110
BRIEF COMMUNICATIONS
The Time Course of Action Potential Repolarization
Affects Delayed Afterdepolarization Amplitude in
Atrial Fibers of the Canine Coronary Sinus
Berthold Henning and Andrew L. Wit
From the Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
SUMMARY. The effects of changing the time course of action potential repolarization on the
amplitude and coupling interval of delayed afterdepolarizations were studied in small preparations
of coronary sinus atrial fibers exposed to catecholamines. Repolarization was accelerated or
retarded by current pulses passed through an intracellular microelectrode in the depolarizing or
repolarizing direction. Acceleration of repolarization decreased the amplitude of delayed afterdepolarizations, prolonged their coupling interval to the action potential upstroke, and prevented
triggered activity. Prolonging the time for repolarization increased afterdepolarization amplitude,
shortened the coupling interval, and caused triggered activity. The afterdepolarization amplitude
and coupling interval had a linear relationship to the duration of the action potential plateau. In
some preparations, the action potential plateau increased spontaneously at stimulation rates that
caused afterdepolarization amplitude to increase and triggering to occur, and this may have
contributed to the occurrence of triggering. The effects of action potential repolarization on
delayed afterdepolarizations suggest that pharmacological agents such as antiarrhythmic drugs
which alter action potential duration should influence afterdepolarizations. Drugs which shorten
action potential duration might prevent triggered activity from occurring, whereas drugs which
prolong duration might cause triggering. (Circ Res 55: 110-115, 1984)
DELAYED afterdepolarizations are subthreshold depolarizations occurring after repolarization of the
action potential is complete or nearly complete
(Cranefield, 1977). This definition is a descriptive
one, and does not imply a specific mechanism. A
number of different factors can cause delayed afterdepolarizations, including cardiac glycosides (Davis,
1973; Ferrier et al., 1973; Rosen et al., 1973; Ferrier,
1977), solutions low in K+ (Eisner and Lederer, 1979;
Hiraoka et al., 1981), or high in Ca++ (Tempte and
Davis, 1967). Wit and Cranefield (1977) and Wit et
al. (1980, 1981) have previously shown that delayed
afterdepolarizations and triggered activity can be
caused by norepinephrine in the atrial fibers of the
canine coronary sinus. This region appears to be
more prone to the effect of catecholamines than
other parts of the atria or ventricles (e.g., Nathan
and Beeler, 1975).
A transient inward current has been shown to
generate the delayed afterdepolarizations caused by
cardiac glycosides (Lederer and Tsien, 1976; Kass et
al., 1978a, 1978b; Karagueuzian and Katzung,
1982), low K+ (Eisner and Lederer, 1979), or high
Ca++ solutions (Vassalle and Mugelli, 1980). The
transient inward current can be activated by repolarization after a depolarizing voltage clamp pulse.
Increasing the magnitude of the depolarization in
the plateau voltage range increases the magnitude
of the current and causes the peak to be reached
more rapidly. The transient inward current also increases in amplitude with increasing duration of the
voltage clamp pulse (Lederer and Tsien, 1976; Karagueuzian and Katzung, 1982; Vassalle and Mugelli,
1980). Therefore, the amplitude and duration of the
action potential plateau is also expected to influence
the time course and amplitude of these delayed
afterdepolarizations.
The membrane current(s) causing the catecholamine-induced delayed afterdepolarizations in the
coronary sinus, however, have not yet been elucidated. Many of the properties of these delayed
afterdepolarizations which might eventually enable
their mechanisms to be defined must still be determined. One important unknown is the influence of
the prior depolarization on the characteristics of the
afterdepolarizations. Is it similar to that shown in
the other experiments on delayed afterdepolarizations referred to above? We have, therefore, studied
the effects of changing the time course of action
potential repolarization on the afterdepolarizations
in atrial fibers of the coronary sinus (Henning and
Wit, 1981).
