration at the onset of exercise, that has its METHODS origin in the muscles and the vagal nerves as its efferent pathway.
heart rate regulation; isometric traction; vagal blockade; muscle
exercise; receptor;
electrically exercise;
induced tachycardia
con-
DESPITE INTENSIVE INVESTIGATIONS Over 80 years the understanding of the mechanisms underlying the cardiac acceleration at the onset of muscular exercise is lacking. Differences in opinion still exist with regards to origin and pathway of the heart rate response in man produced by muscular exercise. In 1894 Johansson (19) postulated irradiation of cortical impulses; others (4, 21) supported the idea of a central origin.
In 1898 Athanasiu et al. (3) suggested a regulation of heart rate during muscular work ‘-g;overned by reflex impulses from the working Inuscles, and also this idea found a considerable support ( 1, 7, 14). In recent years Lind et al. ( 10, 23, 24) and Freyschuss (12, 13) worked on human subjects to discern between the two possible origins, but the results are rather conflicting. The origin and the afferent pathway of cardiac acceleration elicited by muscular contractions is not the only unsolved problem. From experiments in which the lag time between the start of the muscular contraction and the first detectable increase in heart rate was estimated (5, 6, 27, 29) it was concluded that inhibition of the vagal nerve played a major role in cardiac acceleration. However, Freyschuss (12, 13) reported still small changes in heart rate evoked by muscular contractions after intravenous administration of
Five female and ten male students from an institute of physical education volunteered in the three series of experiments. Age, height, and weight ranges were : 18-24 yr, 1.661.90 m, and 52-84 kg; seven subjects participated in more than one series. No subject had a history of cardiovascular disease or recent illness. The subjects were instructed about the general course of the experiment but information concerning the purpose of the investigations was not provided. After a 5-min rest period the R-R interval (the time interval between two corresponding points of successive R waves) was studied before, during, and after isometric contractions of different muscles. All experimental data were obtained while the subjects were sitting as relaxed as possible in a comfortable bucket seat connected to an arm dynamometer and a leg dynamometer both constructed for the types of isometric contractions involved. A more detailed description of both dynamometers is presented in earlier papers from our group (5, 29). A bipolar ECG was obtained by means of electrodes fixed on the thorax. The contraction force was converted into an electrical signal by means of strain gauges. A detailed description of nrethods and block diagram of the recording circuit was presented earlier (5). Series 1. Lag time aftu mm and leg contractions. In response to an acoustic signal the subject had to exert as quick as possible a maximal contraction of either arm or leg muscles in random order. The group of nzuscles that had to be used was indicated well ahead of time by a red or a green light. All contractions lasted for less than one second. The acoustic
272
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
A MUSCLE-HEART
REFLEX
IN
signal was presented with a variable interval of 40-55 s to avoid anticipation. To spread the start of the muscle contractions along the R-R interval the acoustic signal was given with a variable delay after an R wave. The delay was varied in random order between 0 and 700 ms in steps of 100 IIIS. During one experiment the subjects performed about 75 contractions both with arm and ‘leg muscles. An experiment lasted about 2.5 h, includin. PI (j) is defined as (the contraction starts in the 6th R-R interval) By means of this normalization technique A(i, j) of normalized intervals arises. The interval duration MPT (mean precontraction calculated according to the following equation MPI
a new array mean resting interval) was
=
From the normalized interval array mean value and standard error of the mean (SE) of intervals with equal sequential numbers (= ;) was calculated. Deviations from the mean precontraction interval (MPI) or from the 100 % level in the case of the normalized intervals were established with the Student t-test (two-tailed, x) = O-05).
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
274
A.
RESULTS
Series 1. Lug time after mm and leg muscle contractions. This series of experiments was performed on 11 subjects, showing a normal heart rate response to voluntary isometric contractions. The average MPI in the experiments was 988 + 43.3 ms for observations with arm flexion and 999 j= 42.4 ms for observations with plantar flexion. The maximal shortening of the R-R interval due to arm flexion was 13 1 =t 30.9 ms (12.4% of MPI) and due to plantar flexion of the leg muscles 125 =I= 25.3 ms (12.5 % of MPI) although in the latter the exerted force and muscle mass involved is much larger than in contractions of the muscles of the arm. The subjects performed in this series altogether 676 contractions of the arm muscles and 678 contractions of the plantar flexors of the ankle. The observations were grouped in classes of 50 ms, according to the estimation of time elapsing between the start of the contraction and the next R wave, assuming that no shortening occurs. In Fig. 1 the proportional mean interval length of 30-40 observations & SE is plotted for each class. From Fig. 1 we starts about gather that a shortening c of the R-R interval 550 ms after the first detectable point of the muscular contraction. These 550 ms, obtained both for the flexor muscles of the arm and the plantar flexors of the ankle, is in accordance with earlier results (5, 6, 29). No distinction between the changes in R-R interval after contractions of arm or leg muscles neither in amplitude of the averaged response nor in lag time could be demonstrated. The deviation from the 100 % level of the mean value of c/b X 100 % in the classes up to 100 ms for b - cl is brought on by the way of plotting the values. The value b - cl is only small in two cases namely if the contraction starts late in the interval so that cl will be large or if b is a very short interval. If cl is large no interval shortening will appear and c/b X 100 % will be approximately 100 %. If interval b is very short the value b - cl will be small and c/b X 100 %
_._._ - - I - - - - - - -
P.
HOLLANDER
AND
L.
N.
