(Circulation. 1999;99:1623-1629.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Effects of Ischemia on Discontinuous Action Potential Conduction in Hybrid Pairs of Ventricular Cells
From the Department of Medical Physiology and Sports Medicine, Utrecht University (R.W., E.E.V., H.J.J.), and the Academic Medical Center, University of Amsterdam, Department of Physiology, Amsterdam (R.W., E.E.V., A.C.G.v.G., L.N.B.), Netherlands; and Todd Franklin Cardiac Research Laboratory, The Children's Heart Center, Department of Pediatrics, Emory University, Atlanta, Ga (R.W.J., D.A.G., R.K.).
Correspondence to Ronald Wilders, Department of Medical Physiology and Sports Medicine, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, PO Box 80043, 3508 TA Utrecht, Netherlands. E-mail r.wilders{at}med.uu.nl
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Abstract |
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Background—Acute ischemia often occurs in cardiac tissue that has prior injury, resulting in spatially inhomogeneous distributions of membrane properties and intercellular coupling. Changes in action potential conduction with ischemia, which can be associated with release of catecholamines, may be particularly important in tissue that has discontinuous conduction resulting from prior infarction, hypertrophy, or myopathy.
Methods and Results—Isolated guinea pig ventricular myocytes were electrically coupled by a coupling-clamp circuit to a comprehensive computer model of a guinea pig ventricular myocyte to assess alterations in the critical value of coupling conductance required for action potential conduction from the real cell to the model cell when the real cell was exposed to a solution that included hypoxia, acidosis, and an elevated extracellular potassium concentration to simulate acute ischemia. The "ischemic" solution increased critical coupling conductance from 6.2±0.1 to 7.4±0.2 nS and decreased the associated maximum conduction delay from 31±1 to 23±1 ms (mean±SEM, n=11). The ischemic solution plus 1 µmol/L norepinephrine decreased critical coupling conductance from 5.9±0.2 to 5.0±0.1 nS and increased maximum conduction delay from 31±2 to 54±4 ms (mean±SEM, n=8).
Conclusions—The release of catecholamines with ischemia, in a setting of partially uncoupled cells, may play a major role in producing long conduction delays, which may allow reentrant pathways.
Key Words: arrhythmia • catecholamines • conduction • ischemia
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Introduction |
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Many episodes of acute myocardial ischemia occur in tissue that is already abnormal, ie, that has spatially inhomogeneous distributions of membrane properties and intercellular coupling resulting from prior injury. Sudden cardiac death is commonly associated with a preexisting structural abnormality1 from prior infarction, hypertrophy, or myopathy that may serve as a substrate from which arrhythmias can arise. Conduction becomes slow and discontinuous, with an irregular (zigzag) spatial pattern.2 Surviving muscle fiber bundles are separated by connective tissue, and extracellular recordings show fractionated electrograms with discrete deflections.3 Action potentials in these regions have prepotentials and notches due to electrotonic interactions with nearby cells.4 During acute ischemia, excessive concentrations of catecholamines are observed within the unperfused myocardium.5 Depletion of catecholamines or treatment with ß-blockers decreases the incidence of ischemia-induced arrhythmias.6
In normal myocardium, fast sodium current (INa) is responsible for excitability and conduction. Under conditions of discontinuous conduction, however, L-type calcium current (ICa,L) may play a major role in sustaining conduction.7 8 9 10 For a pair of electrically coupled ventricular myocytes, we have previously shown that block of ICa,L significantly increased conduction delay when cells were relatively uncoupled but had no effect on conduction when cells were well coupled.7 Our further study using pharmacological modulation of ICa,L8 suggested that the facilitating effects on conduction produced by ß-agonist activity might counteract the inhibitory effects on conduction of acute ischemia.
