Direct Evidence of Nonuniform
Distribution of Vagal Effects on Dog Atria
By Ithio Ninomiyo, M.D.
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ABSTRACT
The duration of the monophasic action potential (APD), the interval between atrial beats and the delay time between excitation of the right and
left atria of dogs were measured, using coaxial suction electrodes, before
and during vagal stimulation.
The effect of vagal stimulation on the degree of shortening of APD varied
at different recording sites in the atrium, the shortening being more pronounced in the right than in the left atrium. Threshold and rate of recovery
after cessation of stimulation varied throughout the atrium. The results indicate
that the vagal effect is nonuniformly distributed over the atrium.
The time difference between excitation of the right and left atria increased
with vagal stimulation under the present experimental condition, suggesting
that a reduction of synchrony of excitation occurred in the atrial myocardial
fibers as a whole. The same conclusion was derived from analysis of the pattern of the P wave before and during vagal stimulation.
ADDITIONAL KEY WORDS
vagal stimulation
monophasic atrial action potential
averaged P wave
shift of pacemaker
atrial
fibrillation
synchronization of atrial excitation
coaxial suction electrode
data-averaging computer right vs. left atrium
• Studies on the distribution of vagal
effects in the atrium provide important data
regarding the frequency, conduction and recovery of myocardial excitation in normal and
pathologic conditions such as tachycardia,
flutter, and fibrillation. Measurement of the
refractory period in various parts of the right
atrium in the dog during vagal stimulation
has shown that the vagal effect is nonuniformly distributed. 1 Such nonuniformity of
vagal effects is assumed to be one of the possible causes of atrial fibrillation.2' 3
Recently, the effect of vagal stimulation or
acetylcholine on electrically driven or spontaneously active atrial fibers has been studied
with intracellular electrodes 4 " 7 and also with
From the Department of Physiology, School of
Medicine, Hiroshima University, Kasumi-cho, Hiroshima, Japan.
This work was supported in part by research grants
from the Japanese Ministry of Education, from the
U. S. Public Health Service (HE 06968-04), and
U. S. Army Research and Development, Far East
Office, to H. Irisawa, in whose laboratory the work
was done.
Accepted for publication May 9, 1966.
576
monophasic records taken from the turtle8 and
dog9 atrium by recording potentials between
injured and normal tissue. These studies have
demonstrated that the duration of the action
potential is shortened dramatically during
vagal stimulation. The duration of the monophasic action potential (APD) can be used
as an index of the vagal effect on the myocardial fibers in various parts of the atrium.
The purpose of the current experiments is
to secure information on the distribution of
vagal effect in the canine heart in situ.
Methods
Ten mongrel dogs (6 to 10 kg) were used in
this study. Each was anesthetized with sodium
pentobarbital (Nembutal, 25 mg/kg), the trachea was intubated and the lungs were ventilated with intermittent positive pressure from a
Harvard pump. Additional doses of 5 mg/kg sodium pentobarbital were injected intravenously
whenever the electromyogram confounded the
electrocardiogram (ECG). The heart was exposed by a transstemal approach at the third
intercostal space. Two coaxial suction electrodes
were used in recording the monophasic potentials simultaneously from both sides of the atria.
CircmUtion Rutmrcb, Vol. XIX, Stpumitr 1966
NONUNIFORM DISTRIBUTION OF VAGAL EFFECTS
577
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The details of the coaxial suction electrodes have
been described previously.10 Since the coaxial
suction electrode is flexible enough to follow the
vigorous movement of the atrial surface, monophasic potentials could be recorded for a long
time after applying negative pressure with a hydroaspirator. The changes in monophasic action
potential detected by the recording electrodes
were fed into a conventional high-grain differential d-c amplifier and displayed on a four-channel
cathode ray oscilloscope (Model VC 7, Nihon
Koden). Since it is difficult to determine the end
of repolarization precisely, in the present experiments, APD was measured as the interval between the onset of depolarization and the intercepted time obtained by the extrapolation of the
repolarization slope to the base line.
The vagus nerves were cut high in the neck.