BOUMAN
will be larger than 100 %. Due to the latter ease one had to expect a mean value for c/b X 100 % above the 100 % level. Series 2. Voluntary and ellectrically induced muscle contractions. The results of three experiments of this series are summarized in Table 1 both in absolute values and proportional to the duration of MPI. In one experiment the R-R interval in which the contraction starts shows already a marked shortening, in all experiments the next interval is shortened both after voluntary contractions and after electrically induced contractions. Figure 2 displays the normalized R-R interval change caused by volunta.ry and electrically induced contractions, and in Fig. 3 also a control experiment is added. The responses of voluntary contractions and of electrically induced contractions are strikingly similar in all three subjects and no significant difference could be demonstrated in the intervals numbered 0, 1, 2, and 3. In the control experiments with electrical stimulation of the tibia1 skin and without any contraction a shortening of the interval was never observed. Although the lag time between the start of the contraction and the first detectable change in interval length was not determined in the same accurate way as it was in series 1, from Table 1 and Figs. 2 and 3 we infer that the lag time after the start of a voluntary contraction and after the beginning of an electrically induced contraction is approximately the same. Series 3. R-R interval response ufter vugal blockade. In three experiments the R-R interval response to a contraction of the flexor muscles of the upperarm before and after intravenous injection of atropine sulfate (0.04 mg/kg body wt) was studied. Intravenous administration caused a rapid increase in heart rate and a complete disappearance of respiratory arrhythmia. In the control experiments before the administration of atropine the subjects had a normal response as is shown in Table 2 and Fig. 4. The R-R interval in which the contraction starts is already shortened in two subjects, the following intervals are shortened in all three subjects. After injection of atropine contractions of the same muscle with the same force as before did not cause any change in duration of the R-R intervals (see Table 2). From Fig. 4 it can be seen that after administration of atropine no shortening of R-R intervals appears within 9 s after the start of the contraction. Thus with an efKcient vagal blockade the instantaneous cardiac acceleration elicited by muscle contractions disappeared. DISCUSSION
I
I 100
1 200
I 300
I
I 400
1
1 500
I 600
I
I 700
I
I 800
b-cl
(MSEC)
II
I 1000
I 900
FIG. 1. Relation between the proportional interval duration (mean + SE) after arm and leg contractions and the time elapsing between the start of the contraction and the expected moment of the next R wave. Inset: schematic drawing of the ECG (ujfer) and the contraction wave (lower). Last normal R-R interval is coded b and the R-R interval in which the contraction starts is coded G. R-R interval c is divided by the start of the contraction in two parts, cl and c2 (see further text).
The shortening of the R-R interval as observed quickly after the start of muscular contraction theoretically can be caused by another mechanism than the contraction itself. Anticipation, a change of respiration, or perception of the signal might be responsible for the instantaneous change in heart rate. These three factors, however, have already been exluded in earlier investigations of our group (5, 6, 29). An increase in heart rate is only observed when there is an actual muscle contraction, hence it seems likely that the increase in heart rate is due to the muscular action. This is supported by series 2, in which electrical stimulation also results in an identical change of the R-R interval. The present experiments, showing a lag time of 550 ms
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
R MUSCLE-IIEART
mmx --X.-
REFLEX
IN
275
MAN
1. R-R interval changes to voluntary and electrically :----
induced contractions
-.
Interval MPI -.
zt56.1 EleCtI”
C0lltr01 ---
2
1
884 ~t36.1
897
879
zk49.4 872 xt61.5
zt37.2 865 zt50.8
4
822* zk49.8
816* zt39.4 886 1t56.4
818*
A44.7 4317*
832* 1t58.8 830* h40.1 872 rt58.1
847* zt53.8 855* rt53.4 866 h54.2
zt35.7 904 dz67.4 Interval
907
0
98.1 zk2.01
Electr #Control
5
3
7
6
843*
It37
818"
.o 860*
A49.9 874 h51.1
821*
zt19.0
zt15.1
862* zt39.2 875 dz54.7
852 zt53.7 854* zt56.7
-.---MPI
Volunt
ms
-.
907
Volunt
0
Duration,
897 872
98.6 ztl.55
1
91.1” ztO.60
91.5*
100.8
kO.76 103.3
zt0.21
dzO.69
Duration,
2
% MPI
3
90,8*
4
92.1*
hO.71
93.8*
91.8*
93.2* 1tO.65 100.4
ztO.85
zlz1.15
zkO.81
6
91.4*
dr3.60
96.3*
101.3
7
92.1*
93.6* h1.70
M.74 95.7*
AO.84
zt1.17 102.7 dz2.32
5
k3.75
95.7*
jzO.06
H.22
100 .o ztl .oe
zt1.33
95.6* ztZ.ll
100.4
99.4 ztl.60
R-R interval duration (mean & SE) in milliseconds and as a percentage of the mean precontraction interval (= MPI). In interval muscle contractions; Electr = electrically induced contractions; 0 the contraction starts, or the stimulation starts. Volunt = voluntary Control = electrical stimuXation of the tibia1 skin without contractions. Presented values are the mean of 3 experiments =t SE. * Significant interval decrease (P < 0.05).
between
the start of a short-lasting isometric muscle conand the shortening of the R-R interval, confirm our previous estimations (5, 6, 29) and are in accordance with the values given by Paulev (27) and Wigertz (32). In earlier papers (5, 6, 29) we have already put forward that the relative short lag time between the start of a muscle contraction and the increase of heart rate strongly suggests an important role of the vagal nerves. In the present experiments conclusive evidence for this assumption is given by the total disappearance of the cardiac response after atropinization. From in vitro experiments it is known that the latency of the accelerant nerves is about 3-6 s (31) so our registration time is long enough to exclude sympathetic influences, if any, on heart rate after the contractions. Therefore we conclude that the cardiac acceleration elicited by short isometric muscle contractions is only a result of inhibition of the cardiac vagal tone and not a result of a concomitant increase of sympathetic activity. This conclusion is not in accordance with the results of Freyschuss (12, 13) who reported a small but significant increase in heart rate due to a 10-s lasting isometric contraction of arm muscles after administration of atropine. The main differences between the experiments of Freyschuss and ours concern contraction time and the dose of atropine administered. In Freyschuss’ experiments the amount of atropine was too low to expect a total vagal blockade (15, 20). In one experiment we also injected 2.0 mg atropine sulfate (i.e., 0.024 mg/kg body wt) and an incomplete vagal blockade was shown by a continuing respiratory arrhythmia. Shortening of the R-R interval as a result of muscular contractions was still clear in this experiment. It is still an open question where the input to the cardioinhibitory center arises. From the short lag time it is likely that also this input is of a neural nature. In our view there are only two possible origins of those nervous impulses (see Fig. 5) : cortical, being an irradiation from the motor cortex at the start of the muscular activity, and muscular,
INTERVAL LENGTH
traction
ARM
FLEXION
l-3-73
Pc!H
d
IN %
875
--I--d---__
a 0
MSEC
--I----
VOLUNTARY STIMULATED INTERVAL NUMBER I1
-5
I
-4
-3
I
-2
II
-1
11
11
11
11
,
0123456789
FIG. 2. Proportional R-R interval response to voluntary and electrically induced contractions of arm muscles. Precontraction intervals are coded with negative numbers. Acoustic signal was triggered by the R-wave at the start of interval 0. Arrow indicates the start of the contractions. Contraction lasted less than 1 s. Ordinate: mean value of 30 normalized R-R intervals.