Henmng and W;7/Action Potentials and Afterdepolarizations
Methods
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
Mongrel dogs weighing 10-25 kg were anesthetized
with sodium pentobarbital (30 mg/kg, iv). The hearts were
then removed rapidly through a thoracotomy and rinsed
in cool modified Tyrode's solution with the following
composition in HIM: NaCl, 137; KC1, 4; NaHCO3/ 24;
dextrose, 5.5; NaH2PO4, 1.8; MgCl2, 0.5; CaCl2, 2.7. The
entire coronary sinus was removed from the heart, cut
open along its length, and pinned out flat (Wit and Cranefield, 1977). Then, under a dissecting microscope, small
strips of tissue 1-2 mm long and less than 1 mm wide
were carefully dissected from the internal surface of the
opened coronary sinus (Wit et al., 1981; Boyden et al.,
1983a, 1983b). The coronary sinus strips were suspended
between insect pins (100 yum wide) in the narrow channel
of a fast flow system (Gadsby and Cranefield, 1977) and
were superfused with the Tyrode's solution at a rate of 6
ml/min. The superfusing solution was gassed with 95%
O2-5% CO2 and preheated before entering the chamber.
The pH of the solution was 7.3-7 .4. The temperature was
monitored with a small thermistor bead positioned close
to the preparation. The experiments were carried out at
35-37°C, but during any single experiment, the variation
in temperature was less than ±0.2°C.
The quiescent preparations were initially superfused for
30-60 minutes with the Tyrode's solution. After that time,
resting potentials were around —60 mV (Wit and Cranefield, 1977; Boyden et al., 1983a, 1983b). Then, for all
experiments, norepinephrine was added to the superfusate
from a stock solution with a concentration of 1 mg/ml to
give final concentrations ranging from 1 X 10~8 to 5 X
10~7 M. The disodium salt of ethylenediaminetetraacetic
acid (EDTA) was also added (final concentration, 10 HM)
to prevent oxidation of the catecholamine (Furchgott,
1955). The concentration of norepinephrine chosen for
each experiment was sufficient to produce hyperpolarization to between —70 and —90 mV, and to cause delayed
afterdepolarizations (Wit and Cranefield, 1977; Boyden et
al., 1983b). Most of the cells in each individual preparation
had afterdepolarizations with similar amplitudes.
After exposure to norepinephrine, the preparations
were stimulated through external bipolar electrodes (Teflon-coated silver wire) with rectangular pulses 1.5 to 2
times threshold and 1-2 msec in duration. Intracellular
potentials were recorded with conventional microelectrodes filled with 3 M KC1. Rectangular current pulses from
a constant current generator were injected intracellularly
through microelectrodes filled with 1.6 M K-citrate and 0.8
M KG and positioned less than 100 ^m from the recording
microelectrode. Additional details on the techniques and
instrumentation for recording transmembrane potentials
and applied currents are described in Boyden et al. (1983a,
1983b).
The preparations were driven at a constant cycle length
of 10 seconds. Diastolic potential, action potential duration, and afterdepolarization time course and amplitude
were constant, and triggered activity did not occur at this
stimulus cycle length in 27 experiments. In three experiments, triggered activity occurred even at this long stimulus cycle length (see results). Action potential duration
was changed by depolarizing or repolarizing current
pulses applied during the plateau phase, beginning 10 to
25 msec after the peak of the upstroke and lasting for 50
to 110 msec. The duration of a sequence of successively
driven action potentials was changed either randomly
(some lengthened, some shortened) or progressively in
111
one direction (different degrees of lengthening and/or
shortening), and the effects on afterdepolarization amplitude and coupling interval were determined. After each
sequence of action potentials, during which current had
been applied, we always verified that the original steady
state control situation was present by observing action
potential duration and afterdepolarization amplitude in
the absence of current.
Action potential duration was measured until repolarization intercepted the 0-mV voltage axis and to 90% of
complete repolarization (90% of the steady state diastolic
potential). Afterdepolarization amplitude was measured
from the peak positive voltage during the afterdepolarization to the level of membrane potential after repolarization of the afterdepolarization. Afterdepolarization coupling interval was measured from this peak amplitude to
the midpoint of the action potential upstroke.