Either the right or left peripheral trunk was
placed on bipolar silver electrodes and stimulated
with square-wave shocks of 5 msec in pulse width
and 20 cycle/sec in frequency by an electronic
stimulator (Model 160 series, Tektronix). The
intensity of the stimulation was varied from 2 to
16 volts. Lead II ECG was recorded simultaneously to show the pattern of A-V conduction, to
analyze the effect of vagal stimulation on the
configuration of the P wave, and to monitor the
electromyogram. The averaged P-wave pattern
was obtained by a digital memory averaging device (ND 800, Enhancetron, Nuclear Data, Inc.).
During the experiment, warm physiologic saline
solution was dropped on the epicardium to maintain constant moisture and temperature. The
temperature of the atrial surface was approximately 32°C and room temperature was 25°C.
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EFFECT OF VAGAL STIMULATION ON APD
Vagal stimulation of low intensity primarily
affects the frequency of pacemaker activity.
Vagal stimulation of relatively high intensity
was needed to significantly alter the atrial
APD in all sites at which it was measured.
For example, during right vagal stimulation,
the APD in the right atrium shortened
slightly from 215 ± 12 msec to 186 ± 11 msec,
i.e., to 86% of the control value, while the
interval between atrial beats increased remarkably from 452 ± 9 msec to 1249 ±305
msec, i.e., to 276% of the control value (Table
1). At the onset of vagal stimulation, there
was a rapid change in the plateau phase from
upward concavity to downward concavity in
the monophasic action potential pattern, and
CkcuUsion Ris-rcb, Vol. XIX, Stpumbtr 1966
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NINOMIYA
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CARDIAC CYCLE
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FIGURE 1
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Sequential changes in the duration of the monophasic action potential during vagal stimulation
(APD). APD was recorded at one site on the right atrium at the onset (A) and end (B) of right
vagal stimulation. The 10-msec time calibration in A applies to A and B. Voltage calibration is
10 mv. In C, APD (ordinate) was measured in a series of cardiac cycles (abscissa). Horizontal
bar in C shows the interval of vagal stimulation.
quickly recovered to one-half of the control
level, and then gradually returned to the previous level (Fig. 1, B and C). These observations almost coincided with the previous
results obtained with the ultramicroelectrode
technique.4 In many instances, the time
course of recovery in the APD after cessation
of vagal stimulation was different from site
to site within the same atrial tissue. Two examples are illustrated in Figures 2 and 4.
200
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DIFFERENCES IN THE THRESHOLD TO VAGAL
STIMULATION AT VARIOUS SITES OF THE ATRIUM
s-—
0
2
4
6
CARDIAC CYCLE
8
10
12
FIGURE 2
Time course of recovery in APD at seven different
recording sites after cessation of right vagal stimulation. At zero cardiac cycle the stimulation ceased. Inset is a schematic illustration of recording sites as
shown by different symbols.
shortening in the APD resulted from shortening of the second phase of the plateau. The
data illustrated in Figure 1 were recorded
from one site of the right atrial appendage.
After the onset of vagal stimulation, the APD
shortened to almost minimum length within
three cardiac cycles and then continued at a
relatively constant level (Fig. 1, A and C).
After cessation of stimulation, the APD
The shortening of the atrial APD could not
be observed until the stimulus intensity was
increased to a certain voltage. In the example
shown in Figure 3, monophasic action potentials were recorded at four different sites on
the right atrium before and during vagal
stimulation. In the vicinity of the pacemaker
region the APD was longest in the control,
and shortened at the lowest intensity. At 6
volts it decreased to about 89% below that of
the control level, but in other regions (2 and
3 in Fig. 3), the duration shortened only
when the stimulus intensity was greater than
6 volts. Figure 3 clearly shows that for a
given intensity of vagal stimulation the degree
of shortening of the APD varied at different
recording sites. These differences in the
CircuUtion Rts—rcb, Vol. XIX, StpUmbtr
1966
579
NONUNIFORM DISTRIBUTION OF VAGAL EFFECTS
Control
300.
RVS
LVS
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6
8
10
INTENSITY (VOLT)
FIGURE 3
Effect of stimulus intensity of vagal stimulation on
APD. Threshold intensity and the degree of shortening
of APD varied at four different recording sites on
the same atria. Numerals in the graph correspond to
the diagrammatic inset of the right atrium. SVC =:
superior vena cava; WC = inferior vena cava. Frequency of stimulation = 20 cps; duration = 5 msec.
threshold to vagal stimulation and in the degree of shortening of the APD were observed
in all other experiments, which indicates that
the effect of vagal stimulation is not uniform
in various parts of the atrium. A significant
increase in the standard deviation of the APD
during vagal stimulation in all experiments
suggests that there is a remarkable variation
of the APD at different recording sites of the
atrium during vagal stimulation (Table 1).