from the contracting muscles. The results of the experiments in series 1 do not support the concept of a peripheral origin. In this series a difference in lag time after arm and leg contractions is not demonstrable. Nevertheless, a similarity of the time taken for the heart rate to increase after contractions of different muscles is not proved either. Time
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
276
A. P. ITOLEANDER 1o5
INTERVAL LENGTH IN %
AND
L,. N. BOUMAN ARM
I
FLEXION
t
FIG. 3. Proportional R-R interval response to voluntary muscle contractions (left), electrically induced contractions (middle) and to electrical stimulation of the tibia1 skin (right). Arrow indicates the start of the voluntary contractions or the start of the electrical stimulation. Contraction lasted less than 1 s. Or&nate: mean value A SE of 30 normalized intervals.
I
:~llI1IlIII1lIIII~lIIIIl1lrI1rl,~~1Il1I1l1I1lIllr
5
0
0
VOLUNTARY
TABLE
---
C;y;;;lI ---^
2. i?fect
of uugal _-
-
blockade
0
5
CONTROL
----_ Interval
MPI
AZ 90.9 * 32.4
5
STIMULATED
--
Control 1,115 Block 592 ~ --. h/lean R-R interval by atropine-sulfate of 3 experiments *
tNTERVAL NUMBER
0
1,054 593
zt 63,8* zt 32.3
Duration,
1
973 zk 592 zt
ms 2
3
4 .-
109.6* 31.8
953 h 591 zt
duration (=I= SE) in milliseconds in voluntary contracting (= block). MPI = mean precontraction interval. In interval SE. * Significant interval decrease (P < 0.05).
resolution of the method used in this series is about 50-100 ms. Fibers with a conduction velocity over 10 m/s and a difference in afferent conduction distance between arm and leg muscles of 75 cm result in a difference in lag time of 75 ins. Smaller differences are not detectable with the method used, which means that the experiments of series 1 do not distinguish between a muscle-heart reflex and a central origin of the cardiac accelerationThe experiments of series 2 give strong evidence that indeed a peripheral receptor is involved in the origin of a muscle-heart reflex. In this series of experiments it was demonstrated that by electrical stimulation and without any central motor command a cardiac acceleration can be observed that is identical to the one seen during voluntary muscular action. The existence of a muscle-heart reflex in human was already suggested in 1943 by Asmussen et al. for steadystate exercise (2). But also for the onset of exercise a muscleheart reflex seemed to be involved in heart rate regulation. Central irradiation accompanying voluntary . contractions as suggested by Goodwin et al. ( 16) cannot be precluded from the results of series 2. It is conceivable that besides a muscle-heart reflex a central irradiation is involved, which might or might not be from cortical origin. The muscular origin of the muscle-heart reflex presumes the presence of a receptor that discharges early during the contraction. The total lag time between the start of the contraction and the first ensuing change of the R-R interval estimated from the results of series I is 550 ms. From Fig. 5 can be inferred that the level of the contraction signal used to mark the beginning of the latent period is not the very start. Since the contraction in fact started some 30 ms
125.0* 32.6
subjects before 0 the contractions
947 591 (=
+ *
114.5* 31.9
996 31 131,3* 591 zt 32.0
control) and during vagal blockade start, Presented values are the mean
before the trigger point, the real lae time is 580 ms. The efferent pathway requires about 396 ms, i.e., a measured P-Q time of 170 ms, a la? time between vayal stimulation and next atria1 depolarizition of 170 ms ($2) and a vagal conduction time of 50 ms ( 18). SO only 190 ms are left for central transmission and for afferent conduction. Estimations of the central transmission time can only be made with great uncertainty. On account of the conduction velocity of the different types of afferent fibers however it is possible to estimate the time required for the afferent conduction of impulses from the muscle receptors to the brain stem, assuming a conduction path of 1.3 m. The duration of aRerent conduction will be shorter than 40 ms if type I or II fibers are involved. Assuming type III fibers are involved conduction time will be from 45 to 300 ms. Afferent impulses from the slowly conducting type IV fibers as suggested by Coote et al. (8), McCloskey and Mitchell (26) and Pgrez-Gonzhlez and Coote (28) can be excluded because the afferent conduction time will be more than 0.5 s. Impulses conducted by group I and II fibers and also the fastest conducting III fibers can be at the medullar center early enough to fit well in a muscle-heart reflex \vith the lag time found in series 1. This fits with the conclusion from series 1 that if there is an afferent path involved the difference in afferent conduction time between arm and leg muscles must be less than 100 ms. Freyschuss’ experiments (12) on the effects of a blockade of muscle by succinylcholine and the observation of McCloskey et al. (25) of the negative effect of vibration of the muscle, known as a powerful stimulus to the primary afferents of muscle spindles, make it unlikely that IA or II
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
A
MUSCLE-HEL4RT
REFLEX
IN
277
MAN
ARM
INTERVAL LENGTH 0
CONTR~4CTTON
ACOUSTIC STIMULUS)
In
FlEXION
16 _ 112’72
MZ.
