© 2000 American Heart Association, Inc.
Integrative Physiology |
Nonlinear Changes of Transmembrane Potential During Defibrillation Shocks
Role of Ca2+ Current
From the Departments of Biomedical Engineering (E.R.C., R.E.I., V.G.F.), Medicine (R.E.I.), and Physiology (R.E.I.), University of Alabama at Birmingham, Birmingham, Ala.
Correspondence to Vladimir G. Fast, PhD, University of Alabama at Birmingham, 1670 University Blvd, VH B149, Birmingham, AL 35294. E-mail fast{at}crml.uab.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
|---|
Abstract—Defibrillation shocks induce complex nonlinear changes of transmembrane potential (
Vm). To elucidate the ionic mechanisms of nonlinear
Vm, we studied the effects of ionic channel blockers on
Vm in geometrically defined myocyte cultures.
Experiments were carried out in cell strands with widths of 0.2 mm
(narrow strands) and 0.8 mm (wide strands) produced using a
technique of directed cell growth. Uniform-field shocks were applied
across strands during the action potential (AP) plateau, and the
distribution of shock-induced Vm was measured using an
optical mapping technique. Nifedipine and
4-aminopyridine were applied to inhibit the L-type
calcium current (ICa) and the transient
outward current (Ito), respectively. In
control conditions, the distribution of Vm across cell
strands was highly asymmetrical with a large ratio of negative to
positive Vm
(V-m/V+m)
measured at the opposite strand borders. Application of
nifedipine caused a large increase of
V+m and a decrease of
V-m/V+m,
indicating involvement of ICa in the
asymmetrical Vm, likely as a result of the outward flow
of ICa when Vm exceeded the
ICa reversal potential.
V-m decreased in the narrow strands but
remained unchanged in the wide strands, indicating that the changes of
V-m were caused by electrotonic interaction
with an area of depolarization. 4-Aminopyridine did not
change
V-m/V+m.
These results provide evidence that (1) the asymmetry of shock-induced
Vm during the AP plateau is due to outward flow of
ICa in the depolarized portions of the
strands, (2) Ito is not involved in the
mechanism of Vm asymmetry, and (3) the effects of drugs
on Vm are modulated by the tissue geometry.
Key Words: electrophysiology • defibrillation • mapping • voltage-sensitive dyes
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
|---|
Electric shocks are routinely used to terminate fibrillation in patients, yet the mechanisms of defibrillation are not well understood. Particularly, it is not yet known how the shock field changes the transmembrane potential of cardiac cells (Vm). Because shocks are applied in the extracellular space, both positive and negative changes of Vm are produced by the shocks. It is believed that Vm changes during shocks can be due to several factors, including nonuniformity of the electric field1 2 3 4 and nonuniformity of the tissue structure.5 6 Combination of these 2 factors can fully predict the magnitude and the distribution pattern of Vm changes in the linear model systems.7 Particularly,
Vm in a
linear system is directly proportional to the strength of the shock
field. In real cardiac tissue, however, Vm
changes are strongly nonlinear, suggesting the involvement of some
additional factors.
Three types of nonlinear Vm were reported.
First, unlike in linear systems, strong shocks applied during the
plateau phase of the action potential (AP) in isolated guinea pig
papillary muscles,8 9 in cultured strands of neonatal rat
myocytes,10 11 and in isolated guinea pig
myocytes12 induced asymmetrical changes with negative
Vm
(V-m) larger than
positive Vm
(V+m). Second, with
increasing shock strength the amplitude of Vm
in cardiac tissue did not increase proportionally but reached a
saturation level.8 9 11 Third, large negative
Vm in cultured cell monolayers11
and in isolated myocytes12 exhibited a nonmonotonic
behavior whereby a strong initial hyperpolarization
was followed by a positive shift of Vm.