Results
Figure 1, lefthand panels, shows the records from
an experiment in which action potential duration
was shortened, and illustrates the effects of shortening duration on the afterdepolarization. The results of this experiment are representative of a series
of 25 experiments in which this was accomplished.
The control, steady state action potential and delayed afterdepolarization at the 10-second drive
cycle length are shown in the top left panel. Panels
Control
Control
0
mV
-50
nA
°r
mV
-50L
100
nA c—U~
200 msec
FIGURE 1. Effects of accelerating (left panels) and prolonging (right
panels) the time course of action potential repolarization on delayed
afterdepolarizations (DAD). The bottom traces show the amount of
current passed through the intracellular microelectrode (hyperpolarizing current shown by downward deflection). Norepinephrine concentration in the superfusate was I x JO"8 M Records from two
different preparations are shown. In the left panels, the control action
potential duration to the 0-mV level (APDo) is 88 msec; DAD amplitude is 28 mV. In panel A, APD0 is decreased to 75 msec, and DAD
amplitude to 13 mV; in panel B, APD0 is decreased to 60 msec, and
DAD amplitude to 5 mV. In the right panels, the control APDo is 63
msec, while DAD amplitude is 4 mV. In panel A, APD0 is increased
to 75 msec, and DAD amplitude to 23 mV, in panel B, APD0 is
increased to 88 msec and triggered activity occurs.
Circulation Research/Vol. 55, No. 1, July 1984
112
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
A and B show records of the next two stimulated
action potentials during which repolarization was
accelerated by repolarizing current pulses with increasing strength but the same duration. The peak
plateau voltage is not displaced, but action potential
duration at the 0-mV level and to 90% repolarization
is reduced; the reduction is greater in B than in A.
A decrease in the afterdepolarization amplitude and
an increase in its coupling interval is associated with
the reduction of action potential duration; the
greater the acceleration of repolarization, the more
the reduction of the afterdepolarization amplitude.
In three experiments, there was a progressive,
spontaneous increase in amplitude of the delayed
afterdepolarizations with each stimulated impulse
at the 10-second stimulus cycle length until triggered
activity occurred. Triggered activity stopped spontaneously after 30-60 seconds (Wit et al., 1981).
After triggered activity stopped, afterdepolarization
amplitude was small, and then increased progressively during stimulation until triggered activity occurred again. This sequence of events kept repeating
itself. In these experiments, triggered activity could
always be prevented by shortening the action potential duration. Records from one of these experiments
are shown in Figure 2. The first action potential and
delayed afterdepolarization at the left are actually
the 14th during the period of drive after prior termination of triggered activity. The amplitude of the
afterdepolarization is almost large enough to cause
triggering; based on the results of prior stimulation
periods in this preparation, triggering would have
occurred after the next or following action potential.
However, the duration of action potential 2 in the
figure was decreased with a repolarizing current
pulse, and the afterdepolarization amplitude was
markedly diminished, so that triggered activity was
prevented. The amount of injected current then was
decreased during the 3rd, 4th, and 5th action potentials, gradually increasing action potential duration
and afterdepolarization amplitude. No current was
applied during the 6th action potential, and triggered activity occurred immediately.
