Determinants of action potential initiation in
isolated rabbit atrial and ventricular myocytes
DAVID A. GOLOD, RAJIV KUMAR, AND RONALD W. JOYNER
Todd Franklin Cardiac Research Laboratory, The Children’s Heart Center,
Department of Pediatrics, Emory University, Atlanta, Georgia 30322
electrophysiology; arrhythmia; inward rectifier current; cell
coupling
DIFFERENCES IN resting membrane potential (RMP),
amplitude, duration, and threshold of the action potentials produced by cardiac myocytes from different regions of the heart are important when trying to understand the underlying mechanisms responsible for
conduction through the heart. As current flows ahead of
the advancing wave front through gap junctions, both
the conduction velocity and the safety factor for conduction depend critically on the efficacy of this current to
depolarize cells in advance of the wave front and bring
them to their activation threshold. Thus the cellular
properties of input impedance, cell capacitance, and the
voltage threshold for activation of a net inward current
are critical components of the process for both normal
and abnormal action potential conduction. Differences
in the activation properties of atrial and ventricular
cells might be expected from the very different characteristics of action potential conduction in the two
H1902
regions. The cells of the atrial wall and septum have
significant electrotonic interactions with cells that are
of the slow response, intrinsically automatic, action
potential type at the margins of both the sinoatrial
node and the atrioventricular node, whereas cells within
the ventricular wall do not normally interact electrotonically with cells of the slow response type or with cells of
high intrinsic automaticity.
Although there have been numerous publications
investigating action potential initiation properties and
waveforms of cells isolated from the ventricle, sinoatrial node, and atrioventricular node, there is much
less information available from studies of cells isolated
from the atrial walls and septum, which make up most
of the atria. Data from whole cell voltage-clamp experiments on atrial cells have generally been performed at
room temperature and have utilized various pharmacological conditions and pulse protocols to isolate a single
ionic conductance or transport system for study. These
voltage-clamp studies have shown several fundamental
differences between the ionic conductances of atrial
cells compared with ventricular cells. Hume and Uehara (7) compared myocytes isolated from guinea pig
atria and ventricles using the whole cell voltage-clamp
technique at room temperature and showed marked
differences in background potassium currents thought
to be due to different gating kinetics. Giles and Imaizumi (4) further investigated the differences in potassium currents between cells isolated from rabbit atria
and ventricles, also using the whole cell voltage-clamp
technique at room temperature. They noted that the
transient outward current (It ) is larger in atrial cells
than in ventricular cells, but the inward rectifying potassium current (IK1 ) is larger in ventricular cells than in
atrial cells. Whalley et al. (19) showed that IK1 currents
in freshly isolated rabbit ventricular cells were much
larger than those in cultured rabbit atrial cells.
We have previously studied the activation properties
at physiological temperature of rabbit ventricular cells
either as single isolated cells (9, 14) or as cell pairs
consisting of either two real isolated rabbit ventricular
cells (10) or one real isolated rabbit ventricular cell
coupled to a mathematical model of another cell (18). In
this work we showed that the properties of action
potential initiation were significantly altered by changes
in the coupling conductance and in the extracellular
potassium concentration that could be explained by
alterations in the strength-duration relationship for
the isolated ventricular cells. Our values of RMP for the
isolated ventricular cells have been generally in the
range of 280 to 286 mV, and values for the maximum
rate of rise of the action potential (Vmax ) have been in
the range of 250–400 V/s.
0363-6135/98 $5.00 Copyright r 1998 the American Physiological Society
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Golod, David A., Rajiv Kumar, and Ronald W. Joyner.
Determinants of action potential initiation in isolated rabbit
atrial and ventricular myocytes. Am. J. Physiol. 274 (Heart
Circ. Physiol. 43): H1902–H1913, 1998.—Action potential
conduction through the atrium and the ventricle of the heart
depends on the membrane properties of the atrial and
ventricular cells, particularly with respect to the determinants of the initiation of action potentials in each cell type.
We have utilized both current- and voltage-clamp techniques
on isolated cells to examine biophysical properties of the two
cell types at physiological temperature. The resting membrane potential, action potential amplitude, current threshold, voltage threshold, and maximum rate of rise measured
from atrial cells (280 6 1 mV, 109 6 3 mV, 0.69 6 0.05 nA,
259 6 1 mV, and 206 6 17 V/s, respectively; means 6 SE)
differed significantly (P , 0.05) from those values measured
from ventricular cells (282.7 6 0.4 mV, 127 6 1 mV, 2.45 6
0.13 nA, 246 6 2 mV, and 395 6 21 V/s, respectively). Input
impedance, capacitance, time constant, and critical depolarization for activation also were significantly different between
atrial (341 6 41 MV, 70 6 4 pF, 23.8 6 2.3 ms, and 19 6 1 mV,
respectively) and ventricular (16.5 6 5.4 MV, 99 6 4.3 pF,
1.56 6 0.32 ms, and 36 6 1 mV, respectively) cells. The major
mechanism of these differences is the much greater magnitude of the inward rectifying potassium current in ventricular
cells compared with that in atrial cells, with an additional
difference of an apparently lower availability of inward Na
current in atrial cells. These differences in the two cell types
may be important in allowing the atrial cells to be driven
successfully by normal regions of automaticity (e.g., the
sinoatrial node), whereas ventricular cells would suppress
action potential initiation from a region of automaticity (e.g.,
an ectopic focus).