MOTOR
0
f
I
CORTEX
:T 1
1060
-
M SEC --
CONTROL
i
VENTRICULAR
CONTRACTING MUSCLE
85
DEPOLARIZATION
80 I
555
MSEC
---I
I
+p
AfROPINE FIG.
t -5
-4
FIG. 4. R-R before and after the vagal nerves SE of 30 normalized normalized R-R
-3
-2
-1
0
I
2
3
4
5
6
7
TIME
(SEC
8
910
1
interval response to voluntary muscle contractions administration of atropine-sulfate sufficient to block completely. Ordinate; in control experiments mean + R-R intervals, in atropine experiments mean of 30 intervals (SE within the size of the circles).
fibers are involved in a muscle-heart reflex. McCloskey and Mitchell (26) d emonstrated in cats that circulatory changes due to isometrically exercising muscles disappeared after preferentially blocking the unmyelinated and small myelinated fibers and did not disappear after se1ective anodal block of the large fibers. Further evidence for the participation of slow conducting nerve fibers, type III, in a reflex response of the cardiac muscle has recently been given (8, 9, 2% The next question to be considered, therefore, is that of the nature of the receptors within the muscles that are innervated via type III nerve fibers. Metabolic and mechanoreceptors are suggested bv many authors (9, 10, 28, 30). However, it is unlikely that metabolic receptors (30), either within the muscle or outside it, could be the origin of the afferent part of the muscle-heart reflex that we describe because the reflex time seems to be too short to allow for the detection of any metabolic change. Mechanoreceptors connected to type III fibers and excited by muscular contraction without movements are more likely the kind of receptor involved. The Pacinian corpuscles located within the muscles (11) and stimulated by pressure could be the origin of the affer-
diac part
LATENT
PERIOD
5. Diagram of two neural pathways possible acceleration caused by muscular contractions. conduction and transmission times are indicated
y
involved in carFor the efferent in milliseconds.
ent part of the reflex. In favour of a pressure receptor are the results of Lind ( 10, 24) and of our group (5) showing a tendency for a stronger contraction to be followed by a larger change in interval duration. The observations that the interval decrease is independent of the mass of muscle involved (5) also agree with a receptor sensitive to intramuscular pressure. Moreover, pressure applied to the muscle by manual squeezing elicits changes in heart rate, too (25). However, until further experimental evidence is available about muscle receptors or free nerve endings that may play a role in cardiac acceleration at the onset of exercise, the nature and modality of activation of the receptor will remain unknown. In summary the present results constitute evidence for the existence of a muscle-heart reflex which causes an instantaneous cardiac acceleration at the onset of exercise. The nature of the muscle receptor is still unknown, but impulses from the muscle have to be mediated by nerve fibers from group III, the efferent pathway of this muscleheart reflex consists of the vagal nerves only. The authors gratefully acknowledge the participation of C. Borst, M.D., in the first phase of the present investigations, the encouraging and helpful discussions with Prof. Dr. J. T. F. Boeles and the medical assistance of A. J. PouIus, M.D. Mrs. A. ,4. Meijer, A. W. Schreurs, H. de Best, and G. W. A. M. Scheers helped us generously by their indispensable technical assistance. We thank Dept. of Medical Physics in Amsterdam for giving access to the PDP-9 computer and the help in handling it. Received
for
publication
19 February
1974.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
278
A. Pa HOLLANDER
AND
L. TV. BOUMAN
REFERENCES 1. ALAM,
2.
3. 4. 5.
6.
7.
8.
9,.
10.
11.
12. 13. 14.
15. 16.
hi., AND F. H. SMIRK. Observations in man on a pulse acceleration reflex from the voluntary muscles of the legs. J. Physiol., London 92: 167-l 77, 1938. ASMUSSEN, E., M, NIELSEN, AND G. WIETH-PEDERSEN. On the regulation of circulation during muscular work. Acta Physiol, &and. 6: 353-358, 1943. ATHANASIU, J ., AND J. CARVALLO. Le travail musculaire et le rythme du coeur. Arch. PhysioZ. 30: 552-567, 1898. AULO, T. A. Weiteres tiber die Ursache der Herzbeschleunigung bei der Muskelarbeit. Stand. Arch. Physiol. 25 : 347-360, 1911. BORST, C., A. P. HOLLANDER, AND L. N. BOUMAN. Cardiac acceleration elicited by voluntary muscle contractions of minimal duration. J. ApfZ. Physiol. 32: 70-77, 1972. BORST, C., A. P, HOLLANDER, AND L. N. BOUMAN. Cardiac acceleration at the onset of exercise. In: Onset of &XX&, edited by A. Gilbert and P. Guille. Toulouse: Centre d’Hemotypologie CHU Purpan, 1971, p. 9-18. BOWEN, W. P. A study of the pulse rate in man, as modified by muscular work. In : Contributions to Medical Research. Michigan : Wahr, 1903, p. 462-494. COOTE, .J. H., S. r\f. HILTON, AND J. F. PEREZ-GONZALEZ. The reflex nature of the pressor response to muscular exercise. J. Physiol., London 215: 789-804, 1971. COOTE, J. H., AND J. F. PEREZ-GONZ~;LEZ. The response of some sympathetic neurones to volleys in various afferent nerves. J. Physiol., London 208 : 26 l-278, 1970. DONALD, K. W., A. I
Vol.
OF APPLIED PHYSIOLOGY 38, No. 2, February 2975. P~inled
in U.S.A.