The mechanisms of these nonlinear Vm changes are
not known. The Vm asymmetry with
V-m>V+m
reflects an increase of the net outward current. We hypothesized that
such Vms are related to modulation of activity
of ionic channels. During the early plateau phase of AP, the main
currents in neonatal rat myocytes are the calcium current
(ICa) and the transient outward current
(Ito). To understand the role of these
currents in the Vm asymmetry, we investigated
the effect of respective channel blockers on
Vm. Because Vm changes
are dependent on the geometry of cardiac tissue and electric field,
experiments were performed with uniform-field shocks in geometrically
defined strands of cultured myocytes. Also, because electrotonic
interaction between the areas depolarized and hyperpolarized by shocks
can affect the Vm
changes,11 conditions with both strong and weak
electrotonic interaction were studied using narrow (width<
, the
electrotonic space constant) and wide (width>) strands,
respectively.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
|---|
Cell Cultures
Ventricular myocytes from 2-day-old Wistar rats were grown in cell strands (Figure 1A
) using
the technique of directed cell growth.11 13 The widths of
the strands (Figure 1B) were 0.2 and 0.8 mm, below or above
the space constant (0.35 mm).14 Strands were first
incubated in medium M199 (Life Technologies) containing Earl’s salts,
20 mmol/L HEPES, 10% FBS (Sigma), 20 µg/mL vitamin
B12, and antibiotics at 37°C in a humidified
atmosphere of 5% CO2. Starting on the second
day, a serum-free medium, UltraCulture (BioWhittaker), was used.
To stimulate cell beating, the medium was supplemented with 2
µmol/L norepinephrine.
|
Optical Measurements of Vm
After 4 to 6 days in culture, monolayers were transferred into a
perfusion bath and superfused with Hanks solution (Life Technologies)
with pH 7.4 and temperature 35°C to 36°C. Cells were stained for 3
to 6 minutes with 2.5 µmol/L of the
Vm-sensitive dye RH-237 (Molecular Probes).
Optical measurements were performed at areas without visible anatomic
discontinuities in monolayer structure. The dye fluorescence
was measured using a 16x16-photodiode array (Hamamatsu) and a
microscopic mapping system described previously.11 The
bandwidth of the system was 1 kHz. With 10x, 20x, and 40x objectives
used, the spatial resolution (center-to-center interdiode distance) was
110, 55, and 27.5 µm, respectively, and the sampling rate was 10
kHz per channel.
The cells were paced at a cycle length of 500 ms. Rectangular
uniform-field shocks (duration 10 ms) were applied via 2 large platinum
electrodes positioned at the bath ends (Figure 1A
). The field
strength, E, was measured in the bath using a bipolar silver
electrode (wire diameter 0.1 mm, interelectrode distance 1.1
mm). Delivery of shocks was synchronized with stimulation pulses. The
delay between AP upstroke and onset of the shocks was 9 to 18 ms. Two
channel blockers were applied: ICa
inhibitor nifedipine (2 µmol/L) and
Ito inhibitor
4-aminopyridine (4-AP; 2 mmol/L). Because
nifedipine is photosensitive, a fresh solution was prepared
in the dark for each day of use.
Shock-induced Vm was measured as the
difference between a linear fit of the plateau phase and the magnitude
of the shock response 5 ms after shock onset (Figure 1C). The
fit was determined using linear regression of the signal during the
5-ms interval before shock application. Comparison with a
recording without shock shows that the fitting procedure
allowed the reduction of errors in Vm
associated with changes in fluorescence intensity due to
factors other than the shock. The Vm was
normalized by the AP amplitude (APA). The degree of
Vm asymmetry was characterized by the ratio of
V-m and
V+m measured at the opposite
strand edges. Vms at the edges were spatially
averaged including only those signals that had a constant slope before
shock application. Data were expressed as mean±SD. Differences were
compared using the 2-tailed paired t test. All statistical
probability values are expressed for differences from control
conditions. Results were considered statistically significant if
P<0.05.