ATRIAL VS. VENTRICULAR CELL ACTIVATION
METHODS
Cell isolation and electrodes. Single atrial and ventricular
myocytes were prepared from adult New Zealand White
rabbits weighing 2.5–3.5 kg. The rabbits were anesthetized
intravenously with 50 mg/kg pentobarbital sodium and 500 U
heparin, the heart was rapidly extracted via thoracotomy
with artificial respiration, and the aorta was cannulated for
Langendorff perfusion. Single cells were isolated according to
the methods described previously by Hancox et al. (5). Briefly,
the cannulated heart was perfused sequentially at 37°C with
a base solution plus 750 µM CaCl2 for 3 min, base solution
plus 100 µM EGTA for 4 min, and enzyme solution for 6 min.
The intra-atrial septum was then excised, cut into thin
strips, and further digested in the recirculated enzyme solution used above, with 2% BSA added, for 10 min. Cells were
isolated by triturating the tissue strips and were then placed
in a potassium glutamate solution plus 3% BSA for 1 h at
room temperature. To clean the membrane further, cells were
separated from the potassium glutamate solution by centrifugation at 500 g for 3 min, the supernatant was replaced with
potassium glutamate plus 1 mg/ml protease, and the centrifugation tube was placed in a shaker bath at 37°C for 5 min. The
cells were again centrifuged at 500 g for 3 min, the supernatant was replaced with the potassium glutamate solution,
and the cells were refrigerated until use.
Endocardial pieces of the right ventricular wall and intraventricular septum were excised and placed in the potassium
glutamate solution. The tissue was then cut into small
chunks, triturated, and filtered through nylon gauze (200-µmdiameter mesh). The filtered cells were stored in potassium
glutamate and refrigerated until use.
The cells were placed in a chamber that was continuously
perfused with Tyrode solution at 2 ml/min, with the temperature always maintained at 35 6 0.5°C. Only cells that were
quiescent and had a rod-shaped appearance were used in this
study. The pipettes were pulled from borosilicate glass that,
after fire polishing, had resistances of 3–6 MV when filled
with the internal solution. High-resistance seals were formed
with the cell membrane by applying light suction, and the
membrane was disrupted by applying transient suction. The
junctional potential was corrected by zeroing the potential
before the pipette tip touched the cell membrane.
Solutions. The base solution contained (in mM) 130 NaCl,
4.5 KCl, 3.5 MgCl2, 0.4 NaH2PO4, 5 HEPES, and 10 dextrose,
pH 7.25. The enzyme solution contained 1 mg/ml collagenase
(type IIA, Worthington), 0.07 mg/ml protease (type XIV,
Sigma), and base solution plus 240 µM CaCl2. The potassium
glutamate solution contained (in mM) 100 potassium gluta-
mate, 25 KCl, 10 KH2PO4, 0.5 EGTA, 1 MgSO4, 20 taurine, 5
HEPES, and 10 dextrose, pH 7.2. The normal Tyrode solution
contained (in mM) 148.8 NaCl, 4 KCl, 1.8 CaCl2, 0.53 MgCl2,
0.33 NaH2PO4, 5 HEPES, and 5 dextrose, pH 7.4. The
internal solution was composed of (in mM) 135 KCl, 5
Na2CrPh, 5 MgATP, and 10 HEPES, pH 7.2.
Current- and voltage-clamp studies on isolated cells. Membrane potentials were recorded using the whole cell patchclamp technique with an Axoclamp 2A dual amplifier (Axon
Instruments, Foster City, CA) in the current-clamp mode, as
previously described (9, 14). Series resistance was carefully
compensated by internal bridge balance adjustments after
recording of the membrane potential was established. For
voltage-clamp studies we used an Axopatch 200 voltageclamp amplifier with the same external solution and pipette
solution as for the current-clamp recordings. We used a
holding potential of 284 mV to approximate the measured
RMP of the ventricular cells. Cell capacitance and series
resistance were measured and compensated. Step pulses
were applied from the holding potential in 2-mV steps with
durations of 50 ms and an interpulse interval of 1 s.
Statistical analysis. Statistical analysis was performed
using SigmaStat for Windows (Jandel Scientific, San Rafael,
CA). Statistical significance between atrial and ventricular
cells was determined by using Student’s t-test for unpaired
data. P values ,0.05 were regarded as significant. Data are
presented as means 6 SE in the text.
RESULTS
Differences in atrial and ventricular action potentials. To examine the characteristics of action potentials generated by isolated rabbit atrial and ventricular
cells, whole cell current-clamp studies were performed
in which each cell was stimulated with current pulses
of 2-ms duration and an amplitude slightly greater
than the stimulus current threshold of that cell (Fig.
1A). The stimulus frequency was set to a physiological
rate of 3 Hz, and all experiments were performed at
35°C. The data for the ventricular cell in Fig. 1 are
indicated by dotted lines, whereas the data for the
atrial cell are indicated by solid lines. Figure 1A shows
that the current required to initiate an action potential
in the two cells is very different. The threshold current
for the ventricular cell was 2.6 nA, whereas that for the
atrial cell was 0.62 nA for this short stimulus duration.
Figure 1B shows the action potentials generated by the
rabbit atrial and ventricular cells in response to the
currents plotted in Fig. 1A. As expected from previous
studies (see introduction), there are marked differences
between the atrial and ventricular cells with respect to
the Vmax and action potential duration. The RMP of the
atrial cell is 280 mV, and the Vmax is 121 V/s, compared
with an RMP of 285 mV and a Vmax of 279 V/s for the
ventricular cell.
To further characterize differences between atrial
and ventricular cells in the initiation of an action
potential, we used current pulses of either 2- or 15-ms
duration and a magnitude slightly greater than the
stimulus current threshold of each cell for the given
stimulus duration. Figure 2 shows the recorded action
potentials generated by such stimulus protocols and
the critical depolarization from the resting potential
level required to initiate an action potential. The
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In the present study we have used both whole cell
current- and voltage-clamp techniques at physiological
temperature to compare the membrane characteristics
and study the mechanisms responsible for differences
in action potential generation between isolated rabbit
atrial and ventricular myocytes. Data from whole cell
current-clamp protocols allowed measurements of cell
RMP, amplitude, Vmax, and current stimulus threshold
for the two cell types. Further comparisons between
atrial and ventricular cells were made from calculations of input impedance, membrane time constant,
critical depolarization for action potential generation,
and membrane capacitance. Voltage-clamp protocols
for ventricular cells were used to investigate the underlying mechanisms responsible for differences in the
activation properties of the two cell types.
