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Transient Depolarizations Induced by Acetylstrophanthidin
in Specialized Tissue of Dog Atrium and Ventricle
By Keitaro Hashimoto and Gordon K. Moe
ABSTRACT
Isolated preparations of atrial specialized conduction fibers ("plateau" fibers)
qualitatively resembled ventricular Purkinje fibers (false tendons) in their response
to acetylstrophanthidin. Acetylstrophanthidin in concentrations of 1-3 X 10~7 g/ml
caused coupled, frequency-dependent transient depolarizations (TDs) in both types
of fiber. In free-running strands of plateau fibers the TDs could reach threshold and
generate coupled action potentials, but TDs and automatic responses did not occur in
ordinary atrial muscle fibers. TDs were suppressed by elevation of the external
potassium concentration. Automatic activity and TDs in atrial plateau fibers were
abolished by acetylcholine. Automatic activity was also sometimes suppressed in false
tendons by acetylcholine, but TDs and related coupled responses were not influenced.
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KEY WORDS
potassium toxicity
atrial automaticity
atrial plateau
fibers
acetylcholine toxicity
Purkinje fibers
• Isolated preparations of Purkinje tissue excised
from dog ventricles exhibit transient depolarizations
(TDs) when they are exposed to moderate
concentrations of acetylstrophanthidin (1, 2). The
TDs, usually two sequential events, are frequency
dependent: their coupling intervals and their
amplitudes are direct functions of the preceding
cycle length. With suitable manipulation of the
pattern of stimulation, the TDs can reach threshold
and give rise to one or more automatic responses
when a train of driving pulses is interrupted. It has
been proposed that the digitalis-induced repetitive
ventricular responses to premature stimulation of
the ventricles described by Lown et al. (3) and the
postpacing acceleration of idioventricular pacemakers observed by Wittenberg et al. (4) are
manifestations of TDs in the intact heart (1). TDs,
regularly demonstrable in Purkinje tissue (false
tendons), have not been seen in ventricular muscle
Recent anatomic and electrophysiological studies
of the specialized conducting fibers of the atria
("plateau" fibers) have emphasized their similarities to the Purkinje fibers of the ventricles (5-8). The
experiments described in the present paper were
undertaken to determine whether the plateau fibers,
From the Masonic Medical Research Laboratory, Utica,
New York 13501.
This study was supported in part by a grant from the
American Heart Association.
Dr. Hashimoto was a Royal Arch Mason Fellow,
1971-1973, on leave from Tohoku University School of
Medicine.
Received September 25, 1972. Accepted for publication
March 15, 1973.
618
digitalis toxicity
like ventricular false tendons, develop TDs and
automatic activity in response to acetylstrophanthidin.
Methods
Hearts were excised from dogs (18-25 kg) anesthetized with sodium pentobarbital (30 mg/kg, iv). The
right atrium and the left ventricular false tendons were
removed and immersed in modified Tyrode's solution
equilibrated with 95% O2-5% CO 2 at room temperature.
False tendons used in these experiments were 0.5-1.0
mm in diameter and 5-10 mm long, and they did not
have branches or connections to muscle. Small strands
of pectinate muscle without branches were carefully
isolated from the upper and the lower part of the right
atrium. A free-running strand connecting the upper
pectinate muscle with the crista terminalis was found in
10 of 65 atria. As reported by Hogan and Davis (8), it
had the gross appearance of the ventricular false tendon
but was generally smaller in diameter and shorter in
length. The atrial tissue samples, except for the freerunning strands, were about 5 mm long and 1 mm in
diameter.
The atrial and the ventricular preparations were
pinned on a paraffin block under slight tension in the
perfusion solution at room temperature for at least 60
minutes before use. Two preparations, either atrial and
ventricular specialized fibers or atrial specialized and
atrial muscle fibers, were then selected for simultaneous
study in a 15-ml perfusion chamber. Modified Tyrode's
solution equilibrated with 95% O2-5% CO 2 flowed
continuously through the bath at a rate of about 5
ml/min, and the temperature was maintained at
36-37 °C. The millimolar composition of the solution
was: NaCl 137.0, KC1 4.0, NaHCO 3 12.0, CaCl2 2.5,
NaH^POj 0.9, MgSO4 0.5, and dextrose 5.5. The pH of
the solution was 7.1-7.3.