acceleration in man b y a muscle-heart reflex Cardiac
A. P. HOLLANDER Ijepar
AND
tmen t of Physiology,
elicited
L. N. BOUMAN
University
of
Amsterdam,Amsterdm, The lV&erlands
HOLEANDER, A. P., AND L.N. BOUMAN. Curdiac acceleration in man atropine. Coote et al. (8) mentioned the existence of an elicited by a muscle-heart reJex. J. Appl. Physiol. 38(2): 272-278. CLexercise reflex” in cats that was unchanged after cutting 1975.-The shortening of the R-R interval in response to volunboth vagal nerves. tary and electrically induced isometric muscle contractions of short The present experiments were undertaken in the first duration was investigated in 15 volunteers. In some of those explace to decide between peripheral or the central origin of periments the elect of vagal blockade was also studied. The results the impulse that accelerates the heart at the onset of exercise. show: I) a lag time between the start of the contraction and the In series 1 the lag time between the onset of arm contracfollowing decrease in R-R interval duration of 550 milliseconds; 2) tions and cardiac acceleration is compared to the lag time a similar R-R interval response due to voluntary and electrically between leg contractions and cardiac acceleration. induced contractions of the same force; 3) no shortening of the R-K interval when the skin is stimulated without ensuing muscular In series 2 the effect on heart rate was studied of arm contraction; 4) a complete disappearance of the response to isomuscle contractions that were elicited by electrical stimulametric contractions during vagal blockade. A difference in lag tion. time between the onset of arm contraction and cardiac acceleraThe second objective was to clear the efferent way of the tion and the onset of leg contraction and cardiac acceleration could cardiac accelerating system at the onset of exercise b’y pharnot be demonstrated. Most of the results give strong evidence to the macological blockade (series 3). existence of a muscle-heart reflex in man, involved in the instantaneous cardiac acceleration at the onset of exercise, that has its METHODS origin in the muscles and the vagal nerves as its efferent pathway.
heart rate regulation; isometric traction; vagal blockade; muscle
exercise; receptor;
electrically exercise;
induced tachycardia
con-
DESPITE INTENSIVE INVESTIGATIONS Over 80 years the understanding of the mechanisms underlying the cardiac acceleration at the onset of muscular exercise is lacking. Differences in opinion still exist with regards to origin and pathway of the heart rate response in man produced by muscular exercise. In 1894 Johansson (19) postulated irradiation of cortical impulses; others (4, 21) supported the idea of a central origin.
In 1898 Athanasiu et al. (3) suggested a regulation of heart rate during muscular work ‘-g;overned by reflex impulses from the working Inuscles, and also this idea found a considerable support ( 1, 7, 14). In recent years Lind et al. ( 10, 23, 24) and Freyschuss (12, 13) worked on human subjects to discern between the two possible origins, but the results are rather conflicting. The origin and the afferent pathway of cardiac acceleration elicited by muscular contractions is not the only unsolved problem. From experiments in which the lag time between the start of the muscular contraction and the first detectable increase in heart rate was estimated (5, 6, 27, 29) it was concluded that inhibition of the vagal nerve played a major role in cardiac acceleration. However, Freyschuss (12, 13) reported still small changes in heart rate evoked by muscular contractions after intravenous administration of
Five female and ten male students from an institute of physical education volunteered in the three series of experiments. Age, height, and weight ranges were : 18-24 yr, 1.661.90 m, and 52-84 kg; seven subjects participated in more than one series. No subject had a history of cardiovascular disease or recent illness. The subjects were instructed about the general course of the experiment but information concerning the purpose of the investigations was not provided. After a 5-min rest period the R-R interval (the time interval between two corresponding points of successive R waves) was studied before, during, and after isometric contractions of different muscles. All experimental data were obtained while the subjects were sitting as relaxed as possible in a comfortable bucket seat connected to an arm dynamometer and a leg dynamometer both constructed for the types of isometric contractions involved. A more detailed description of both dynamometers is presented in earlier papers from our group (5, 29). A bipolar ECG was obtained by means of electrodes fixed on the thorax. The contraction force was converted into an electrical signal by means of strain gauges. A detailed description of nrethods and block diagram of the recording circuit was presented earlier (5). Series 1. Lag time aftu mm and leg contractions. In response to an acoustic signal the subject had to exert as quick as possible a maximal contraction of either arm or leg muscles in random order. The group of nzuscles that had to be used was indicated well ahead of time by a red or a green light. All contractions lasted for less than one second. The acoustic
272
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
A MUSCLE-HEART
REFLEX
IN
signal was presented with a variable interval of 40-55 s to avoid anticipation. To spread the start of the muscle contractions along the R-R interval the acoustic signal was given with a variable delay after an R wave. The delay was varied in random order between 0 and 700 ms in steps of 100 IIIS. During one experiment the subjects performed about 75 contractions both with arm and ‘leg muscles. An experiment lasted about 2.5 h, includin. PI (j) is defined as (the contraction starts in the 6th R-R interval) By means of this normalization technique A(i, j) of normalized intervals arises. The interval duration MPT (mean precontraction calculated according to the following equation MPI
a new array mean resting interval) was
=
From the normalized interval array mean value and standard error of the mean (SE) of intervals with equal sequential numbers (= ;) was calculated. Deviations from the mean precontraction interval (MPI) or from the 100 % level in the case of the normalized intervals were established with the Student t-test (two-tailed, x) = O-05).
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
274
A.
RESULTS
Series 1. Lug time after mm and leg muscle contractions. This series of experiments was performed on 11 subjects, showing a normal heart rate response to voluntary isometric contractions. The average MPI in the experiments was 988 + 43.3 ms for observations with arm flexion and 999 j= 42.4 ms for observations with plantar flexion. The maximal shortening of the R-R interval due to arm flexion was 13 1 =t 30.9 ms (12.4% of MPI) and due to plantar flexion of the leg muscles 125 =I= 25.3 ms (12.5 % of MPI) although in the latter the exerted force and muscle mass involved is much larger than in contractions of the muscles of the arm. The subjects performed in this series altogether 676 contractions of the arm muscles and 678 contractions of the plantar flexors of the ankle. The observations were grouped in classes of 50 ms, according to the estimation of time elapsing between the start of the contraction and the next R wave, assuming that no shortening occurs. In Fig. 1 the proportional mean interval length of 30-40 observations & SE is plotted for each class. From Fig. 1 we starts about gather that a shortening c of the R-R interval 550 ms after the first detectable point of the muscular contraction. These 550 ms, obtained both for the flexor muscles of the arm and the plantar flexors of the ankle, is in accordance with earlier results (5, 6, 29). No distinction between the changes in R-R interval after contractions of arm or leg muscles neither in amplitude of the averaged response nor in lag time could be demonstrated. The deviation from the 100 % level of the mean value of c/b X 100 % in the classes up to 100 ms for b - cl is brought on by the way of plotting the values. The value b - cl is only small in two cases namely if the contraction starts late in the interval so that cl will be large or if b is a very short interval. If cl is large no interval shortening will appear and c/b X 100 % will be approximately 100 %. If interval b is very short the value b - cl will be small and c/b X 100 %
_._._ - - I - - - - - - -
P.