H1903
H1904
ATRIAL VS. VENTRICULAR CELL ACTIVATION
Fig. 1. Comparison of current threshold (A) and action
potential waveform (B) for an isolated ventricular (V)
myocyte (dotted lines) and an isolated atrial (A) myocyte. A: threshold current pulse for a pulse duration of 2
ms. B: recorded action potentials from the two cells with
maximum rate of rise of upstroke (V/s) indicated for
each cell.
Fig. 2. Comparison of voltage threshold and critical
depolarization required for activation for an isolated A
cell (A) and an isolated V cell (B) in response to current
stimuli of either 2- or 15-ms duration. Solid lines
indicate successful activations, and dotted lines indicate
largest subthreshold responses.
In excitable cells, a classic experiment for characterizing the excitability properties of a cell is to create a
strength-duration curve by finding the magnitude of
the required current for action potential initiation as a
function of the duration of the stimulating pulse.
Figure 3A demonstrates the mean strength-duration
curves obtained from 10 atrial and 6 ventricular cells.
From these curves it is apparent that, overall, much
less current is needed to generate an action potential in
atrial cells than in ventricular cells at all stimulus
durations. This observation is to be expected because
atrial cells have been reported (see introduction) to
have a much higher input impedance than ventricular
cells. In Fig. 3B, the mean strength-duration curves for
the atrial and ventricular cells were normalized by
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critical depolarization is much smaller in the atrial cell
(19.3 mV) than in the ventricular cell (36.4 mV) and
was not affected by increasing the stimulus duration
from 2 to 15 ms for either the atrial or ventricular cell.
An interesting phenomenon was noticed when measuring the delay from stimulation, defined as the time
delay from turning off the current stimulus to the Vmax
of the action potential upstroke. As we applied current
pulses that were very close to the current threshold,
atrial cells were able to generate action potentials with
delays of more than two to three times those of ventricular cells without affecting Vmax. To begin to probe for
answers as to why there are such differences between
these cells of a common organ, we needed to investigate
the membrane characteristics of each cell type.
ATRIAL VS. VENTRICULAR CELL ACTIVATION
H1905
Fig. 3. Comparison of strength-duration relationships
for V and A cells. A: averaged data for 10 A cells and 6 V
cells. B: data from A normalized such that, for each cell
type, data have been scaled by the mean current threshold for 2-ms duration stimulus. Dashed line represents
common relationship for both V and A cells if relationships for each cell type were produced by a constant
charge injection for all stimulus durations (see text).
Inset: ratio of V cell current threshold (Ith ) to A cell
threshold as a function of stimulus duration.
More current would thus be needed for a ventricular
cell, compared with an atrial cell, to overcome these
obstacles before the membrane could be depolarized
enough to generate an action potential. If the outward
current were specific for potassium ions, this might also
explain the more negative RMP in the ventricular cells
but would not account for the higher value of Vmax for
the ventricular cells compared with the atrial cells.
Membrane characteristics of atrial and ventricular
cells. Further investigation of the charging of the
membranes of atrial and ventricular myocytes can be
performed if the ionic conductances of the membrane do
not change significantly as the cell membrane is depolarized or hyperpolarized over a narrow range of potential from the value of RMP. We can express the voltage
waveform with time in response to a small step of
positive or negative current through the pipette as an
exponential charging function for which the time constant (in ms) is equal to the product of the membrane
resistance (in MV) and the membrane capacitance (in
pF). To compute the membrane time constant of atrial
and ventricular cells, a small stimulus current of 50-ms
duration was injected into an atrial or a ventricular
cell, the final depolarization was measured and the
time for the voltage to rise (or fall) to 63% of final
depolarization (or hyperpolarization) was measured.
Figure 4 shows atrial and ventricular cell membrane
potential changes after injection of such currents. The
membrane time constant for a small depolarization of
the atrial cell (21 ms; Fig. 4A) is much longer than that
for the ventricular cell (2 ms; Fig. 4B), which means
that the atrial cell membrane charges more slowly in
response to a stimulus current and also remains charged
for a much longer period than the ventricular cell
membrane after the stimulus current is turned off. The
long membrane time constant of atrial cells may explain the long delays from stimulation that can be
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scaling the values by a factor of the average threshold
stimulus current at the 2-ms duration for each cell type
to compare the shapes of the curves. The dotted line in
Fig. 3B represents a theoretical hyperbolic curve that
would have resulted from a condition in which a
constant amount of charge (stimulus current magnitude 3 stimulus duration) was required for each value
of stimulus duration. The atrial strength-duration curve
closely approximates the theoretical hyperbolic curve,
whereas the ventricular strength-duration curve deviates significantly toward greater values of required
current magnitude than that predicted by the ‘‘constant
charge’’ relationship. This deviation suggests that, although almost all of the current being injected into the
atrial cell is used to charge membrane capacitance,
most of the current being injected into the ventricular
cell, for stimuli of longer duration, is lost from the cell
as a membrane ionic current flow.
Another way of expressing the differences in the
dependence of the current threshold on the stimulus
duration for ventricular versus atrial cells is to compute the ratio of the current threshold for the two cell
types as a function of stimulus duration (see inset, Fig.