The preparations were stimulated electrically through
bipolar silver electrodes. Stimuli were rectangular
pulses 5 msec in duration and of suprathreshold
Circulation Research, Vol. XXX11, May 1973
619
ACETYLSTROPHANTHIDIN AND ATRIAL AUTOMATICITY
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voltage. They were obtained from a Tektronix pulse
generator and passed through an isolation transformer.
The pulse generator was triggered by a digitally
controlled interval generator. To drive the two
preparations with the same stimulus pattern, two pulse
generators and isolation transformers were triggered by
the same interval generator. Pulses were applied in
trains of ten stimuli of constant basic cycle length
followed by 2-second pauses. The basic cycle length
used was 500 msec, but longer or shorter cycles were
examined for short periods when necessary. The initial
threshold voltage was 1-2 v in all preparations. During
exposure to acetylstrophanthidin, it increased gradually,
especially in the atrial preparations.
Transmembrane action potentials were recorded
using glass microelectrodes filled with 3 M KC1. To
maintain the impalement in atrial tissue, the electrodes
were flexibly mounted. In the atrial upper pectinate
muscle, the recording site was selected from several
sampling sites so that the recorded action potential had
the longest duration and the most prominent plateau.
Acetylstrophanthidin1 was dissolved in 95% ethyl
alcohol and then diluted with distilled water to make a
stock solution with a drug concentration of 10"4 g/ml.
This stock solution was diluted with modified Tyrode's
solution to make a final concentration of 1-3 X 10~7
g/ml. Perfusion with acetylstrophanthidin started at
least 30 minutes after the recorded action potentials
became stable. When acetylstrophanthidin was not
used, both the atrial and the ventricular tissues
maintained their control action potential configurations
and threshold voltages for at least 2 hours. The effects
of acetylcholine and of elevated potassium concentration were studied in some experiments. Acetylcholine
chloride was prepared in a concentration of 10"4 g/ml,
and 0.45 ml was injected directly into the bath.
Potassium chloride was added to the solution to
increase the concentration of potassium from 4 mM to
10 mM.
Results
CONTROL ACTION POTENTIAL CHARACTERISTICS
The action potentials of the atrial free-running
strands showed a prominent phase-2 plateau and
phase-4 depolarization (Fig. 1A, bottom). These
characteristics are typical of the atrial specialized
(plateau) fibers (6). Although the configuration of
the action potential of the atrial specialized fibers
was very similar to that of the ventricular false
tendons, the atrial fibers had a lower resting
potential, a smaller action potential amplitude,
and a shorter action potential duration. The
plateaus were prominent, but the duration of phase
2 was shorter than it was in the ventricular false
tendon. This characteristic was also shown by the
short action potential duration at the 50% level of
Generously supplied by Eli Lilly Co., Indianapolis,
Indiana.
Circulation Research, Vol. XXXII, May 1973
o-,'!!
: ! i - i i i i , I I i | ! i l!,l
i!i:
I sec
100 msec
FIGURE 1
Action potentials during control periods. The top trace is
from a ventricular false tendon, and the bottom trace is from
an atrial plateau fiber. Left: Continuous recordings show
the stimulation pattern. Right: Multiple sweeps of the first,
third, fifth, seventh, and ninth action potentials were superimposed at the basic cycle length of 500 msec. The plateau
fiber of A was obtained from a free-running strand and that
of B from an upper pectinate muscle. Experiments A and B
were done in different dogs.
repolarization relative to the duration at the 90%
level. These data are summarized in Table 1.
The action potential configurations of atrial lower
pectinate muscles were typical of atrial muscle
fibers, but the resting potentials were slightly lower
than those reported previously (9). This observation
might have been due to the higher concentration of
potassium in our perfusion medium.