In canine coronary sinus fibers exposed to norepinephrine, membrane potential during repolarization often increases to a more negative voltage
than the steady state diastolic membrane potential—
there is an afterhyperpolarization (Cranefield, 1977)
(see Fig. 1 control). In our experiments, the repolarizing current pulses always caused an increase in
this afterhyperpolarization (Fig. 1, left panels A and
B). Since it is possible the afterhyperpolarizations
caused by the current pulses might influence the
time course and voltage change of the following
delayed afterdepolarizations, we investigated in five
experiments the effects of afterhyperpolarizations
caused by rectangular current pulses applied after
repolarization was complete so that action potential
duration was not affected. Hyperpolarizing pulses
of different duration and amplitude were used. Representative results from one experiment are shown
in Figure 3. In the left panels are the control action
potentials and afterdepolarizations. The middle and
right panels show the effects of hyperpolarizing
current pulses 50, 100, and 200 msec long, with
50 msec
100 msec
I
Or
Or
mV
200 msec
-100
lOOi
nA
-100
I00C
10 sec
FIGURE 2. Shortening action potential duration can prevent the
occurrence of triggered activity. The action potentials and afterdepolarizations are shown in the top trace; current applied through the
microelectrode is shown in the bottom trace. Norepinephrine concentration in the superfusate was I x I0" 8 M. Action potential 1: APD0
= 92 msec, DAD amplitude - 30 mV; action potential 2: APD0 = 63
msec, DAD amplitude = 6 mV; action potential 6: APD0 = 96 msec.
I sec
FIGURE 3. Effects of "afterhyperpolarizations" on delayed afterdepolarizations. The preparation was stimulated at a cycle length of 10
seconds. Norepinephrine concentration in the superfusate was 1 x
10~7 M. Control action potentials are at the left in each row. The
middle and right panels in each row show the effects of 50-, 100-,
and 200-msec current pulses of different amplitudes, applied at the
end of repolarization. These current pulses did not affect APD0 or
APDm
Henning and Wit/Action Potentials and Afterdepolarizations
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
increasing strengths. The afterhyperpolarizations
caused by current pulses 50-100 msec in duration
did not affect the afterdepolarization amplitude, although 100-msec pulses shortened the coupling interval. Long afterhyperpolarizations with 200-msec
current pulses were followed by afterdepolarizations
with increased amplitude and shorter coupling intervals, as illustrated by the records in the bottom
row in Figure 3. From these experiments, we conclude that, in fibers in which action potential duration was shortened by repolarizing current pulses,
the decrease in afterdepolarization amplitude was
not a consequence of the afterhyperpolarization
caused by the current pulse. This afterhyperpolarization was always similar to the ones caused by the
50- to 100-msec current pulses in Figure 3.
Prolonging the time course of action potential
repolarization with depolarizing current pulses applied during the plateau had the opposite effect on
afterdepolarizations; it increased their amplitude
and shortened their coupling interval. In these experiments, there was also a small positive shift of
the plateau voltage by 2-4 mV. Figure 1, righthand
panels, illustrates the results of an experiment in
which action potential repolarization was prolonged. The results are representative of the series
of 20 experiments in which this was done. The
control action potential and afterdepolarization at
the 10-second stimulus cycle length are shown at
the top. Prolonging the duration (and increasing the
plateau height) in A immediately increased the afterdepolarization amplitude and shortened the coupling interval. Further prolongation of the action
potential duration in B caused the afterdepolarization to reach threshold, and triggered activity occurred.
In all these experiments in which action potential
repolarization was altered by current pulses, there
was a positive linear relationship between the afterdepolarization amplitude and the action potential
duration, measured either to 0 mV or 90% duration.
The slope of the line describing this relationship was
different for different experiments (Fig. 4, left panel).
y-o.e5i-4i.i
l
28 • r -0.96
Ul 24
o 20
16
t 12
8
4
E
1
1
i
0
50
1. f5x — l.3O
1
APDOmV
0
mV
j» \ ^ r--0.0li^358l
F * /, 00
100
Also, in all experiments, there was a positive linear
relationship between the amplitude of the afterdepolarization and its coupling interval which also
varied in the different experiments (Fig. 4, right
panel). The data shown in Figure 4 are from the two
experiments in which the maximum and minimum
changes occurred. The rest of the experiments
showed linear slopes over a range intermediate between these two. Although, in the experiments in
which repolarization was prolonged, the increase in
plateau amplitude may also have altered the afterdepolarizations, we could not distinguish between
influences of plateau amplitude and duration.