3B). For short-duration stimuli the ventricular cells
require a current magnitude 3–4 times as great as do
the atrial cells, whereas for stimuli of longer durations
the ventricular cells require ,10 times as much current
amplitude as do the atrial cells. The shape of the
current threshold ratio plot that describes the difference between the two strength-duration curves could
be due to differences in the magnitude or voltage
dependence of an inward current, such as inward
sodium current (INa; which is more difficult to turn on in
ventricular cells than in atrial cells), or to an increased
magnitude of an outward current, such as IK1 (which
may be present in ventricular cells and not in atrial
cells, or at least more prevalent in ventricular cells).
H1906
ATRIAL VS. VENTRICULAR CELL ACTIVATION
Fig. 4. Comparison of response to a 50-ms duration
small depolarizing or hyperpolarizing current step for
an A cell (A; stimulus magnitude 20 pA) and for a V cell
(B; stimulus magnitude 100 pA) with membrane time
constants (t) indicated on traces. RMP, resting membrane potential.
Table 1. Summary of atrial and ventricular
cell characteristics
Cell Characteristics
Measured data
Resting membrane
potential, mV
Action potential
amplitude, mV
Current threshold, nA
(2 ms)
Voltage threshold, mV
Vmax , V/s
Calculated data
Input impedance, MV
Capacitance, pF
Membrane time constant, ms
Critical depolarization, mV
Atrial
n
Ventricular
n
280 6 1*
7
282.7 6 0.4
12
109 6 3*
7
127 6 1
4
0.69 6 0.05*
259 6 1*
206 6 17*
8
5
7
2.45 6 0.13
246 6 2
395 6 21
14
5
5
341 6 41*
70 6 4*
5
5
16.5 6 5.4
99 6 4.3
43
43
23.8 6 2.3*
5
1.56 6 0.32
43
19 6 1*
5
36 6 1
5
Values are means 6 SE for n cells. Vmax , maximum rate of rise of
action potential. * P , 0.05 vs. ventricular cells.
Initiation of action potentials in atrial and ventricular cells. To improve our understanding of the membrane potential changes that occur within the voltage
range between the RMP and the voltage threshold for
action potential generation, we used a current-step
protocol in which cells were injected with current
stimuli of increasing magnitude (each stimulus was of
50-ms duration) to a level at which the threshold for
action potential initiation was reached. Figure 5 shows
the resulting voltage traces for a ventricular cell (Fig.
5A) and an atrial cell (Fig. 5B) recorded from this
protocol. For the atrial cell we used current steps
incremented by 10 pA, whereas for the ventricular cell
we used current steps incremented by 100 pA. Note
that subthreshold depolarizations produced by current
pulses #40 pA for the atrial cell and #500 pA for the
ventricular cell show clear differences in waveform.
The atrial depolarizations show a very gradual increase
in depolarization, as was expected because of the long
time constant of the atrial cells. The ventricular depolarizations show a rapid response for the lowest current
strengths, but for larger current strengths there is a
secondary component of the depolarization that is
much slower than can be accounted for by the membrane time constant. A slight, further increase in
stimulus current produces an action potential in the
atrial cell (current threshold 43 pA) and in the ventricular cell (current threshold 540 pA).
We have plotted in Fig. 5C a current-voltage (I-V)
relationship that was obtained by plotting the amplitude of the injected current versus the value of polarization at the end of the current pulse. This is not a true
‘‘steady-state’’ relationship because the membrane potential is still changing with time at the end of the
stimulus pulse, but it does give an indication of the
degree of rectification of the membrane and the relative
input impedance of the two cells. The values for the
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produced in atrial cells (Fig. 2A). Membrane capacitance was obtained by dividing the membrane time
constant by the measured input impedance (the ratio of
the final polarization to the current amplitude). The
values of input impedance were 341 6 41 MV for atrial
cells and 16.5 6 5.4 MV for ventricular cells; these
values were then used to calculate the respective
values for cell membrane capacitance of 70 6 4 pF and
99 6 4 pF (Table 1). The 41% higher membrane
capacitance in ventricular cells provides one explanation as to why the stimulus current threshold is higher
in ventricular cells than in atrial cells, but this doesn’t
explain the large difference in current threshold (255%)
for short-duration stimuli or the even larger difference
in current threshold for longer stimuli.
ATRIAL VS. VENTRICULAR CELL ACTIVATION
H1907
ventricular cell are plotted as filled squares, whereas
the values for the atrial cell are plotted as open circles.
Note that the slopes of these two relationships are very
different, with the data for the ventricular cell having a
significantly higher slope. To better compare the shapes
of the two I-V relationships, we have also plotted the
data for the atrial cell after scaling all of the current
values for the atrial cell by a factor of 7.4, indicated as
open triangles. The scaling factor was computed from
the relative slopes of the ventricular and the atrial data
to make the slope of the two relationships the same as
they cross the horizontal axis. The data for both cells
have a curvature suggesting inward rectification, but
the actual conductances being changed cannot be determined from this presentation. The rectification may
correspond to the IK1, which has been shown (see
introduction) to be more prevalent in ventricular cells
than in atrial cells, but a slowly activating inward
current with depolarization could also be partly responsible.
Table 1 displays the data measured and calculated
from our whole cell current-clamp studies. As described
earlier, the RMP, amplitude, current threshold, voltage
threshold, and Vmax measured from atrial cells (280 6 1
mV, 109 6 3 mV, 0.69 6 0.05 nA, 259 6 1 mV, and
206 6 17 V/s, respectively) differed significantly (P ,
0.05) from those values measured from ventricular cells
(282.7 6 0.4 mV, 127 6 1.12 mV, 2.45 6 0.13 nA, 246 6
2 mV, and 395 6 21 V/s, respectively). Input impedance,
capacitance, time constant, and critical depolarization,
which were calculated to quantitate the membrane
characteristics of the two cell types, also were significantly different between atrial (341 6 41 MV, 70 6 4
pF, 23.8 6 2.3 ms, and 19 6 1 mV, respectively) and
ventricular (16.5 6 5.4 MV, 99 6 4.3 pF, 1.56 6 0.32 ms,
and 36 6 1 mV, respectively) cells.