To ensure uniformity of cell properties, only those strands were
selected for analysis that exhibited no major discontinuities
in activation spread and spatial distribution of
Vm and had conduction velocity >20 cm/s and
normalized maximal upstroke rate of rise >80 V/s. Experiments were
performed in a total of 37 strands from 26 cell monolayers produced in
7 cell cultures.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
|---|
Effect of Nifedipine on
VmNarrow Strands
Figure 2
presents results of a
typical experiment in a strand 0.22 mm in width. Figure 2A
compares the Vm traces obtained in control
conditions, after 5 minutes of perfusion with 2 µmol/L of
nifedipine, and 15 minutes after washout from a horizontal
row of photodiodes shown in Figure 2B. The strength of the shock
field was 16.4, 16.2, and 16.1 V/cm, respectively. The shocks were
applied during the early plateau phase of the AP, 
12 ms after the AP
upstroke. In control conditions, the shock induced depolarization on
the left side of the strand and hyperpolarization
on the right side with a linear transition in between (Figure 2C). The spatial distribution of Vm
across the strand was rather uniform (Figure 2B) and strongly
asymmetrical with a much larger portion of the strand being
hyperpolarized than depolarized; the asymmetry ratio was 1.96. Such
asymmetrical Vm changes were described previously
as nonlinear Vms of type
II.11
|
Application of nifedipine increased the amplitudes of
V+m and decreased the
amplitudes of V-m at
all sites (Figure 2A, thick traces), preserving the uniformity
(Figure 2B) and linearity (Figure 2C) of the
Vm distribution. The overall effect of
nifedipine on Vm was a positive
shift of Vm without changing the slope of the
spatial Vm gradient (Figure 2C). As a
result, the 0 isoline in the map of Vm
distribution (Figure 2B) shifted toward the center of the
strand, reflecting the reduction in the asymmetry of
Vm distribution. The maximal
V+m increased from 94 to
119%APA, and maximal
V-m decreased from
-184 to –156%APA; the Vm asymmetry ratio
decreased from 1.96 to 1.31. At the same time, the sum of
V+m and
V-m remained nearly
constant. After washout from nifedipine for 15 minutes,
Vm changes were similar to control (thin gray
traces).
Similar results were obtained in 8 strands measuring 0.2 mm in
width. The data from these experiments are summarized in Figure 2D. The mean shock strength was 15.3±1 V/cm. The maximal
V+m was 66±8%APA in
control, and it increased during nifedipine application to
88±16%APA (P<0.001), which represents a change of
34%. On washout, the V+m
returned to the control value (67±9%APA). Nifedipine
caused a reversible decrease of the mean maximal
V-m from 139±14% to
126±20%APA (P<0.05). As a result, the
Vm asymmetry ratio decreased from 2.14±0.4 to
1.5±0.4 (P<0.001) and returned to the control value
(2.07±0.3, NS) after washout.
On average, nifedipine induced a small (5%) and
reversible increase of the sum of
V+m and
V-m from 204±13 to
214±16%APA (P<0.05). In narrow strands (width<<),
V+m+V-m
should remain constant (see Appendix). Therefore, the small increase in
the optically measured
V+m+V-m
can be attributed to a decrease of APA caused by
nifedipine.15 Also,
nifedipine slightly decreased the conduction velocity
(37±5 versus 34±6 cm/s, P<0.05), whereas changes in the
maximal upstroke rate of rise (100±15 versus 95±13 V/s) were not
statistically significant.