Techniques have been developed11 to study isolated cardiac cells under conditions incorporating many of the known phenomena of myocardial ischemia, including hypoxia, elevated potassium, lowered pH, elevated lactate, and lack of glucose. Combining these techniques with our model-clamp technique,12 we have studied the effects of varying coupling conductance for a pair of electrically coupled cells in which the leader (stimulated) cell is a real isolated guinea pig ventricular cell (either in a normal Tyrode's solution, an "ischemic" solution, or an ischemic solution with a ß-agonist drug) and the follower cell is a model guinea pig ventricular cell represented by the Luo-Rudy model.13
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Methods |
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Cell Isolation
Single ventricular myocytes were prepared from adult guinea pigs weighing 200 to 800 g. After decapitation, the heart was excised and consecutively perfused with normal Tyrode's solution (5 mL/min, 3 to 5 minutes), nominally Ca2+-free Tyrode's solution (10 minutes), and nominally Ca2+-free enzyme solution (12 to 14 minutes). Both ventricles were cut into pieces, gently triturated in nominally Ca2+-free Tyrode's solution to which 180 µmol/L Ca2+ was added, and stored at room temperature. Samples of the cell suspension were placed in the recording chamber, and cells were allowed to settle for 5 to 10 minutes, after which superfusion with normal Tyrode's solution was started (1 mL/min, 35±0.5°C). Only single cells that were quiescent with preservation of their rod-shaped appearance were studied. Membrane capacitance, input resistance, and (2-Hz, 2-ms) stimulus current threshold were 163±15 pF, 15.2±1.4 M
, and 3.14±0.16 nA
(mean±SEM, n=19), respectively.
Cell Chamber
Figure 1A
and 1B illustrates the
design of the cell chamber to produce the ischemic conditions
for isolated cells. During ischemia, the cell chamber was
layered with argon, preventing diffusion of atmospheric oxygen into the
bath solution. Partial oxygen pressure was continuously monitored.
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Electrophysiological Recording
Whole-cell patch-clamp recordings were made with
custom-built dual amplifiers using relatively high resistance patch
pipettes (4 to 6 M when filled with pipette solution) to minimize
intracellular dialysis. Series resistance was compensated up to
90%. Apart from zeroing the potential before touching the cell
surface, no attempts were made to correct for liquid junction
potential. In control experiments, action potential configuration and
transmembrane currents remained stable for 40 to 60 minutes.
Solutions
Normal Tyrode's solution contained (in mmol/L) NaCl 140,
KCl 5.4, CaCl2 1.8, MgCl2
1.0, HEPES 10.0, glucose 5.5 (pH 7.4 with NaOH) and was saturated with
100% O2. Nominally
Ca2+-free Tyrode's solution was the same,
without the CaCl2. Enzyme solution contained 0.06
U/mL collagenase-B, 0.19 U/mL collagenase-P,
and 40 mg/mL trypsin inhibitor
(Boehringer-Mannheim) in nominally
Ca2+-free Tyrode's solution. During the last 5
minutes of the enzymatic isolation, 0.28 U/mL protease-XIV (Sigma
Chemical Co) was added. Pipette solution contained (in mmol/L) KCl
140 and HEPES 10 (pH 7.2 with KOH). The ischemia solution
contained (in mmol/L) NaCl 120, KCl 8.0,
CaCl2 1.8, MgCl2 1.0, PIPES
10.0, and sodium lactate 20 (pH 6.8 with NaOH) and was saturated with
100% N2.
Coupling an Isolated Ventricular Cell to a Model
Cell
Figure 1C
diagrams our method of dynamically coupling a
real cell to a real-time solution of a mathematical cell model with an
ohmic coupling conductance Gc.12 The
computer-controlled system, for each 80-µs time step 
t, samples
the membrane potential Vm,A, calculates the
coupling current
Ic=Gcx(Vm,A–Vm,B),
injects this current into the real cell, and integrates the Luo-Rudy
model with Ic as an additional ionic
membrane current. To minimize effects of cell size, we scaled
Ic such that the real cell and the model
cell were of equal size, both exhibiting an effective current threshold
of 2.6 nA.12
Statistics
For each cell, we compared action potential
parameters, critical coupling conductance, and maximum
conduction delay for control versus ischemia using a paired
t test with a significance level of P<0.05.
Comparison of action potential parameters between groups
was performed with a Student-Newman-Keuls test after ANOVA. Data are
presented as mean±SEM.
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Results |
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Experimental Procedure
Figure 2
illustrates our
experimental procedure, with the Tyrode's solution bathing the cell
switched to the ischemic solution for 17 minutes (horizontal
bar). During the initial control period,
PO2 was 215 Pa (158 mm Hg),
action potential duration at 90% repolarization
(APD90) was 138 ms, and resting membrane
potential (RMP) was -85 mV. During ischemia,
PO2 rapidly falls to <13.6 Pa
(<10 mm Hg) within 5 minutes. The APD90
shows some fluctuations, with a small decrease to 125 ms until late
in the ischemic period, when a large, rapid drop to 60 ms
occurs, at which time we switched back to control conditions. The RMP
changes very rapidly with the ischemia (because of the elevated
potassium) and remains stable at -76 mV. On reestablishment of control
conditions, PO2 and RMP rapidly
return to their initial control levels, whereas
APD90 remains slightly shorter after recovering
from the large drop at the end of the ischemic period.