The configurations recorded from the upper
pectinate muscles were sometimes the same as those
recorded from the free-running strands of the atrial
plateau fibers, but at other sites they were the same
as those recorded from atrial muscle fibers.
Transitional forms were also recorded (Fig. IB).
The first action potential after a 2-second pause was
longer than the subsequent action potentials, which
were almost identical (Fig. 1).
EFFECTS OF ACETYLSTROPHANTHIDIN
Depending on the concentration of acetylstrophanthidin and the duration of exposure, three
types of responses were recorded: (1) induction of
TDs during the pause following a train of stimuli,
(2) development of automatic repetitive activity, or
(3) inexcitability. The incidence of these response
patterns as a function of acetylstrophanthidin concentration in the several tissues studied is outlined
in Table 2.
HASHIMOTO, MOE
620
TABLE 1
Control Action Potential Configurations
Tissue
Resting potential
(mv)
AP amplitude
(mv)
92 ="= 5
81 =t 6
79 =t 6
114 =it 8
81 =t 4
77 =t 7
104 =<= 10
VFT (N = 33)
AFR (N = 9)
LPM (N = 10)
UPM
With TDs (N = 16)*
Without TDs (N = 27)t
AP duration
(msec)
90% repolarization
50% repolarization
105 ± 9
92 ± 9
9 0 =<t 8
Phase 4
(mv/sec)
257 =t 27
205 ± 34
139 ± 26
186 :*= 2 8
1 0 6 ••± 42
45 ±: 20
2.5 ± 1.5
2 ± 2
0
196 =t 28
161 =fc 31
99 =t 28
69 :± 32
1 ± 1.5
0.5 ± 1
VFT = ventricular faLse tendon, AFR = atrial free-running strand, LPM = atrial lower pectinate muscle, UPM = atrial
upper pectinate muscle, TDs = transient depolarizations, AP = action potential, and K = number of observations.
*Plateau fibers.
fFibers transitional between plateau fibers and muscle.
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
frequency, the response was a TD-2, i.e., it had a
coupling interval of about twice the preceding cycle
length. After longer exposure to acetylstrophanthidin, the amplitude of both TDs increased; two
distinct TDs (1 and 2) followed the longer driving
cycle, and at 60 minutes the TD which followed the
more rapid train reached threshold and was
followed in turn by two low-amplitude TDs.
Similar behavior was commonly observed in
atrial fibers that were classified as specialized
conduction fibers. In the example shown in Figure
3, the response of the atrial specialized fiber was
almost identical to that of the simultaneously
perfused ventricular false tendon. The records were
obtained after 30 minutes of exposure to acetylstrophanthidin (2 X 10-7 g/ml). In both fibers the
amplitude of the TDs increased when the driving
Development of Transient Depolarizations.—An
example of TD in a ventricular false tendon is
illustrated in Figure 2. Before exposure to acetylstrophanthidin, the impaled fiber exhibited phase-4
depolarization during the 2-second pauses, but no
sign of TDs was seen. After 30 minutes of exposure
to acetylstrophanthidin ( l X l O 7 g/ml), the tendency toward phase-4 depolarization disappeared,
and a coupled TD appeared early in the pause
following a train of driven responses at a cycle
length of 500 msec. When the driving frequency
was increased (basic cycle length 300 msec), the
amplitude of the TD increased. By the criteria
developed by Ferrier et al. (1), the TD which
occurred at the longer cycle length was a TD-1, i.e.,
the coupling interval was approximately equal to
the preceding cycle length. At the faster driving
TABLE 2
Responses of Atrial Tissues and Ventricular False Tendons to Acetylstrophanihidin
Concentration of
AS (X 10-' g/ml)
Ventricular false tendon
3
2
1
TOTAL
Atrial free-running strand
4
3
2
1
11
19
TOTAL
6
Repetitive
activity
Transien t
depolarization
5
1
7
2
8
3
3
3
2
Inevitability
1
1
10
TOTAL
Lower pectinate muscle
6
15
5
26
3
2
TOTAL
Upper pectinate muscle
N
5
35
3
10
2
10
20
r>
9
2
e
10
3
10
10
AS = acetylstrophanthidin and x = number of experiments.