One very interesting contrast between atrial and
ventricular cells is that the apparent voltage threshold
for action potential initiation is significantly more
negative in atrial cells than in ventricular cells (which
might suggest a greater density of sodium channels or a
hyperpolarized shift in the voltage dependence for
sodium channels for the atrial cells), whereas the
actual Vmax for atrial cells is significantly lower than
that for ventricular cells (which might suggest either a
lower density of sodium channels or a significant
contribution of outward current during the upstroke of
the action potential for the atrial cells). The data in Fig.
5 show that the atrial cells have much less outward
current over the voltage range from the RMP to the
threshold potential.
Whole cell voltage-clamp studies to examine ‘‘threshold’’ in ventricular myocytes. The interplay between the
currents over this voltage range and the voltage threshold for activation is difficult to interpret. One approach
is to voltage clamp the cells with step potentials over
this voltage range and use the resulting ionic membrane currents to estimate the voltage dependence of
activation. By definition, a cell cannot produce an
‘‘action potential’’ while under voltage control conditions, but the voltage clamp does provide a way of
determining at what value of step depolarization the
net ionic membrane current (the sum of the inward and
outward currents) becomes negative (inward) during
the pulse, which would establish the minimum depolarization for which a cell might generate an action
potential under current-clamp conditions. Our hypothesis was that the presence of a large outward current in
the ventricular cells, such as IK1, is responsible for the
differences in the voltage threshold for action potential
generation in the two cell types. We thus proposed to
define the activation threshold for ventricular cells
using the whole cell voltage-clamp technique, block the
outward current IK1 with 100 µM BaCl2, and compare
the new activation threshold with the control value to
test whether the shift in activation threshold was
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Fig. 5. Comparison of activation of a V cell and an A
cell. A: successive application of increasing positive
or negative current steps of 50-ms duration with a
step increment of 100 pA for a V cell, with threshold
response to a current magnitude of 540 pA also
shown. B: successive application of increasing positive or negative current steps of 50-ms duration with
a step increment of 10 pA for an A cell, with threshold
response to a current magnitude of 43 pA also shown.
C: relationship between magnitude of current step
and membrane potential at end of current step for V
cell (j) and A cell (s). Also shown are data for A cell
scaled by a factor of 7.4 (n), which were computed
from relative slopes of V and A cell data to make the
slopes of the two relationships equal as they cross
the horizontal axis.
H1908
ATRIAL VS. VENTRICULAR CELL ACTIVATION
Fig. 6. Voltage-clamp responses of a V cell in control
external solution, with a holding potential of 284 mV
and successive steps with a 2-mV increment from 286
to 262 mV (A, tracings a–m) and from 260 to 244 mV
(B, tracings n–v).
then decays over ,10 ms, as seen in Fig. 6 (control
solution). In Fig. 7A there is a very rapid small surge in
net outward current, which then declines rapidly (see
tracing i) and increases slowly again. As shown in Fig.
7B, with stronger depolarizing step potentials, this
declining phase in the net current becomes more and
more pronounced until it finally becomes a net inward
membrane current (shown by tracing q) that defines an
activation threshold of 254 mV for this cell in the 100
µM BaCl2 solution. Note that this new activation
threshold is 10 mV more negative than that obtained in
the control solution for the same cell. This more negative value of activation threshold, produced by blocking
IK1, corresponds quite well to the value of 259 6 1 mV
obtained from the atrial cells in the current-clamp
conditions.
To show the effects of blocking IK1, an I-V relationship
for the voltage-clamp data was plotted in Fig. 8 by
using the values of net membrane current at the end of
the voltage-clamp pulse of 50-ms duration plotted
against the value of the membrane potential during the
test pulse, using a range from 294 to 260 mV to
exclude the higher depolarizations for which some
sodium current was activated. The control curve (filled
squares) is plotted as a nearly linear slope over the
voltage range from 290 to 280 mV and then shows a
significant rectification with depolarizations from 270
to 260 mV producing no increased net outward current, similar in shape to the relationship we obtained
for the ventricular cell under current-clamp conditions
(Fig. 5C). Over this voltage range there is no actual
negative slope of the IK1 I-V relationship, consistent
with previous results from Whalley et al. (19) for rabbit
ventricular cells. The results obtained after the addition of 100 µM BaCl2 are shown as open circles and
demonstrate significantly less current for each of the
test potentials, similar to those obtained for the atrial
cell of Fig. 5. To better compare the shape of the two
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comparable to the difference in activation threshold for
atrial cells compared with that for ventricular cells. If
the activation threshold for ventricular cells after IK1
was blocked was unchanged from control, this would
suggest that a shift in the voltage dependence for INa
might be responsible for the differences in activation
threshold for atrial cells compared with ventricular
cells.