We considered the possibility that spontaneously
occurring increases in action potential duration
might cause the increases in afterdepolarization amplitude which result in triggering at critical stimulation cycle lengths (Wit and Cranefield, 1977; Wit et
al., 1981). In 28 experiments, we stimulated the
fibers at this critical cycle length following a 30second quiescent period. We found two different
types of responses which are illustrated in Figure 5.
The left panel shows the results of an experiment in
which action potential duration did not change very
much during the period of stimulation. The first
driven action potential and the accompanying afterdepolarization are indicated by the black arrows.
During the next 12 driven action potentials (superimposed), membrane potential depolarized by 5 mV,
and a slight positive shift of the plateau level occurred. Action potential duration to 0 mV or to 90%
repolarization increased by less than 5 msec. The
afterdepolarization amplitude increased markedly,
and there was a decrease of the coupling interval. A
triggered action potential occurred after the 12th
stimulated impulse. Similar results were obtained in
17 other preparations in which duration to 0 mV or
to 90% of complete repolarization increased from 1
msec to less than 10 msec during the stimulation
period. The right panel of Figure 5 shows an example of an experiment in which the time course of
repolarization and the height of the plateau markedly increased during the period of stimulation. The
-O.I5I*I48.OI
-: \\V
V
:M
y-
113
-100
I
150 200
3
500 1000 1500 2000
DAD COUPLING INTERVAL
(msec)
FIGURE 4. Relationship between delayed afterdepolarization amplitude (ordinate) and action potential duration at the 0-mV level
(APDonv) (abscissa) is shown for two representative experiments, each
indicated by a different symbol, in the left panel. The relationship
between the DAD amplitude and the coupling interval for two
experiments is shown in the right panel.
100msec
FIGURE 5. Effects of stimulation at a cycle length that causes triggered
activity on action potential repolarization and delayed afterdepolarization amplitude in fibers from two different preparations. In each
panel, superimposed action potentials and afterdepolarizations are
shown during a stimulation train. The first stimulated action potential
and afterdepolarization are indicated by the solid black arrows; the
last stimulated action potential and afterdepolarization before triggered activity occurred are indicated by the unfilled arrows. Norepinephrine concentration in the superfusate was 5 x 10'7 M.
Circulation Research/Vol. 55, No. 1, July 1984
114
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
repolarization phase and afterdepolarization of the
first stimulated action potential in this sequence are
indicated by the solid black arrows. There is no
distinct plateau phase on the action potential. During the subsequent stimulated impulses, maximum
diastolic potential declined and a plateau phase appeared. The level of the plateau occurred at progressively more positive voltages, and its duration
increased with each stimulated impulse. At the same
time there was a progressive increase in afterdepolarization amplitude and a shortening of the afterdepolarization coupling interval until a triggered
action potential occurred. A similar increase in action
potential duration and plateau amplitude was observed in 11 fibers. In these fibers, application of
repolarizing current to prevent the maximal increase
in plateau duration (see Fig. 2) prevented the occurrence of triggered activity. In general, in each of the
small preparations, all the cells from which we
recorded transmembrane potentials showed similar
characteristics, although in larger preparations (Wit
and Cranefield, 1977) there appears to be a gradation between the cell types shown in Figure 5.
Discussion
Tsien et al. (1979) have proposed that the transient
inward current which causes digitalis-induced delayed afterdepolarizations is carried by Na+ and
perhaps other cations through a nonspecific membrane channel (Kass et al., 1978a, 1978b). The
permeability of this channel is transiently increased
on repolarization under conditions that promote
elevated Caj. The mechanism for the intracellular
calcium release that causes the transient inward
current on repolarization is still not well understood
(Tsien et al., 1979; Kass and Tsien, 1982). However,
the observations that increasing the amplitude or
duration of the depolarization used to elicit the
transient inward current in voltage clamp studies,
increases this current (Lederer and Tsien, 1976; Vassalle and Mugelli, 1980; Karagueuzian and Katzung,
1982) suggests that this intervention might increase
Ca++ entry into the cell, either via the slow inward
current (Kass et al., 1976; Reuter, 1979; Coraboeuf,
1980) or by some other mechanism (Vassalle and
Mugelli, 1980).