To test whether the effect of nifedipine was different for
small and symmetrical Vms described
previously,11 measurements were carried out at lower shock
strengths. Figures 3A and 3B
illustrate a typical measurement, and Figure 3C presents
statistical data from 6 strands. The shock strength in these
measurements was 2.3±0.1 V/cm inducing nearly equal maximal
V+m and
V-m (16.8±3.0 and
18.7±3.2%APA, NS). Nifedipine caused small increases in
both V+m and
V-m (to 21.3±2.7 and
22.2±4.3%APA) without changing the asymmetry ratio (1.13±0.2 versus
1.05±0.2%APA, NS).
|
Wide Strands
To test whether the strand width modulated the effects of
nifedipine on Vm, measurements
were performed in strands 0.8 mm in width. The shock strength in
these experiments was adjusted to produce asymmetrical
Vm with magnitudes similar to the ones
observed in the narrow strands. Figures 4A through 4C present a typical
example of Vm caused by 10.8 V/cm (control)
and 10.6 V/cm (nifedipine) shocks. The spatial distribution
of Vm was uniform (Figure 4B) and
nonlinear (Figure 4C), as expected from
Vm in strands with width larger than . The
maximal amplitudes of V+m and
V-m were 57 and
-200%APA, respectively, resulting in the asymmetry ratio of 3.5. As
in the narrow strands, application of nifedipine caused a
strong increase of the V+m
(100%APA). Contrary to the narrow strands, however, the maximal
V-m slightly increased
(–207%APA). The increase of
V+m reduced the asymmetry
ratio to 2.1.
|
Similar results were obtained in 8 strands measuring 0.8 mm in
width (Figure 4D). The mean shock strength was 9.3±0.8 V/cm. In
the control, the magnitudes of maximal
V+m and
V-m were 83±8 and
156±17%APA, respectively. Nifedipine caused a large and
reversible increase of V+m to
107±11%APA (P<0.001), which represents a change
of 70%, and a small increase of
V-m to 171±20%APA
(P<0.001). Because of the increase of
V+m, the
Vm asymmetry was reduced from 2.52±0.5 to
1.62±0.2 (P<0.001).
Effect of 4-AP on Vm
The effects of 4-AP (2 mmol/L) on shock-induced
Vm were determined in 7 narrow strands. In 6
of 7 strands, 4-AP caused a small reduction in
V+m and
V-m, whereas in 1
strand they were slightly increased. Figure 5A presents an example of the
Vm recordings during application of a
15.6 V/cm shock in which Vm was decreased. For
simplicity, only the traces measured at the strand edges with maximal
V+m and
V-m are shown. The
relative changes in V+m and
V-m were similar, which
is reflected in the decrease of the slope of the spatial profile of
Vm with only a slight shift of the 0 point
(Figure 5B), reflecting no change in the
Vm asymmetry. Figure 5C presents
data of Vm measurements in the 6 strands in
which Vm was decreased. 4-AP caused small
reductions in the average
V+m,
V-m and
V+m+V-m,
but no change in the asymmetry ratio in these strands or in the
remaining strand. The decrease of
V+m+V-m
without change of the
V-m/V+m
can be attributed to a decrease of the APA and not to changes in
Vm per se.
|
Effect of Shocks on Diastolic Vm
It has been previously suggested that Vm
asymmetry is caused by membrane electroporation.16
Membrane electroporation is typically manifested by reduction of
diastolic potential after shock application.17
To test whether shocks induced such changes of Vm
in cell cultures, 500-ms recordings of Vm
were carried out in 4 narrow strands (shock strength 18.7±2 V/cm) and
4 wide strands (shock strength 9.8±0.9 V/cm). Figure 6 compares Vm
recordings with and without a shock in a typical case with
asymmetrical Vm (Figure 6A) caused by
9.9 V/cm shock in a 0.8-mm strand. The repolarization phase of the AP
(Figure 6B), although being compromised by the motion artifact,
was not significantly different in traces with and without shock. Most
importantly, there were no changes in the diastolic level
of Vm, indicating an absence of electroporation.