HOLLANDER
AND
L.
N.
BOUMAN
will be larger than 100 %. Due to the latter ease one had to expect a mean value for c/b X 100 % above the 100 % level. Series 2. Voluntary and ellectrically induced muscle contractions. The results of three experiments of this series are summarized in Table 1 both in absolute values and proportional to the duration of MPI. In one experiment the R-R interval in which the contraction starts shows already a marked shortening, in all experiments the next interval is shortened both after voluntary contractions and after electrically induced contractions. Figure 2 displays the normalized R-R interval change caused by volunta.ry and electrically induced contractions, and in Fig. 3 also a control experiment is added. The responses of voluntary contractions and of electrically induced contractions are strikingly similar in all three subjects and no significant difference could be demonstrated in the intervals numbered 0, 1, 2, and 3. In the control experiments with electrical stimulation of the tibia1 skin and without any contraction a shortening of the interval was never observed. Although the lag time between the start of the contraction and the first detectable change in interval length was not determined in the same accurate way as it was in series 1, from Table 1 and Figs. 2 and 3 we infer that the lag time after the start of a voluntary contraction and after the beginning of an electrically induced contraction is approximately the same. Series 3. R-R interval response ufter vugal blockade. In three experiments the R-R interval response to a contraction of the flexor muscles of the upperarm before and after intravenous injection of atropine sulfate (0.04 mg/kg body wt) was studied. Intravenous administration caused a rapid increase in heart rate and a complete disappearance of respiratory arrhythmia. In the control experiments before the administration of atropine the subjects had a normal response as is shown in Table 2 and Fig. 4. The R-R interval in which the contraction starts is already shortened in two subjects, the following intervals are shortened in all three subjects. After injection of atropine contractions of the same muscle with the same force as before did not cause any change in duration of the R-R intervals (see Table 2). From Fig. 4 it can be seen that after administration of atropine no shortening of R-R intervals appears within 9 s after the start of the contraction. Thus with an efKcient vagal blockade the instantaneous cardiac acceleration elicited by muscle contractions disappeared. DISCUSSION
I
I 100
1 200
I 300
I
I 400
1
1 500
I 600
I
I 700
I
I 800
b-cl
(MSEC)
II
I 1000
I 900
FIG. 1. Relation between the proportional interval duration (mean + SE) after arm and leg contractions and the time elapsing between the start of the contraction and the expected moment of the next R wave. Inset: schematic drawing of the ECG (ujfer) and the contraction wave (lower). Last normal R-R interval is coded b and the R-R interval in which the contraction starts is coded G. R-R interval c is divided by the start of the contraction in two parts, cl and c2 (see further text).
The shortening of the R-R interval as observed quickly after the start of muscular contraction theoretically can be caused by another mechanism than the contraction itself. Anticipation, a change of respiration, or perception of the signal might be responsible for the instantaneous change in heart rate. These three factors, however, have already been exluded in earlier investigations of our group (5, 6, 29). An increase in heart rate is only observed when there is an actual muscle contraction, hence it seems likely that the increase in heart rate is due to the muscular action. This is supported by series 2, in which electrical stimulation also results in an identical change of the R-R interval. The present experiments, showing a lag time of 550 ms
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
R MUSCLE-IIEART
mmx --X.-
REFLEX
IN
275
MAN
1. R-R interval changes to voluntary and electrically :----
induced contractions
-.
Interval MPI -.
zt56.1 EleCtI”
C0lltr01 ---
2
1
884 ~t36.1
897
879
zk49.4 872 xt61.5
zt37.2 865 zt50.8
4
822* zk49.8
816* zt39.4 886 1t56.4
818*
A44.7 4317*
832* 1t58.8 830* h40.1 872 rt58.1
847* zt53.8 855* rt53.4 866 h54.2
zt35.7 904 dz67.4 Interval
907
0
98.1 zk2.01
Electr #Control
5
3
7
6
843*
It37
818"
.o 860*
A49.9 874 h51.1
821*
zt19.0
zt15.1
862* zt39.2 875 dz54.7
852 zt53.7 854* zt56.7
-.---MPI
Volunt
ms
-.
907
Volunt
0
Duration,
897 872
98.6 ztl.55
1
91.1” ztO.60
91.5*
100.8
kO.76 103.3
zt0.21
dzO.69
Duration,
2
% MPI
3
90,8*
4
92.1*
hO.71
93.8*
91.8*
93.2* 1tO.65 100.4
ztO.85
zlz1.15
zkO.81
6
91.4*
dr3.60
96.3*
101.3
7
92.1*
93.6* h1.70
M.74 95.7*
AO.84
zt1.17 102.7 dz2.32
5
k3.75
95.7*
jzO.06
H.22
100 .o ztl .oe
zt1.33
95.6* ztZ.ll
100.4
99.4 ztl.60
R-R interval duration (mean & SE) in milliseconds and as a percentage of the mean precontraction interval (= MPI). In interval muscle contractions; Electr = electrically induced contractions; 0 the contraction starts, or the stimulation starts. Volunt = voluntary Control = electrical stimuXation of the tibia1 skin without contractions. Presented values are the mean of 3 experiments =t SE. * Significant interval decrease (P < 0.05).