We do not know whether the mechanism for the
delayed afterdepolarizations caused by norepinephrine in coronary sinus fibers is similar to the mechanism described above. Norepinephrine increases
the plateau height in coronary sinus fibers (unpublished observations), as it does in other cardiac preparations (Reuter, 1974; Nathan and Beeler, 1975).
The effect on the plateau is believed to result from
an increase in slow inward current (Reuter, 1967,
1979; Reuter and Scholz, 1977a, 1977b; Tsien et al.,
1972; Vassort et al., 1969). The increase in slow
inward current in ventricular muscle is accompanied
by a net influx of Ca++ (Rahn and Reuter, 1966). If
this also occurs in coronary sinus fibers, it may load
the sarcoplasmic reticulum, leading to the release
required for activation of a transient inward current
according to the hypothesis of Kass et al. (1978a,
1978b). In sheep Purkinje fibers, norepinephrine
also increased the range of depolarization and repolarization potentials at which the transient inward
current occurred, increased its amplitude, and
caused it to peak sooner (Vassalle and Mugelli,
1980). Norepinephrine, however, might also cause
oscillatory changes in membrane potential by other
mechanisms. Other mechanisms for pacemaker oscillations are reviewed in the articles by Tsien et al.
(1979) and Brown et al. (1979).
If a mechanism similar to that which causes the
transient inward current in Purkinje and ventricular
muscle fibers also causes afterdepolarizations in coronary sinus fibers, the afterdepolarization amplitude
should be influenced by the duration of the action
potential and amplitude of the plateau which are
the natural depolarizing stimuli for eliciting the afterdepolarization. We found that—in fact—accelerating repolarization (Cranefield and Hoffman, 1958)
diminished afterdepolarization amplitude, whereas
prolonging repolarization and increasing plateau
amplitude increased afterdepolarization amplitude,
and even caused triggered activity. Changing action
potential repolarization might influence Ca++ entry,
as discussed previously. However, other possible
effects of changing action potential repolarization
must not be neglected. Changes in inward sodium
current or in outward currents during repolarization
might have influenced the membrane currents, causing the afterdepolarization in our study. Thus, the
response of the afterdepolarizations to changes in
repolarization of the action potential do not prove
that changes in Ca++ influx are an important factor
in the genesis of these delayed afterdepolarizations.
That changes in action potential duration of coronary sinus fibers have profound influences on afterdepolarizations may have physiological and pharmacological consequences. Action potential duration
sometimes increased at drive cycle lengths that
caused an increase in afterdepolarization amplitude
(Fig. 5). It is likely that the increase in duration is
one of the causes of the increased afterdepolarization amplitude that leads to triggering in these fibers,
since prevention of the increase in action potential
duration prevents triggering or prolongs the stimulus period necessary to cause triggered activity.
However, since afterdepolarization amplitude can
also increase without marked changes in action potential duration, the change in duration is not the
only cause, and not the most important cause for
triggering. The reason why action potential duration
increases with drive in some fibers is unclear, as is
the reason for the variability in these results. The
effects of stimulation on action potential duration
and shape is very complex, and there are major
differences among different types of tissues and
species (Carmeliet, 1977; Boyett and Jewell, 1980).
Henning and W;7/Action Potentials and Afterdepolarizations
We also predict, from our results, that pharmacological agents which alter action potential duration
should influence afterdepolarizations, even if they
have no direct effect on the transient inward current.
Antiarrhythmic drugs which shorten action potential duration might prevent triggered activity from
occurring. Drugs which prolong action potential duration might increase afterdepolarization amplitude
and cause triggered activity (Henning and Wit,
1982).