COMPARISON OF RIGHT AND LEFT ATRIAL
MONOPHASIC ACTION POTENTIALS
Monophasic action potentials were recorded
simultaneously from the right and left atrium
in ten instances. The mean APD was 215 ±
12 msec in the right and 186 ± 11 in the left
atrium, a difference of 15%. During right
vagal stimulation, the APD in the right atrium
was shortened to 132 ± 16 msec, i.e., to 62%
of the control duration, while that in the left
atrium decreased to 135 ± 13 msec, i.e., to
73% of the control level (Table 1 and Fig. 4).
Thus, right vagal stimulation caused a greater
reduction of the APD in the right atrium
than in the left atrium. Similar findings were
observed during left vagal stimulation.
Circulation Rttmrch, Vol. XIX, Stpumhn 1966
FIGURE 4
Simultaneous records of Lead II ECC (upper trace)
and monophasic action potential in the right and left
atrium (lower traces) before (control) and during
right (RVS) and left (LVS) vagal stimulation. Note
the change in configuration of the P wave, P-Q interval, delay time of excitation between the two recording sites and shortening in APD both during vagal
stimulation (in 1 of RVS and LVS) and after the
cessation of stimulation (in 2, 3 and 4). The bottom
dots indicate time reference of 68-msec interval. The
rising limb of monophasic action potentials was retouched.
EFFECT OF VAGAL STIMULATION ON THE
SYNCHRONIZATION OF EXCITATION IN THE ATRIA
The delay between the onset of excitation
in the right atrium and that in the left was
measured in all experiments before and during vagal stimulation by using two electrodes,
NINOMIYA
580
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Time difference of excitation between the
two atria increased from 30 ±1.6 (SE) msec
to 35 ± 1.9 (SE) msec during right vagal stimulation and to 34± 1.5 (SE) msec during left
vagal stimulation. The difference was significant at the 5% level In the example illustrated
in Figure 4, two monophasic action potentials were recorded simultaneously at both the
pacemaker region and the left atrial appendage during right and left vagal stimulation of
constant intensity. However, in some cases
the delay time of excitation between two different sites in the right atrium shortened
slightly. The increase in mean delay time of
onset of excitation between the right and left
atrium suggests that the net result of vagal
stimulation is a reduction in the synchrony of
excitation in the atrial myocardium as a whole
under the present experimental condition.
CONFIGURATION OF THE P WAVE DURING
VAGAL STIMULATION
The amplitude, duration and shape of the
P wave of Lead II ECG changed during vagal
stimulation, as can be seen in Figure 4. In order to analyze the effect of vagal stimulation
on the P-wave pattern more precisely, the
averaged P wave was recorded by the method described previously.11 In Figure 5, two
examples of the averaged P-wave pattern
during control (1A and 2A) and during vagal
stimulation (IB and 2B) are illustrated. In
general, as shown previously,11 two notches
were found in the configuration of the averaged P wave in both normal human subjects
and dogs. The initial notch (arrow in Fig. 5)
was deeper than the second notch, which
was often obliterated by noise. In most cases
pronounced notches, decrease in amplitude,
and prolonged duration of the P wave were
observed during vagal stimulation. These phenomena may reflect a change in the summation of individual action potentials in the
atrium as a whole, because of a reduction in
the synchrony of atrial excitations.
Discussion
In the present study, monophasic action potentials from atrial myocardial fibers before
and during vagal stimulation were recorded
by using two coaxial suction electrodes. In
the attempt to detect differences in vagal
effect on the APD, several variables were
selected: (1) threshold intensity, (2) degree
of shortening in the APD, and (3) time course
of recovery from shortening of duration after
the cessation of vagal stimulation. From the
FIGURE 5
Average configuration of the P wave in Lead II ECG obtained from 20 cardiac cycles before
(1A and 2A) and during vagal stimulation (IB and 2B) in two dogs. Note the increase in magnitude of notches (arrow) during vagal stimulation. Increase in duration of the P waoe and P-Q
interval, and decrease in amplitude were observed.