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We applied this procedure of an 20-minute exposure to
ischemic conditions to 11 cells. For times at 8 to 10 minutes
into the ischemic period, these cells showed, in addition to
the changes in RMP and APD90, a decrease in
APD50, a decrease in maximum rate of rise of the
action potential upstroke (
max) (not
significant, P=0.05), and a 4-mV reduction in overshoot
potential (Table, left columns).
The large, rapid drop in APD90 at the end of the
ischemic period was observed for 5 of the 11 cells and is most
likely due to hypoxia-induced activation of ATP-sensitive
potassium current.14
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Conduction Under Ischemic Conditions
Figure 3 shows results from coupling
the real guinea pig ventricular cell of Figure 2 to
the Luo-Rudy model cell during the initial control period. Figure 3A shows membrane potential and coupling current for the
6-second period of coupling with a Gc of 6.6 nS
as well as the preceding and following 2-second periods of uncoupling.
The real cell is stimulated at 2 Hz, and no stimuli are applied to the
model cell. After coupling has been established, some but not all
action potentials of the real cell propagate to the model cell: action
potentials 3, 6, and 11 fail to propagate, as indicated by their short
duration and monophasic coupling current transient. At
Gc=6.7 nS, however, every real cell action
potential propagates to the model cell (Figure 3B), thus
establishing 6.7 nS as the critical value of Gc
for successful, uniform propagation under control conditions. At
Gc<6.6 nS, action potentials propagate less
frequently or not at all; at Gc>6.7 nS,
conduction was uniformly successful (not shown).
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For the same cell, we also determined critical Gc
after 8 minutes of ischemia. At Gc=7.8
nS, action potentials 3 and 8 during coupling fail to propagate (Figure 4A), but at Gc=7.9
nS, there is uniform propagation (Figure 4B). Because of
electrotonic interactions, the amount of depolarization of the real
cell is slightly reduced during coupling. From Figures 3 and 4, we see that critical Gc has been
increased by the ischemic conditions from 6.7 to 7.9 nS.
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Figure 5 contrasts propagation at
critical Gc under control versus ischemic
conditions by expanding Figures 3B and 4B, respectively,
to illustrate only the last action potential propagated (asterisks).
Under control conditions (Figure 5A), there is a rapid upstroke,
followed by a partial repolarization of the real cell as current is
transferred from real cell to model cell. When the model cell
activates after a 28-ms delay, it rapidly depolarizes,
producing a second phase of depolarization of the real cell. Under
ischemic conditions (Figure 5B), the real cell shows a
depolarized RMP and a slightly decreased peak amplitude, and the
conduction time is decreased to 24 ms. Because for both Figure 5A and 5B, the value of Gc was the
minimum value that allowed uniform conduction, these values of 28 and
24 ms represent the maximum conduction delay under control
versus ischemic conditions, showing that the ischemia
decreased the maximum conduction delay. Similar results were obtained
for each of the 10 other cells studied under ischemic
conditions.
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Conduction Under Ischemic Conditions With
Norepinephrine
For another 8 cells, we performed the same procedure of exposure
to ischemic conditions but also including 1 µmol/L
norepinephrine (ischemia+NA) in the
ischemic solution. Like the 11 cells that were exposed to
ischemic conditions without the norepinephrine, the
cells showed a 9-mV depolarization of RMP, a decrease in
max (not significant, P=0.09),
and a 4-mV reduction in overshoot potential (Table, right
columns). However, no changes in APD50 or
APD90 were observed. Also, the large, rapid drop
in APD90 at the end of the ischemic
period was observed for only 1 of these 8 cells.
Figure 6 illustrates, in the same format
as Figure 5, results from 1 of the 8 cells exposed in the
ischemia+NA solution. We determined that critical
Gc was 6.2 nS in the control solution and 5.2 nS
in the ischemia+NA solution (not shown). The results under
control conditions (Figure 6A) are very similar to those shown
for a different cell in Figure 5A. In the ischemia+NA
solution (Figure 6B), the partial repolarization during the
conduction process is much slower and is maintained at a higher voltage
level, allowing for a much longer maximum conduction delay (60 ms).