Circulation Research, Vol. XXXII, May 1973
621
ACETYLSTROPHANTHIDIN AND ATRIAL AUTOMATICITY
BCL = 500 msec
100 mv
400
50min
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300
60min
1 sec
FIGURE 2
Development of TDs and coupled responses in a false
tendon. Impalement of the same cell was maintained
throughout. See text for explanation. AS = acetylstrophanthidin.
FIGURE 3
frequency was accelerated, and at a basic cycle
length of 300 msec both fibers responded with a
coupled automatic discharge as the TDs reached
their respective threshold voltages.
Although the behavior illustrated in Figure 3
suggests that the specialized fibers of the atrium
and the ventricle are indeed similar, the response
patterns were not usually so closely matched.
Coupled ectopic beats were observed in almost all
ventricular false tendons, but the TDs in atrial
plateau fibers were observed to reach threshold in
only 2 of 21 preparations when ventricular and
atrial tissues were compared during simultaneous
perfusion. Two additional examples are shown in
Figure 4. In Figure 4A, the atrial fiber was a
plateau fiber obtained from an upper pectinate
muscle and therefore was presumably in functional
contact with ordinary atrial muscle fibers. In B, the
impaled fiber was in a free-running strand in which
all or most of the fibers were "specialized." In
Figure 4A, the ventricular fiber had developed
rapid automatic activity after 30 minutes, while the
atrial plateau fiber showed only a low-amplitude,
coupled TD. In B, the TDs reached threshold and
generated two automatic responses in the atrial
fiber, but only subthreshold TDs were recorded in
the false tendon.
Effect on Atrial Muscle.-ln
Circulation Research, Vol. XXXII, May 1973
the experiments
Effect of driving frequency on TDs in a false tendon (top
trace) and a plateau fiber (bottom trace). BCL = basic
cycle length.
reported by Ferrier et al. (1), TDs were routinely
observed in Purkinje strands, but they were never
seen in ventricular muscle. Furthermore, the
amplitude of the TDs was always diminished in
Purkinje fibers impaled close to their attachment to
muscle. In 20 experiments we examined the
response to acetylstrophanthidin of atrial fibers
identified by their action potential configuration as
ordinary muscle. Neither automatic activity nor
TDs were observed. In all cases the resting
membrane potential slowly decreased, the stimulated action potentials diminished in amplitude, and
eventually the fibers became inexcitable. Characteristic behavior is illustrated in Figure 5.
Effect of Increased Potassium Concentration.—
The effect of elevating the potassium concentration
of the perfusion fluid was tested in eight experiments in which ventricular false tendons and atrial
plateau fibers were simultaneously perfused. After
TDs or repetitive automatic activity had been
induced by acetylstrophanthidin, perfusion with
Tyrode's solution containing 10 HIM KC1 was
substituted for the normal perfusion medium
(K = 4 HIM). In all cases automatic activity was
622
HASHIMOTO, MOE
A
llilil1
M—liiuu
! 1
-\
U Ji1
AS 2.10
20 min
-UlUl
FIGURE 4
Comparative responses of false tendons (top trace) and
plateau fibers (bottom trace) to acetylstrophanthidin (AS)
in two experiments. A: Plateau fiber from upper pectinate
muscle. B: Free-running atrial strand.
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suppressed. In the example shown in Figure 6, the
Purkinje fiber had become automatic at a spontaneous frequency slightly higher than that of the
driving stimuli after 35 minutes of exposure to
acetylstrophanthidin; the atrial fiber had only
developed a subthreshold TD. Within 6 minutes
after switching to the higher potassium concentration, automatic activity in the false tendon ceased.,
and a subthreshold TD was again exposed. The TD
in the plateau fiber disappeared as the resting
membrane potential diminished. After 20 minutes
in the high potassium environment and with
continued exposure to acetylstrophanthidin, the TD
in the false tendon had also disappeared, and the
atrial fiber had depolarized to 42 mv and was no
longer excitable.