To correlate these results with those measured using
the whole cell current-clamp technique, the whole cell
voltage-clamp studies were performed at 35°C, using
the same external solution and pipette solution as for
the current-clamp experiments. A standard step protocol with 2-mV increments was used from a holding
potential equal to the ventricular cell RMP (284 mV) to
a voltage level at which a net inward current was
produced. Figure 6, A and B, shows the recordings from
a ventricular cell. The current tracings were separated
to show the results for pulse potentials to 2-mV increments from 286 to 262 mV (Fig. 6A, a–m) and from
260 to 244 mV (Fig. 6B, n–v). This separation better
shows the transition from purely outward net current
to an increasing early phase of inward current that
finally becomes a net inward current at a voltage-step
level of 244 mV, which we define as the activation
threshold. Note that this value of activation threshold
corresponds quite well to the value of 246 6 2 mV
obtained for ventricular cells under current-clamp conditions. We then applied 100 µM BaCl2 [which has been
shown (3) to specifically block IK1] to the external
Tyrode solution and repeated the voltage-clamp protocol for the same cell, as shown in Fig. 7, A and B. Note
that the currents are considerably smaller after 100 µM
BaCl2 were added. Data for pulse potentials to 2-mV
increments from 286 to 270 mV are shown in Fig. 7A
(a–i), and data from 268 to 254 mV are shown in Fig.
7B ( j–q). In the 100 µM BaCl2 solution there is no
longer the initial surge of net outward current that
ATRIAL VS. VENTRICULAR CELL ACTIVATION
H1909
Fig. 7. Voltage-clamp responses of same V cell in Fig. 6
in an external solution containing 100 µM BaCl2, with a
holding potential of 284 mV and successive steps with a
2-mV increment from 286 to 270 mV (A, tracings a–i)
and from 268 to 254 mV (B, tracings j–q).
Fig. 8. Comparison of membrane current at end of voltage-step
pulses of Figs. 6 and 7 under conditions of either normal external
solution (control) or 100 µM BaCl2, with a holding potential of 284
mV. Also shown are data for BaCl2 solution scaled by a factor of 12,
which were computed from relative slopes of data in control and 100
µM BaCl2 solutions to make the slopes of the two relationships equal
as they cross the horizontal axis.
100 µM BaCl2 solutions demonstrated a shift in the
voltage threshold and the critical depolarization. Addition of 100 µM BaCl2 caused a change in threshold from
249.2 6 9.3 to 260.8 6 11.5 mV and a change in critical
depolarization from 36.0 6 6.8 to 24.4 6 4.8 mV. By
specifically blocking IK1 with 100 µM BaCl2, the voltage
threshold and the critical depolarization for ventricular
myocytes, as determined using the voltage-clamp technique, were significantly (P , 0.05) changed by 11.6
mV, a value similar to the difference of 13 mV in voltage
threshold and the difference of 17 mV in critical depolarization observed between ventricular and atrial myocytes (see Table 1).
Figure 9 shows results we obtained from a rabbit
atrial cell by using the same voltage-clamp protocol and
solutions as for the ventricular cell in Fig. 6. Comparison of the atrial cell data with the ventricular cell data
reveals that the atrial cell data have a much smaller
magnitude of currents, even smaller than the magnitude of the ventricular cell currents in the BaCl2
solution. As shown in Fig. 9B, the current becomes net
inward at a pulse potential of 256 mV, which agrees
quite well with the value of 259 6 1 mV for the voltage
threshold obtained in the current-clamp conditions for
atrial cells. Note that the voltage threshold determined
using the voltage-clamp technique is very similar when
the atrial cell in control solution (Fig. 9) is compared
with the ventricular cell in the BaCl2 solution (Fig. 7).
Similar results were obtained from two additional
atrial cells studied with this technique.
The voltage-clamp results with ventricular cells suggested that current-clamp experiments with ventricular cells in control solutions versus those in BaCl2
solution would also show differences in cell activation
that might mimic some of the differences between
ventricular and atrial cells. Figure 10 shows the responses of a ventricular cell in control solution (Fig.
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curves, the values plotted for the ventricular cell in 100
µM BaCl2 were scaled by a factor of 12, which matched
the slope of the control data near the zero-crossing
point (open triangles). Note that this residual current
not blocked by 100 µM BaCl2 shows no rectification in
the voltage range from 284 to 260 mV, although there
does appear to be some rectification in the more negative voltage range from 294 to 284 mV.
Results obtained from five ventricular cells in which
we used this voltage-clamp protocol for the control and
H1910
ATRIAL VS. VENTRICULAR CELL ACTIVATION
Fig. 9. Voltage-clamp responses of an A cell in control
external solution, with a holding potential of 284 mV
and successive steps with a 2-mV increment from 286
to 270 mV (A, tracings a–i) and from 268 to 254 mV (B,
tracings j–p).
Fig. 10. Comparison of activation of a V cell in control
external solution (A) with activation of same V cell in a
solution containing 50 µM BaCl2 (B). A: successive
application of increasing positive current steps of 50-ms
duration with a step increment of 100 pA, with threshold response to a current magnitude of 920 pA also
shown. B: successive application of increasing positive
current steps of 50-ms duration with a step increment of
10 pA for same V cell as in A, but after addition of 50 µM
BaCl2, with threshold response for a current magnitude
of 130 pA also shown.
Note also that the time course of the subthreshold
responses is clearly changed, with a much slower rise of
potential in the 50 µM BaCl2 solution, similar to that
shown for atrial cells. The changes in the voltage
threshold under current-clamp conditions produced by
50 µM BaCl2 are shown more clearly in Fig. 11, for
which we carefully determined the voltage threshold in
response to current pulses of 2- or 15-ms duration for a
ventricular cell in control solution (Fig. 11B) and in 50
µM BaCl2 solution (Fig. 11A). In the control solution
the voltage threshold is 251.4 mV for the 2-ms duration pulse, with a critical depolarization from RMP of
33.9 mV. For the 15-ms duration pulse these values are
not significantly changed in the control solution. In the
50 µM BaCl2 solution (Fig. 11A) for the same cell, the
voltage threshold has become more negative (259.3 or
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10A) and in 50 µM BaCl2 solution (Fig. 10B) to a
protocol using steps of depolarizing current pulses of
50-ms duration. This ventricular cell was quite large,
with a current threshold of 3.7 nA for a 2-ms duration
stimulus in the control solution and a threshold of only
1.5 nA in the 50 µM BaCl2 solution (a ratio of 2.5). For
the 50-ms duration pulses, we used current step increments of 100 pA for the control solution, with subthreshold responses shown for current steps from 100 to 900
pA and including the threshold response for 920 pA. In
the 50 µM BaCl2 solution, we used current step increments of 10 pA, with subthreshold responses shown for
depolarizing steps from 10 to 120 pA and including the
threshold response for 130 pA (a ratio of current
thresholds of 7.1 for the 50-ms duration compared with
the ratio of 2.5 for the current stimuli of 2-ms duration).