Similar results were obtained for each of the 7 other cells studied in
the ischemia+NA solution.
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Statistical Comparison of Conduction in the Two Test
Solutions
Effects on conduction of the application of ischemia or
ischemia+NA are summarized in Figure 7. Note that each experimental
intervention has its own control data. For the ischemia (n=11),
the critical coupling conductance increases from 6.2±0.1 to 7.4±0.2
nS and the associated maximum conduction delay decreases from 31±1 to
23±1 ms. For the ischemia+NA (n=8), there is a decrease in
critical coupling conductance from 5.9±0.2 to 5.0±0.1 nS and an
increase in maximum conduction delay from 31±2 to 54±4 ms.
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Conduction at a Constant Coupling Conductance in the Two Test
Solutions
Figure 8 emphasizes the differences
in the discontinuous conduction process between control conditions,
ischemia, and ischemia+NA at a constant coupling
conductance of 8.0 nS. For the same real cell as used for Figures 2 through 5, we have plotted the results
under control conditions (Figure 8A) versus ischemia
(Figure 8C). Similarly, for the same real cell as used for
Figure 6, we contrast propagation under control conditions
(Figure 8B) and ischemia+NA (Figure 8D). Under
control conditions (Figure 8A and 8B), coupling current
flowing from each of the real cells to the model cell induces an early
partial repolarization to +10 to +15 mV, and the conduction delay is 12
ms.
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During ischemia (Figure 8C), both the peak amplitude of
the real cell action potential and the potential after this peak
amplitude are reduced. Because the driving force for coupling current
is the difference in membrane potential, less coupling current is
flowing from real cell to model cell during the process of propagation.
The real cell continues to repolarize to -18 mV until, with a 22-ms
delay, the model cell reaches its activation threshold and fires its
action potential.
During ischemia+NA (Figure 8D), the potential after the
peak of the real cell action potential is maintained at a higher level
than in control solution, with a small repolarization during conduction
to only +25 mV. As a consequence, coupling current is larger than under
control conditions, and it takes less time (11 ms) to activate
the follower cell. Thus, Figure 8 demonstrates that, for
discontinuous conduction at constant Gc, impulse
propagation is largely impaired in the ischemia solution but
enhanced in the ischemia+NA solution.
Changes in Ionic Currents
To unmask changes in ionic currents underlying the changes in
conduction properties shown in Figures 3 through 8, we tested for changes in
INa, ICa,L, and
the inward rectifier and delayed rectifier potassium currents
(IK1 and IK,
respectively) as major contributors to the activation and plateau phase
of the action potential.13 15 In accordance with data
from the literature,15 the transient outward current
(Ito) appeared to be absent in our cells
(not shown). Under both ischemic conditions and
ischemic conditions plus norepinephrine, only a
slight decrease in max, reflecting
activation of INa, was observed
(Table).
For 4 of the 19 cells studied—2 cells exposed to the ischemia
solution and 2 cells exposed to the ischemia+NA solution—we
applied voltage clamp protocols under control conditions and after 10
to 15 minutes of ischemia, ie, directly after the determination
of action potential parameters, critical coupling
conductance, and maximum conduction delay at 8 to 10 minutes of
ischemia. Resulting current-voltage relations are shown in
Figure 9, which contrasts data from a
cell exposed to the ischemia solution (Figure 9A and 9B) and a separate cell exposed to the ischemia+NA
solution (Figure 9C and 9D).