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
Supported by Program Project Grant HL-12738 from the Heart,
Lung, and Blood Institutes, National Institutes of Health; Dr. Henning
was supported by Deutsche Forschungsemeinschaft He 1122/1.
Address for reprints: Dr. Andrew L Wit, Department of Pharmacology, College of Physicians and Surgeons of Columbia University,
630 West 168th Street, New York, Nezu York 10032.
Received March 2, 1983; accepted for publication April 10, 1984.
References
Boyden PA, Cranefield PF, Gadsby DC, Wit AL (1983a) The basis
for the membrane potential of quiescent cells of the canine
coronary sinus. J Physiol (Lond) 339: 161-183
Boyden PA, Cranefield PF, Gadsby DC (1983b) Norepinephrine
hyperpolarizes cells of the canine coronary sinus by increasing
their permeability to potassium ions. J Physiol (Lond) 339: 185206
Boyett MR, Jewell BR (1980) Analysis of the effects of changes in
rate and rhythm upon electrical activity in the heart. Prog
Biophys Mol Biol 36: 1-52
Brown H, Difrancesco D, Noble S (1979) Cardiac pacemaker
oscillation and its modulation by autonomic transmitters. J Exp
Biol 81: 175-204
Carmeliet E (1977) Repolarization and frequency in cardiac cells.
J Physiol (Paris) 73: 903-923
Coraboeuf E (1980) Voltage clamp studies of the slow inward
current. In The Slow Inward Current and Cardiac Arrhythmias,
edited by DP Zipes, JC Bailey, V Elharrer. Boston, Martinus
Nijhoff, pp 437-454
Cranefield PF (1977) Action potentials, afterpotentials, and arrhythmias. Circ Res 41: 415-423
Cranefield PF, Hoffman BF (1958) Propagated repolarization in
heart muscle. J Gen Physiol 41: 633-649
Davis LD (1973) Effects of changes in cycle length on diastolic
depolarization produced by ouabain in canine Purkinje fibers.
Circ Res 32: 206-214
Eisner DA, Lederer WJ (1979) The role of the sodium pump in
the effects of potassium-depleted solutions on mammalian
cardiac muscle. J Physiol (Lond) 294: 279-301
Ferrier GR (1977) Digitalis arrhythmias: role of oscillatory afterpotentials. Prog Cardiovasc Dis 19: 459-474
Ferrier GR, Saunders JH, Mendez C (1973) A cellular mechanism
for the generation of ventricular arrhythmias by acetylstrophanthidin. Circ Res 32: 600-609
Furchgott RF (1955) The pharmacology of vascular smooth muscle. Pharmacol Rev 7: 183-265
Gadsby DC, Cranefield PF (1977) Two levels of resting potential
in cardiac Purkinje fibers. J Gen Physiol 70: 725-746
Henning B, Wit AL (1981) Action potential characteristics control
afterdepolarization amplitude and triggered activity in canine
coronary sinus (abstr). Circulation 64 (suppl IV): 50
Henning B, Wit AL (1982) Multiple mechanisms for antiarrhythmic drug action on delayed afterdepolarizations and triggered activity in canine coronary sinus (abstr). Am J Cardiol
49:912
115
Hiraoka M, Okamoto Y, Sano T (1981) Oscillatory afterpotentials
in dog ventricular muscle fibers. Circ Res 48: 510-518
Karagueuzian HS, Katzung BG (1982) Voltage-Clamp studies of
transient inward current and mechanical oscillations induced
by ouabain in ferret papillary muscle. ] Physiol (Lond) 327:
255-268
Kass RS, Tsien RW (1982) Fluctuations in membrane current
driven by intracellular calcium in cardiac Purkinje fibers. Biophys J 38: 259-269
Kass RS, Siegelbaum S, Tsien RW (1976) Incomplete inactivation
of the slow inward current in cardiac Purkinje fibers. ] Physiol
(Lond) 263: 127-128 P
Kass RS, Lederer WJ, Tsien RW, Weingart R (1978a) Role of
calcium ions in transient inward currents and aftercontractions