Effect of Acetylcholine.—Acetylcholine chloride
was added to the perfusion fluid to a final
concentration of 3 X lO"8 g/ml in 15 experiments in
which ventricular false tendons and atrial plateau
fibers were simultaneously exposed to acetylstrophanthidin. Two examples are shown in Figure 7.
In A, the false tendon generated a coupled
automatic beat followed by two TDs, and the
atrial fiber showed a subthreshold TD. After the
addition of acetylcholine, no significant change
occurred in the response pattern of the .false tendon,
but the TD in the plateau fiber was completely
suppressed as the resting membrane potential
increased from about —60 to —73 mv.
In the experiment of Figure 7B, toxicity had
progressed to the point of automatic coupled
activity in both ventricular and atrial tissues.
Acetylcholine abolished automaticity in both fibers.
This somewhat surprising effect of acetylcholine on
spontaneous activity in the Purkinje tissue was
observed in four of six preparations. Spontaneous
discharges reappeared in the false tendons as the
acetylcholine was washed away. Where only a
single coupled response or TDs were present, as in
Figure 7A, acetylcholine never produced a measurable effect on the ventricular fiber. As expected,
acetylcholine always caused hyperpolarization and
abbreviation of the action potential duration in the
atrial plateau fibers, even when these fibers were in
relatively pure culture in the free-running strands.
Discussion
Control
The plateau fibers of the atria, which are widely
believed to represent a specialized atrial conduc-
0-
I ! 1
AS 3* Id 7
AS 1.10'
<
50 min
1
1
, , .
35 min
20 min
0I
1
lull
i
, , ,
70 min
FIGURE 6
FIGURE 5
of an atrial muscle fiber to acetylstrophanthidin
(AS).
Effect of elevated potassium (K + ) concentration on a false
tendon (top trace) and a plateau fiber (bottom trace). AS =
acetylstrophanthidin.
Citadauo* Reuwcb, Vol. XXXII, May 1973
ACETYLSTROPHANTHIDIN AND ATRIAL AUTOMATICITY
ACh
3» 10*
4Ch
3*10°
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•
LLLLI
FIGURE 7
E#ect o/ acetylcholine (ACh) on a false tendon (top
trace) and a plateau fiber (bottom trace). A and B are
separate experiments. AS = acetylstrophanthidin.
tion system comparable to the His-Purkinje system
of the ventricle, resemble Purkinje tissue in their
histological staining properties and in their action
potential configuration. They also resemble the
intraventricular conduction system in their ability to
undergo phase-4 (pacemaker) depolarization. In
the present study, they responded to acetylstrophanthidin in much the same qualitative fashion as
did the ventricular false tendons. Concentrations of
acetylstrophanthidin which induced transient, coupled, frequency-dependent TDs in false tendons
isolated from dog ventricles also caused similar
responses in atrial plateau fibers. In the atria, as in
the ventricles, tissue classified as ordinary myocardium failed to develop either automatic activity or
TDs. Atrial muscle fibers depolarized to a stage of
inexcitability without any sign of spontaneous
activity.
Although they were qualitatively similar, there
were some significant quantitative differences between the atrial and the ventricular conducting
fibers. The atrial plateau fibers appeared to be more
resistant to the action of acetylstrophanthidin: the
time of exposure required to produce TDs was
longer than it was for simultaneously perfused false
Circulation Research, Vol. XXXII, May 1973
623
tendons and self-sustained automatic activity was
less frequently observed.
These differences might be more apparent than
real: they could well be ascribed to the geometry of
the preparations selected for study. The isolated
false tendons of the dog heart represented relatively
pure preparations of Purkinje tissue uncontaminated by ventricular muscle. Comparably pure strands
of atria] conducting tissue were not commonly
available; only 10 of the 65 atrial tissues studied
were free-running strands which could be dissected
free of atrial myocardium. Plateau fibers impaled in
strands of upper pectinate muscles were almost
certainly in functional contact with atrial muscle
fibers. If we assume that the functional connections
are of low internal resistance, it follows that the
electrotonic influence of the muscle fibers would
restrain, retard, or prevent the development of
automatic activity in the attached plateau fibers.