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The amplitude of the peak current, reflecting
ICa,L, decreased in the ischemic
solution (Figure 9A) but showed an 4-fold increase in the
ischemia+NA solution (Figure 9C). Under ischemic
conditions, the quasi–steady-state current, reflecting
IK1 and IK,
shows a shift in reversal potential and a crossover in the negative
voltage range, as expected from the effects of increased extracellular
potassium concentration on
IK1,16 whereas no major
changes are observed in the voltage range positive to -10 mV (Figure 9B). Under ischemic conditions including
norepinephrine, however, quasi–steady-state current shows
a large increase in the latter voltage range (Figure 9D).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We have used isolated guinea pig ventricular myocytes in an experimental system in which an isolated cell exposed to either normal Tyrode's solution or an ischemic solution can be dynamically coupled to a real-time solution of a mathematical model of a guinea pig ventricular cell. Our use of the ischemic solution attempts to recreate the major modulators of acute ischemia to be tested in terms of critical coupling conductance and maximum conduction delay for action potential propagation across a pair of cells in which coupling conductance is much lower than the normal value. We are basically asking: If action potential conduction is already discontinuous, perhaps from some prior injury, what is the effect of the acute imposition of a simulated ischemic condition? Our use of "normal" cells and a normal ventricular model for this experimental model is based on previous work showing that in healed myocardial infarctions, the resting membrane potential has returned to nearly normal values,3 although the membrane properties of surviving cells may be somewhat abnormal, with decreased calcium currents, sodium current, and Ito.17 18
Geometrical Considerations
The slow conduction and fractionated waveforms characteristic of
conduction in ischemic tissue are indications of successive
activation of groups of cells for which the intergroup conductance is
limiting the conduction. Our use of a model of 2 cells can be scaled to
represent the conduction between 2 groups of cells under the
conditions that within each group the cells are well coupled and
essentially isopotential. That this condition is met under certain
ischemic conditions is indicated by the brief duration of each
component of the fractionated signals and also from direct
microelectrode recordings of cells within the
groups.4 Thus, 2 groups of 1000 cells connected by a
conductance of 8000 nS would have the same characteristics of
conduction as 2 single cells connected by a conductance of 8 nS. In the
case of connections between large groups of cells, the interconnections
might be a short bridge of cells, rather than a direct electrical
connection between 1 cell of each group. The major geometrical
limitation of our model system is that we are currently restricted to a
pair of cells without connections to other cells or groups of cells.
Thus, the effects of tissue loading19 are not taken into
account.
Conduction Under Ischemic Conditions
Our results show that the application of ischemia
increases the critical value of coupling conductance required for
action potential propagation and decreases the associated maximum
conduction delay. The analysis is somewhat complex, because it
involves 3 factors: the ability of a proximal cell (leader cell) to
supply current, the coupling conductance, and the requirements for
charge to activate the distal cell (follower cell). For this
experimental model system, we used the Luo-Rudy model cell as the
distal cell, and we did not modify the model description during the
ischemia so that the requirements for activation of the distal
cell would be unchanged. During the experiment, we controlled the
coupling conductance, and this became a dependent variable to
characterize the amount of coupling conductance required for successful
propagation. The actual mechanism by which the ischemia
decreases the ability of the real cell to supply current to the distal
cell (as shown by the increased value of critical coupling conductance)
cannot be uniquely determined by these experiments but is probably
explained by an 50% decrease in ICa,L
during the metabolic inhibition, as observed in our
voltage-clamp experiments (Figure 9A). A similar decrease in
ICa,L was observed by Cordeiro et
al.11 As a result, the amount of partial
repolarization of the proximal cell during the conduction process is
increased and the driving force for coupling current is lowered, as we
have previously shown with pharmacological modulation of
ICa,L.8
Conduction Under Ischemic Conditions With
Norepinephrine
Our results with the application of ischemic conditions
including 1 µmol/L norepinephrine show that the
presence of the norepinephrine completely reverses the
effects of the simulated ischemic condition with respect to
discontinuous propagation. With the norepinephrine, the
critical coupling conductance is decreased, and the maximum conduction
delay is increased. The actual mechanism by which the ability of the
real cell to supply current to the distal cell is increased (as shown
by the decreased value of critical coupling conductance) is probably
explained by an increase in ICa,L (Figure 9C), which, despite the concomitant increase in outward current
(Figure 9D), results in a slower rate of partial repolarization
of the proximal cell during the conduction process and an increased
driving force for coupling current.
Limitations of This Study
Our results suggest that the release of catecholamines
with ischemia, in a setting of partially uncoupled cells, may
play a major role in producing the long conduction delays that may
allow the establishment of a reentrant pathway. In our experimental
model system, the application of simulated ischemia, without
the catecholamine, actually decreased the maximum
conduction delay that could occur. Nevertheless, it is important not to
extrapolate these results for cell pairs too literally for the much
more complex situation of the spatially inhomogeneous
application of ischemia as well as the spatial inhomogeneity of
coupling conductance and intrinsic action potential properties.
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Acknowledgments |
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This study was supported by Netherlands Heart Foundation grant 92.310, Netherlands Organization for Scientific Research grant 805-06-152, National Institutes of Health grant HL-22562, the Georgia Affiliate of the American Heart Association, and the Emory Egleston Children's Research Center.
Received July 1, 1998; revision received November 10, 1998; accepted November 23, 1998.
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