between
the start of a short-lasting isometric muscle conand the shortening of the R-R interval, confirm our previous estimations (5, 6, 29) and are in accordance with the values given by Paulev (27) and Wigertz (32). In earlier papers (5, 6, 29) we have already put forward that the relative short lag time between the start of a muscle contraction and the increase of heart rate strongly suggests an important role of the vagal nerves. In the present experiments conclusive evidence for this assumption is given by the total disappearance of the cardiac response after atropinization. From in vitro experiments it is known that the latency of the accelerant nerves is about 3-6 s (31) so our registration time is long enough to exclude sympathetic influences, if any, on heart rate after the contractions. Therefore we conclude that the cardiac acceleration elicited by short isometric muscle contractions is only a result of inhibition of the cardiac vagal tone and not a result of a concomitant increase of sympathetic activity. This conclusion is not in accordance with the results of Freyschuss (12, 13) who reported a small but significant increase in heart rate due to a 10-s lasting isometric contraction of arm muscles after administration of atropine. The main differences between the experiments of Freyschuss and ours concern contraction time and the dose of atropine administered. In Freyschuss’ experiments the amount of atropine was too low to expect a total vagal blockade (15, 20). In one experiment we also injected 2.0 mg atropine sulfate (i.e., 0.024 mg/kg body wt) and an incomplete vagal blockade was shown by a continuing respiratory arrhythmia. Shortening of the R-R interval as a result of muscular contractions was still clear in this experiment. It is still an open question where the input to the cardioinhibitory center arises. From the short lag time it is likely that also this input is of a neural nature. In our view there are only two possible origins of those nervous impulses (see Fig. 5) : cortical, being an irradiation from the motor cortex at the start of the muscular activity, and muscular,
INTERVAL LENGTH
traction
ARM
FLEXION
l-3-73
Pc!H
d
IN %
875
--I--d---__
a 0
MSEC
--I----
VOLUNTARY STIMULATED INTERVAL NUMBER I1
-5
I
-4
-3
I
-2
II
-1
11
11
11
11
,
0123456789
FIG. 2. Proportional R-R interval response to voluntary and electrically induced contractions of arm muscles. Precontraction intervals are coded with negative numbers. Acoustic signal was triggered by the R-wave at the start of interval 0. Arrow indicates the start of the contractions. Contraction lasted less than 1 s. Ordinate: mean value of 30 normalized R-R intervals.
from the contracting muscles. The results of the experiments in series 1 do not support the concept of a peripheral origin. In this series a difference in lag time after arm and leg contractions is not demonstrable. Nevertheless, a similarity of the time taken for the heart rate to increase after contractions of different muscles is not proved either. Time
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
276
A. P. ITOLEANDER 1o5
INTERVAL LENGTH IN %
AND
L,. N. BOUMAN ARM
I
FLEXION
t
FIG. 3. Proportional R-R interval response to voluntary muscle contractions (left), electrically induced contractions (middle) and to electrical stimulation of the tibia1 skin (right). Arrow indicates the start of the voluntary contractions or the start of the electrical stimulation. Contraction lasted less than 1 s. Or&nate: mean value A SE of 30 normalized intervals.
I
:~llI1IlIII1lIIII~lIIIIl1lrI1rl,~~1Il1I1l1I1lIllr
5
0
0
VOLUNTARY
TABLE
---
C;y;;;lI ---^
2. i?fect
of uugal _-
-
blockade
0
5
CONTROL
----_ Interval
MPI
AZ 90.9 * 32.4
5
STIMULATED
--
Control 1,115 Block 592 ~ --. h/lean R-R interval by atropine-sulfate of 3 experiments *
tNTERVAL NUMBER
0
1,054 593
zt 63,8* zt 32.3
Duration,
1
973 zk 592 zt
ms 2
3
4 .-
109.6* 31.8
953 h 591 zt
duration (=I= SE) in milliseconds in voluntary contracting (= block). MPI = mean precontraction interval. In interval SE. * Significant interval decrease (P < 0.05).
resolution of the method used in this series is about 50-100 ms. Fibers with a conduction velocity over 10 m/s and a difference in afferent conduction distance between arm and leg muscles of 75 cm result in a difference in lag time of 75 ins. Smaller differences are not detectable with the method used, which means that the experiments of series 1 do not distinguish between a muscle-heart reflex and a central origin of the cardiac accelerationThe experiments of series 2 give strong evidence that indeed a peripheral receptor is involved in the origin of a muscle-heart reflex. In this series of experiments it was demonstrated that by electrical stimulation and without any central motor command a cardiac acceleration can be observed that is identical to the one seen during voluntary muscular action. The existence of a muscle-heart reflex in human was already suggested in 1943 by Asmussen et al. for steadystate exercise (2). But also for the onset of exercise a muscleheart reflex seemed to be involved in heart rate regulation. Central irradiation accompanying voluntary . contractions as suggested by Goodwin et al. ( 16) cannot be precluded from the results of series 2. It is conceivable that besides a muscle-heart reflex a central irradiation is involved, which might or might not be from cortical origin. The muscular origin of the muscle-heart reflex presumes the presence of a receptor that discharges early during the contraction. The total lag time between the start of the contraction and the first ensuing change of the R-R interval estimated from the results of series I is 550 ms. From Fig. 5 can be inferred that the level of the contraction signal used to mark the beginning of the latent period is not the very start. Since the contraction in fact started some 30 ms
125.0* 32.6
subjects before 0 the contractions
947 591 (=
+ *
114.5* 31.9
996 31 131,3* 591 zt 32.0
control) and during vagal blockade start, Presented values are the mean
before the trigger point, the real lae time is 580 ms. The efferent pathway requires about 396 ms, i.e., a measured P-Q time of 170 ms, a la? time between vayal stimulation and next atria1 depolarizition of 170 ms ($2) and a vagal conduction time of 50 ms ( 18). SO only 190 ms are left for central transmission and for afferent conduction. Estimations of the central transmission time can only be made with great uncertainty. On account of the conduction velocity of the different types of afferent fibers however it is possible to estimate the time required for the afferent conduction of impulses from the muscle receptors to the brain stem, assuming a conduction path of 1.3 m. The duration of aRerent conduction will be shorter than 40 ms if type I or II fibers are involved. Assuming type III fibers are involved conduction time will be from 45 to 300 ms. Afferent impulses from the slowly conducting type IV fibers as suggested by Coote et al. (8), McCloskey and Mitchell (26) and Pgrez-Gonzhlez and Coote (28) can be excluded because the afferent conduction time will be more than 0.5 s. Impulses conducted by group I and II fibers and also the fastest conducting III fibers can be at the medullar center early enough to fit well in a muscle-heart reflex \vith the lag time found in series 1. This fits with the conclusion from series 1 that if there is an afferent path involved the difference in afferent conduction time between arm and leg muscles must be less than 100 ms. Freyschuss’ experiments (12) on the effects of a blockade of muscle by succinylcholine and the observation of McCloskey et al. (25) of the negative effect of vibration of the muscle, known as a powerful stimulus to the primary afferents of muscle spindles, make it unlikely that IA or II
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
A
MUSCLE-HEL4RT
REFLEX
IN
277
MAN
ARM
INTERVAL LENGTH 0
CONTR~4CTTON
ACOUSTIC STIMULUS)
In
FlEXION
16 _ 112’72
MZ.