Comparable phenomena have been described in
ventricular preparations of false tendons attached
to papillary muscle or ventricular free wall (2).
TDs are regularly of greater amplitude in Purkinje
tissue remote from muscle and decrease progressively as muscle is approached. It is perhaps
significant that intrinsic automaticity (probably a
manifestation of repetitive suprathreshold TD
activity) was observed only in the free-running
atrial strands (Table 2).
Atrial ectopic activity in the heart in situ is a less
common manifestation of digitalis toxicity than is
idioventricular automaticity. This phenomenon
could also be explained by the morphology of the
potentially automatic foci. The conducting system
of the ventricles runs a relatively long distance from
the atrioventricular node to its peripheral communications with ventricular muscle, but the specialized
atrial fibers probably make frequent connections
with surrounding atrial muscle. The opportunity
for the development of suprathreshold TDs unopposed by the electrotonic drag of muscle must be
correspondingly greater in the ventricles. It is also
possible, of course, that intrinsic differences in the
ionic mechanisms in the two tissues exist.
Spontaneous activity induced by acetylstrophanthidin in both false tendon and atrial plateau fibers
was suppressed by elevated external potassium
concentrations. Here again there were quantitative
differences. Although the atrial specialized fibers
were considerably more resistant to the depolarizing influence of potassium than was atrial muscle,
they were less resistant than were the Purkinje
fibers. Accordingly, concentrations of potassium
624
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which restored almost normal responsiveness to
Purkinje fibers poisoned with acetylstrophanthidin
usually resulted in an eventual complete loss of
excitability in the plateau fibers. The results
recorded in the present paper did, however, support
previous observations that a sinoventricular rhythm
might persist in the presence of concentrations of
potassium or of digitalis which completely prevent
activation of atrial muscle (D. Erlij, unpublished
observations, Vassalle and Hoffman [10]).
The response to acetylcholine deserves some additional comment. The fact that repetitive automatic activity in ventricular false tendons was suppressed by acetylcholine in four of six preparations
and that TDs and coupled ectopic responses in
other preparations were unaffected suggests that
the two phenomena might be qualitatively different. However, only a minor quantitative change in
the effective level of toxicity would be necessary to
cause a reversion from repetitive activity to single
coupled responses or TDs. Although acetylcholine
has usually been reported to have no effect on the
electrophysiological properties of ventricular tissue,
a recent study by Bailey et al. (11) clearly shows a
negative chronotropic effect on isolated preparations of the canine His-Purkinje system. Acetylcholine clearly abolished automatic activity and TDs in
atrial plateau fibers. Assuming that the enhanced
vagal activity which accompanies digitalis administration in unanesthetized animals and in patients
would exert a similar effect, this action could also
account for the less common incidence of atria!
ectopic activity (except, of course, fibrillation) as a
manifestation of digitalis toxicity.
In their comparison of the electrophysiological
characteristics of atrial muscle and fibers specialized
for conduction, Wagner et al. (6) have reported
that acetylcholine causes hyperpolarization and
abbreviation of the action potential in both fiber
types. In view of the electrotonic interactions
between functionally connected fibers described by
Mendez and his colleagues (12, 13), it seemed
possible that the accelerated repolarization of the
plateau fibers might have been a passive response to
the action potential abbreviation in the attached
muscle fibers. In the present study, however, the
completely isolated free-running strands of plateau
HASHIMOTO, MOE
fibers also developed brief action potentials when
they were exposed to acetylcholine. This response
must therefore be intrinsic and is another characteristic which distinguishes the specialized atrial
fibers from their counterparts in the ventricles.
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Circulation Research, Vol. XXXll, May 19?i
Transient Depolarizations Induced by Acetylstrophanthidin in Specialized Tissue of Dog
Atrium and Ventricle
KEITARO HASHIMOTO and GORDON K. MOE
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Circ Res. 1973;32:618-624
doi: 10.1161/01.RES.32.5.618
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1973 American Heart Association, Inc. All rights reserved.
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