ATRIAL VS. VENTRICULAR CELL ACTIVATION
H1911
Fig. 11. Comparison of voltage threshold and critical
depolarization required for activation for an isolated V
cell in a solution with 50 µM BaCl2 (A) and same
isolated V cell in control external solution (B) in response to current stimuli of either 2- or 15-ms duration.
Solid lines indicate successful activations, and dashed
lines indicate largest subthreshold responses.
DISCUSSION
Conduction through the heart can be thought of as a
process of current supply and demand. Conduction fails
when either not enough current is supplied to a region
or, equivalently, the amount of current demanded by a
region is greater than that which can be supplied by
neighboring regions that have already undergone activation. An understanding of the mechanisms of initiation of an action potential and what factors influence
the critical amount of depolarization required for action
potential initiation is necessary to address the latter
part of this supply-demand theory of conduction. Previous studies (4, 7, 19) have examined the ionic conductances that appear to differ between atrial and ventricular cells and thus account for some of the differences in
action potential waveforms. In particular, Whalley et
al. (19) showed that the steady-state I-V relationship
for rabbit ventricular cells with 30 µM tetrodotoxin
(TTX) and 100 µM CdCl2 showed a prominent IK1 for
ventricular cells (demonstrated by block with BaCl2 )
and a much smaller current for atrial cells. The focus of
our work is on the biophysical properties of the cell
within the potential range between the RMP and the
threshold potential and how these differences in biophysical properties between atrial and ventricular cells
determine the conditions for action potential initiation
for that cell type. Because our studies were done at the
isolated cell level, we do not try to account for other
variables present in the whole organ such as the
number or distribution of gap junctions that would
alter the cable properties of atrial or ventricular tissue
(1, 15) and, in doing so, might account for some of the
differences in action potential initiation or propagation.
In previous work, Hume and Uehara (7) used isolated
atrial and ventricular myocytes from guinea pigs, and
the RMP, Vmax, input impedance, and membrane time
constant were 273.4 6 5.1 mV, 83.9 6 21.4 V/s, 108.8 6
58.6 MV, and 5.5 6 2.6 ms, respectively, for atrial cells
and 274.1 6 3.3 mV, 80.8 6 17.7 V/s, 32.1 6 13.4 MV,
and 2.3 6 0.9 ms, respectively, for ventricular cells.
Hume and Uehara (7) stated that increasing the experimental temperature to 35°C only affected action potential shape by decreasing action potential duration and
increasing Vmax. Giles and Imaizumi (4) recorded action
potentials from isolated rabbit atrial and ventricular
cells and obtained values for RMP, input impedance,
capacitance, and membrane time constant of 266.9 6
4.8 mV, 617 6 401 MV, 54.3 6 5.9 pF, and 34 ms,
respectively, for atrial cells and 274.2 6 2.6 mV, 33.7 6
22.7 MV, 72.5 6 18.8 pF, and 2.4 ms, respectively, for
ventricular cells. Giles and Imaizumi (4) noted that
increasing the stimulus frequency from 0.5 to 1 Hz in
rabbit atrial and ventricular cells increased the action
potential duration and plateau height, whereas decreasing the frequency from 1 to 0.1 Hz resulted in a very
rapid early repolarization phase in atrial cells that was
thought to be due to It. Whalley et al. (19), using the
whole cell current-clamp technique at room temperature to compare action potentials generated by cultured
rabbit atrial cells that had assumed a spherical shape
versus freshly isolated rabbit ventricular cells, measured RMP, Vmax, capacitance, and input impedance as
266.4 6 1.3 mV, 112.2 6 4.8 V/s, 15–25 pF, and 958 6
158 MV, respectively, for atrial myocytes and 270.0 6
0.9 mV, 161 6 18 V/s, 100–140 pF, and 29.7 6 3.8 MV,
respectively, for ventricular myocytes. All of these
studies determined RMP values for atrial cells that
were somewhat less negative than those for ventricular
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258.4 mV for the 2- or 15-ms duration pulse, respectively), and the critical depolarization has been reduced
to 26.1 mV. The changes in the voltage threshold and
the critical depolarization produced in the ventricular
cell by the 50 µM BaCl2 solution are very similar to
those we observed in comparing ventricular cell to
atrial cells in control solutions.
H1912
ATRIAL VS. VENTRICULAR CELL ACTIVATION
is different from the usual use of this technique to
pharmacologically isolate a particular current and then
study the voltage and time dependence of that current.
We used a normal external and internal solution and a
physiological temperature to assess the voltage level at
which a net inward current occurs. Thus our voltageclamp data are not designed to isolate IK1 other than to
show the effect of BaCl2 (as a blocker of IK1 ) on the
voltage threshold for activating a net inward current
during the potential step for ventricular cells. In particular, we have restricted the voltage range of Fig. 8, in
which we plot the voltage-clamp current at the end of a
50-ms pulse, to those voltage levels below which the
sodium current is activated. The I-V relationship thus
produced does not show the negative slope of the IK1
rectification, which is present only at more depolarized
voltage levels in rabbit ventricular cells (19). As the
pulse potential is increased toward this threshold level
(see Fig. 6B, tracings s, t, and u), there is a phasic
component of inward current, but the presence of a
large outward current prevents the expression of a net
inward current, thus raising the voltage level for
activation.