OraOstion Rnircb, Vol. XIX, Stptmitr 1966
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NONUNIFORM DISTRIBUTION OF VAGAL EFFECTS
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measurements of these variables the author
has demonstrated a nonuniform distribution
of vagal effect in different sites of the atrium,
although the monophasic action potentials
were recorded from an injured area of approximately 0.6 mm2 instead of a single cell.
The results depicted in Figure 3 suggest
that all points are susceptible to vagal stimulation, provided only that the nerve is maximally stimulated. This does not mean that the
vagal effect on the atrium is uniformly distributed, for as described in the foregoing section, the threshold to vagal stimulation is different in various parts of the atrium. Previous
studies on the electrophysiology of the myocardium indicate that there is a limitation in
the shortening of the APD, and therefore at
maximal stimulus intensity, a nonuniform distribution of the vagal stimulation is difficult
to demonstrate. Moreover, as shown in Figure
2, the time course of recovery in the APD
after the cessation of vagal stimulation was
different from site to site within the same
atrial tissue, although the APD shortened
maximally. The variation in the threshold to
vagal stimulation and in the degree of shortening for a given stimulus intensity at different sites of the atrium was probably due to
either the different distribution of vagal ter-
minals or the nonuniformity of sensitivity to
acetylcholine released from vagal terminals.
In either case, during vagal stimulation there
may be areas which are repolarized early,
while neighboring areas remain depolarized.
This may provide flow of local current from
the early repolarized area to the neighboring
depolarized area, causing re-excitation of the
earlier repolarized area and finally leading to
tachycardia, flutter and atrial fibrillation. An
example of this is illustrated in Figure 6, A
and B. This has been predicted by several
investigators.1'2 Furthermore, stimulation of
the vagal trunk might directly or reflexly activate sympathetic fibers to the heart, and
this may oppose the vagal effect. Immediately
after the cessation of vagal stimulation, an
overshoot increase in the heart rate was noted
in all experiments, which suggests an increase
in the sympathetic effect on the frequency of
excitation (Fig. 6, C). However, such overshoot response could not be observed in the
APD. It is well known that the effect on the
APD of stimulating the sympathetic nerve is
far less than that of the vagus nerve; therefore, in the present study, the sympathetic
effect on the APD was not considered as an
important factor in causing the nonuniformity
of vagal effect.
=^MHl§SSi^^
FIGURE 6
Continuous records of Lead II ECG (upper trace) and monophasic action potentials (middle
and lower traces) during and after stimulation of the right vagus. In A, at the 5th cardiac
cycles the right vagus was stimulated (arrow) and at the third cardiac cycle in B the stimulation has ceased (arrow). Monophasic potentials were recorded near the pacemaker region.
Distance between two electrodes was approximately 2 mm in diastole. Tachycardia, flutter,
and fibrillation occurred suddenly during vagal stimulation and disappeared after cessation of
vagal stimulation. In another record of the same experiment (C), the monophasic action
potentials were recorded continuously immediately after cessation of vagal stimulation (arrow).
An overshoot increase in heart rate occurred, and then approached the control level. Time
calibration, 200 msec. Voltage calibration, 10 mo.
Circmlstio* Ruircb,
Vol. XIX. S*pl*mb*r 1966
582
NINOMIYA
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It is well known that one of the characteristics of cardiac action potentials is the variation of repolarization with variations in ionic
composition of the bathing medium,12'18 stimulus rate,14 temperature,16 and cell types. The
factors causing variation in the APD of the
right atrium in the dog heart in situ have been
discussed previously.10 In the present experiments, significant differences were noted
in the APD between the right and left atrium
(Table 1). Such variation in duration may be
due partly to the difference in temperature
between the atria. Because no attempt was
made to control spontaneous frequency of the
heart in these studies, the recorded data may
represent the result of frequency-dependent
and acetylcholine-dependent changes. However, a previous study on the dog atria has
shown that the APD does not shorten until
the heart rate exceeds 60 to 100 beats/min.16
As seen in Table 1, during vagal stimulation
the heart rate exceeded 100 beats/min in only
4 of 20 instances. Furthermore, immediately
after cessation of vagal stimulation, the heart
rate remarkably increased, but no shortening
of the APD was found (Fig. 6, C). These
findings suggest that frequency-dependent
changes may not be a major factor in shortening the APD during vagal stimulation in
this experiment.