induced by strophanthidin in cardiac Purkinje fibers. J Physiol
(Lond) 281: 187-208
Kass RS, Tsien RW, Weingart R (1978b) Ionic basis of transient
inward current induced by strophanthidin in cardiac Purkinje
fibers. J Physiol (Lond) 281: 209-226
Lederer WJ, Tsien RW (1976) Transient inward current underlying
arrhythmogenic effects of cardiotonic steroids in Purkinje fibers. J Physiol (Lond) 263: 73-100
Nathan D, Beeler GW (1975) Elecrrophysiologic correlation of the
inotropic effects of isoproterenol in canine myocardium. J Mol
Cell Cardiol 7: 1-8
Rahn KH, Reuter H (1966) Uber den Zusmmenhang der Wirkungen von Adrenalin, einem B adrenolyhkum und chinidin auf
Kontrakt ions kraft und Calcium-Umsatz des Meerschiueinchen
vorhofs. Naunyn Schmiedebergs Arch Pharmacol 252: 444451
Reuter H (1967) The dependence of slow inward current in
Purkinje fibers on the extracellular calcium-concentration. J
Physiol (Lond) 192: 479-492
Reuter H (1974) Localization of beta adrenergic receptors and
effects of noradrenaline and cyclic nucleotides on action potentials, ionic currents and tension in mammalian cardiac muscle.
J Physiol (Lond) 242: 429-451
Reuter H (1979) Properties of two inward membrane currents in
the heart. Annu Rev Physiol 41: 413-424
Reuter H, Scholz H (1977a) A study of the selectivity and the
kinetic properties of the calcium-dependent slow inward current in mammalian cardiac muscle. J Physiol (Lond) 264: 1747
Reuter H, Scholz H (1977b) The regulation of the Ca conductance
of cardiac muscle by adrenaline. J Physiol (Lond) 264: 49-62
Rosen MR, Gelband H, Merker C, Hoffman BF (1973) Mechanisms of digitalis toxicity. Circulation 47: 681-689
Tempte JV, Davis LD (1967) Effect of calcium concentration on
the transmembrane potentials of Purkinje fibers. Circ Res 20:
32-44
Tsien RW, Giles W, Greengard P (1972) Cyclic AMP mediates
the effects of adrenaline on Cardiac Purkinje fibers. Nature
[New Biol] 240: 181-183
Tsien RW, Kass RS, Weingart R (1979) Cellular and subcellular
mechanisms of cardiac pacemaker oscillations. J Exp Biol 81:
205-215
Vassalle M, Mugelli A (1980) An oscillatory current in sheep
cardiac Purkinje fibers. Circ Res 48: 618-631
Vassort G, Rougier O, Gamier D, Sauviat MP, Coraboeuf E,
Gargouil YM (1969) Effects of adrenaline on membrane inward
currents during the cardiac action potential. Pflugers Arch 309:
70-81
Wit AL, Cranefield PF (1977) Triggered and automatic activity in
the canine coronary sinus. Circ Res 41: 435-445
Wit AL, Cranefield PF, Gadsby DC (1980) Triggered activity. In
The Slow Inward Current and Cardiac Arrhythmias, edited by
DP Zipes, JC Bailey, V Elharrar. Boston, Martinus Nijhoff, pp
437-454
Wit AL, Cranefield PF, Gadsby DC (1981) Electrogenic sodium
extrusion can stop triggered activity in the canine coronary
sinus. Circ Res 49: 1029-1042
INDEX TERMS: Triggered activity • Catecholamines • Cardiac
arrhythmias
The time course of action potential repolarization affects delayed afterdepolarization
amplitude in atrial fibers of the canine coronary sinus.
B Henning and A L Wit
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
Circ Res. 1984;55:110-115
doi: 10.1161/01.RES.55.1.110
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1984 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circres.ahajournals.org/content/55/1/110
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further information
about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation Research is online at:
http://circres.ahajournals.org//subscriptions/