The block of IK1 in ventricular cells did not produce a
decrease in Vmax or a decrease in the action potential
amplitude, suggesting that these differences between
ventricular and atrial myocytes may be produced by a
decreased sodium current in atrial cells. However, we
have no direct data on the magnitude of sodium current
in the atrial or ventricular cells. We previously studied
the relationship between the sodium current and the
strength-duration curve for isolated rabbit ventricular
cells (8). This study showed that 3 µM TTX reduced the
Vmax of the ventricular cell by ,50%, produced only a
13% increase in the current threshold for a 2-ms
duration stimulus, depolarized the voltage threshold by
,5 mV, and shifted the strength-duration curve in the
positive direction with a nearly constant ratio over a
duration range of 1–10 ms. Thus it seems unlikely that
the lower Vmax of the atrial myocytes compared with
that of the ventricular myocytes plays a significant role
in the mechanism of the differences between the
strength-duration curves and the voltage threshold
shifts we observed in atrial and ventricular myocytes.
In fact, the lower amount of outward current in the
atrial myocytes, compared with that in the ventricular
myocytes, during the upstroke of the action potential
may actually serve to partially compensate for a lowered value of sodium conductance in the atrial myocytes, an effect that has been proposed in previous
studies relating changes in the sodium conductance
and Vmax (6, 19).
With these differences in the activation properties of
isolated myocytes from the atrium and the ventricle
established, it is reasonable to discuss how these
differences might be related to the process of normal
and abnormal conduction in the two regions. The
properties we have shown for the atrial cells make
them ideally designed to be activated by current flow
from a slowly depolarizing region of automaticity comprising cells with high input resistance (e.g., the sino-
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cells under comparable conditions, but the values obtained were significantly less negative than those obtained from microelectrode studies from intact atrial
tissue at physiological temperature [e.g., 280 to 284
mV by Spach et al. (16), and 282 mV by Nawrath (13)].
In the present study, we have compared the initiation
properties of isolated rabbit atrial and ventricular
myocytes, with specific reference to differences in RMP,
Vmax, action potential amplitude, action potential duration, and the voltage and current thresholds. From
these data, we also computed the differences in the
membrane time constant, input impedance, critical
depolarization, and membrane capacitance for atrial
and ventricular cells. Although the membrane capacitance was 41% higher in ventricular myocytes than in
atrial myocytes, the input impedance for small depolarizations was 20-fold greater in atrial myocytes than in
ventricular myocytes, producing membrane time constants that were 15-fold greater for atrial myocytes
than for ventricular myocytes. Also, the ventricular
myocyte RMP was only 2.7 mV more negative, Vmax was
92% greater, and the action potential amplitude was
17% greater than the same values for the atrial myocytes. A comparison of strength-duration curves for the
two cell types also revealed that, although the ventricular myocytes required 3.6 times as much current to
initiate an action potential for a short (2 ms) duration,
for longer durations this ratio was much increased,
with ventricular myocytes requiring 10 times as much
current as atrial cells for stimulus durations in the
range of 25–50 ms. The critical depolarization from the
RMP required to initiate an action potential was 90%
greater for ventricular myocytes than for atrial myocytes, with the voltage threshold as determined from
the current-clamp experiments being 13 mV less negative for ventricular myocytes than for atrial myocytes.
To test the hypothesis that many of these differences
could be accounted for by the greater magnitude of IK1
in ventricular myocytes compared with that in atrial
myocytes, we compared the properties of ventricular
myocytes in control solution with the same ventricular
myocytes in a solution containing 50–100 µM BaCl2 to
selectively block the IK1 current. Using both voltageand current-clamp techniques, we showed that the
block of IK1 in the ventricular cells produced 1) a small
depolarization of the RMP, 2) a large increase in the
input resistance and a corresponding large increase in
the membrane time constant, 3) a negative shift in the
voltage threshold for producing a net inward current
under voltage-clamp conditions, 4) a negative shift in
the voltage threshold under current-clamp conditions,
and 5) a decrease in the current threshold for stimuli of
short duration and an even larger decrease in the
current threshold for stimuli of longer duration. All of
these changes in the ventricular cells produced by
50–100 µM BaCl2 were comparable to the differences
we observed between ventricular and atrial myocytes,
suggesting that many of the differences could be accounted for by the relative lack of IK1 in atrial cells.
Our use of the voltage-clamp technique to determine
the voltage level for activation of a net inward current
ATRIAL VS. VENTRICULAR CELL ACTIVATION
This work was partially supported by National Heart, Lung, and
Blood Institute Grant HL-22562 and the Emory Egleston Children’s
Research Center.
Address for reprint requests: R. W. Joyner, Dept. of Pediatrics,
Emory Univ., 2040 Ridgewood Dr. NE, Atlanta, GA 30322.
Received 2 September 1997; accepted in final form 10 February 1998.
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atrial node). The ventricular cells, on the contrary, are
ideally designed to suppress propagation from such a
region (which in the ventricle would be an ectopic focus)
because of their lower input resistance, shorter time
constant, larger critical depolarization, and larger current threshold, especially for a prolonged stimulus. In
fact, the IK1 current has recently been shown to be
reduced in ventricular cells under conditions of hypoxia, decreased intracellular ATP, or by the actions of
lysophosphatidylcholine (2, 11, 12, 17, 20). This partial
block of IK1 in ventricular myocytes under conditions
associated with myocardial ischemia may make them
more susceptible to activation from an ectopic focus by
the mechanism of a greatly reduced current threshold
for prolonged duration stimuli, as we showed with the
BaCl2 solution.
H1913