Using an artificial pacemaker, Hoffman, et al.9
discovered an increase in conduction velocity of excitation in the in situ canine atrium
during vagal stimulation, suggesting that
there must be an increment in synchronization of excitation. On the other hand, the
conduction velocity of excitation has been
found to decrease by administering carbamylcholine to a strip of cat atrial myocardium.7
In the present study, the author did not measure the conduction velocity of excitation, but
measured the delay time of excitation between
multiple sites of the right and left atrium before and during vagal stimulation. This is because the measurement of delay time of excitation between multiple sites can provide im-
FIGURE 7
In A, two parts of continuous records of ECG (upper trace) and monophasic action potential
in the right (middle trace) and left atrium (lower trace) are shown. The right vagus was stimulated at the first cardiac cycle in first part (arrow). At the third cardiac cycle, the excitation in
both atria occurred almost simultaneously and then the excitation of left atrium preceded that
of the right atrium. After the second cardiac cycle in the second part of A when vagal stimulation ceased (arrow), the excitation of left atrium followed that of the right atrium. Such records
suggest that the pacemaker region shifted from the right atrium toward the left atrium
during vagal stimulation. A negative deflection in configuration of the P wave occurred.
In B, monophasic action potentials of another dog were recorded at two different sites on
the right atrium. During vagal stimulation the delay time of excitation between two sites
randomly changed (first part), but after the cessation of stimulation it remained constant
(second part). Such variation in delay time of excitation suggests that there is a shift of
pacemaker region from cycle to cycle. Time calibration, 100 msec. Voltage calibration 10 mo.
Rising limb of action potentials and QRS spikes were retouched.
CiratUiiou Rtsmrcb, VoU XIX, Stpltmbtr 1966
583
NONUNIFORM DISTRIBUTION OF VAGAL EFFECTS
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portant data regarding the excitation pattern
of the atrium as a whole. In some cases, the
pacemaker region shifted markedly from beat
to beat on the atrial surface during vagal stimulation. Figure 7, A, shows that during vagal
stimulation the pacemaker region might have
shifted toward the left atrium and back
again. Another example of this is illustrated
in Figure 7, B. Such variation in pacemaker
region does not permit a precise determination of conduction velocity of excitation in the
spontaneously active atrium during vagal stimulation. However, the mean values of delay
time of excitation between two atria was rather increased, although the sites of the electrodes were fixed before and during vagal
stimulation. Therefore, there must be a reduction in synchrony of excitation in the atria
rather than augmentation. Reduction in synchrony of excitation during vagal stimulation
was also suggested from reduced amplitude,
increased interval and reinforcement of notches in the P wave (Fig. 5). The increased delay
time of excitation between the right and left
atrium may be due either to a partial block in
the conduction pathway from the right to left
atrium or to random distribution of the pacemaker region in the right atrium during vagal
stimulation, but not to increase in conduction
velocity of excitation as a whole, under the
conditions of stimulation used in the present
experiments.
Acknowledgment
The author wishes to express his appreciation to
Professor H. Irisawa for many valuable suggestions
and constructive criticisms throughout the course of
this work, and to Dr. R. Uemura, Professor of Surgery, School of Medicine, Hiroshima University for
the encouragement he kindly extended, and to Mr.
K. Joji and Miss S. Fukui for editorial assistance.
2.
lation as a self-sustaining arrhythmia independent of focal discharge. Am. Heart J. 58: 59,
1959.
3.
4.
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HOFFMAN, B. F., AND SUCKLING, E. E.: Cardiac
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5.
H UTTER, O. F., AND TRAUTWEIN, W.: Effect of
vagal stimulation on sinus venosus of the
frog's heart. Nature 176: 512, 1955.
6. TODA, N., AND WEST, T. C.: Changes in sino-atri-
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BUHGEN, A. S. V., AND TERROUX, K. G.: On the
negative inorropic effect in the cat's auricle.
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HOFFMAN, B. F., SIEBENS, A. A., AND BROOKS,
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IRISAWA, H., NINOMIYA, I., AND SEYAMA,
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Direct Evidence of Nonuniform Distribution of Vagal Effects on Dog Atria
ISHIO NINOMIYA
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Circ Res. 1966;19:576-583
doi: 10.1161/01.RES.19.3.576
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