MOTOR
0
f
I
CORTEX
:T 1
1060
-
M SEC --
CONTROL
i
VENTRICULAR
CONTRACTING MUSCLE
85
DEPOLARIZATION
80 I
555
MSEC
---I
I
+p
AfROPINE FIG.
t -5
-4
FIG. 4. R-R before and after the vagal nerves SE of 30 normalized normalized R-R
-3
-2
-1
0
I
2
3
4
5
6
7
TIME
(SEC
8
910
1
interval response to voluntary muscle contractions administration of atropine-sulfate sufficient to block completely. Ordinate; in control experiments mean + R-R intervals, in atropine experiments mean of 30 intervals (SE within the size of the circles).
fibers are involved in a muscle-heart reflex. McCloskey and Mitchell (26) d emonstrated in cats that circulatory changes due to isometrically exercising muscles disappeared after preferentially blocking the unmyelinated and small myelinated fibers and did not disappear after se1ective anodal block of the large fibers. Further evidence for the participation of slow conducting nerve fibers, type III, in a reflex response of the cardiac muscle has recently been given (8, 9, 2% The next question to be considered, therefore, is that of the nature of the receptors within the muscles that are innervated via type III nerve fibers. Metabolic and mechanoreceptors are suggested bv many authors (9, 10, 28, 30). However, it is unlikely that metabolic receptors (30), either within the muscle or outside it, could be the origin of the afferent part of the muscle-heart reflex that we describe because the reflex time seems to be too short to allow for the detection of any metabolic change. Mechanoreceptors connected to type III fibers and excited by muscular contraction without movements are more likely the kind of receptor involved. The Pacinian corpuscles located within the muscles (11) and stimulated by pressure could be the origin of the affer-
diac part
LATENT
PERIOD
5. Diagram of two neural pathways possible acceleration caused by muscular contractions. conduction and transmission times are indicated
y
involved in carFor the efferent in milliseconds.
ent part of the reflex. In favour of a pressure receptor are the results of Lind ( 10, 24) and of our group (5) showing a tendency for a stronger contraction to be followed by a larger change in interval duration. The observations that the interval decrease is independent of the mass of muscle involved (5) also agree with a receptor sensitive to intramuscular pressure. Moreover, pressure applied to the muscle by manual squeezing elicits changes in heart rate, too (25). However, until further experimental evidence is available about muscle receptors or free nerve endings that may play a role in cardiac acceleration at the onset of exercise, the nature and modality of activation of the receptor will remain unknown. In summary the present results constitute evidence for the existence of a muscle-heart reflex which causes an instantaneous cardiac acceleration at the onset of exercise. The nature of the muscle receptor is still unknown, but impulses from the muscle have to be mediated by nerve fibers from group III, the efferent pathway of this muscleheart reflex consists of the vagal nerves only. The authors gratefully acknowledge the participation of C. Borst, M.D., in the first phase of the present investigations, the encouraging and helpful discussions with Prof. Dr. J. T. F. Boeles and the medical assistance of A. J. PouIus, M.D. Mrs. A. ,4. Meijer, A. W. Schreurs, H. de Best, and G. W. A. M. Scheers helped us generously by their indispensable technical assistance. We thank Dept. of Medical Physics in Amsterdam for giving access to the PDP-9 computer and the help in handling it. Received
for
publication
19 February
1974.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 11, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
278
A. Pa HOLLANDER
AND
L. TV. BOUMAN
REFERENCES 1. ALAM,
2.
3. 4. 5.
6.
7.
8.
9,.
10.
11.
12. 13. 14.
15. 16.
hi., AND F. H. SMIRK. Observations in man on a pulse acceleration reflex from the voluntary muscles of the legs. J. Physiol., London 92: 167-l 77, 1938. ASMUSSEN, E., M, NIELSEN, AND G. WIETH-PEDERSEN. On the regulation of circulation during muscular work. Acta Physiol, &and. 6: 353-358, 1943. ATHANASIU, J ., AND J. CARVALLO. Le travail musculaire et le rythme du coeur. Arch. PhysioZ. 30: 552-567, 1898. AULO, T. A. Weiteres tiber die Ursache der Herzbeschleunigung bei der Muskelarbeit. Stand. Arch. Physiol. 25 : 347-360, 1911. BORST, C., A. P. HOLLANDER, AND L. N. BOUMAN. Cardiac acceleration elicited by voluntary muscle contractions of minimal duration. J. ApfZ. Physiol. 32: 70-77, 1972. BORST, C., A. P, HOLLANDER, AND L. N. BOUMAN. Cardiac acceleration at the onset of exercise. In: Onset of &XX&, edited by A. Gilbert and P. Guille. Toulouse: Centre d’Hemotypologie CHU Purpan, 1971, p. 9-18. BOWEN, W. P. A study of the pulse rate in man, as modified by muscular work. In : Contributions to Medical Research. Michigan : Wahr, 1903, p. 462-494. COOTE, .J. H., S. r\f. HILTON, AND J. F. PEREZ-GONZALEZ. The reflex nature of the pressor response to muscular exercise. J. Physiol., London 215: 789-804, 1971. COOTE, J. H., AND J. F. PEREZ-GONZ~;LEZ. The response of some sympathetic neurones to volleys in various afferent nerves. J. Physiol., London 208 : 26 l-278, 1970. DONALD, K. W., A. I