Similar results were obtained in all 8 strands.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
|---|
Understanding the mechanisms of Vm changes induced by an electric field is essential for understanding the mechanism of defibrillation. In the present work, we used ionic channel blockers to evaluate the contribution of Ca2+ and potassium ionic currents in the nonlinear Vm changes in cultured monolayers of neonatal rat myocytes. The most important findings of this work are that (1) blocking the L-type Ca2+ current with nifedipine caused an increase in the shock-induced
V+m and a reduction in the
Vm asymmetry, (2) application of the
Ito blocker 4-AP did not reduce the
Vm asymmetry, and (3) effects of the drugs on
Vm were modulated by the tissue geometry.
Roles of K+ Currents in Nonlinear
Vm
The asymmetry in the shock-induced Vm
with larger negative than positive Vm changes
reflects an increase in the net outward current. Therefore, it could be
expected that the mechanism of the Vm
asymmetry was related to the flow of an outward
K+ current and application of potassium channel
blockers should reduce the degree of the Vm
asymmetry. In a previous study, we tested the effects of barium
chloride and dofetilide, inhibitors of inward rectifier and
delayed rectifier potassium currents.11 Neither of these
channel blockers reversed the asymmetrical distribution of
Vm. Another possible candidate for such an
outward current is Ito, which is prominent
during the early plateau phase.15 We found that
application of Ito blocker 4-AP reduced
both V-m and
V+m without change in the
Vm asymmetry ratio (Figure 5). Part of
the changes in the optically measured Vm
caused by 4-AP might be attributed to the effect of 4-AP on the APA. An
increase of APA by 4-AP is indicated by the decrease of
V-m+V+m
(Figure 5C). Because APA was used to normalize
Vm measurements, an increase of APA by 4-AP
can explain the apparent decrease of Vm.
Importantly for the questions addressed in this work, however, 4-AP did
not change the asymmetry ratio, which excludes
Ito as the outward current responsible for
the mechanism of Vm asymmetry. On the basis of
these results, as well as the results of the previous
study,11 it can be concluded that the outward
potassium currents are not responsible for the asymmetrical nonlinear
dynamics of Vm in myocyte cultures.
Role of Ca2+ Current in Nonlinear
Vm
Quite unexpectedly, it was found that the asymmetrical nonlinear
behavior of Vm was reversed by application of
Ca2+ channel blocker nifedipine. As
seen in Figures 2 and 4, nifedipine caused a
strong increase in the magnitude of the maximal positive
Vm, but either no change (wide strands) or a
decrease (narrow strands) of the negative Vm.
In both cases, the Vm asymmetry was strongly
reduced.
As we argue below, the effect of nifedipine on the
V-m in the narrow
strands was not direct but was mediated via electrotonic interaction
with the area of positive Vm. Thus, the key
effect of nifedipine was the increase of the
V+m. In general, 2 different
explanations for this effect are possible. First,
nifedipine could directly affect the
V+m. Second, similarly to the
effect of 4-AP, nifedipine could affect APA, thus changing
the optically measured V+m.
Although it is known that nifedipine can slightly reduce
APA in neonatal rat myocytes,15 this effect does not
explain the available data. Indeed, the degree of the APA change can be
inferred from the change in the sum of optical
V+m and
V-m in the narrow
strands. This sum equals E*L/APA, where E and L are the field strength
and the strand width, respectively (see Appendix). As shown in Figure 2D, this parameter changed in average by only
5%. The average change in
V+m was 6-fold larger in the
narrow strands (33%) and >10-fold larger in the wide strands
(73%). Another argument against this interpretation is that
nifedipine strongly reduced the asymmetry ratio, which is
independent of APA. Thus, the APA changes cannot account for the
measured changes in the optical Vm.
More likely, nifedipine caused a direct effect on the
shock-induced V+m. The fact
that nifedipine increased
V+m indicates that the flow
of Ca2+ current in control conditions prevented
the positive changes of Vm or, in other words,
ICa was directed outward. Normally,
ICa is inward but it changes direction when
the Vm is above the reversal potential. This line
of reasoning leads to a conclusion that the Vm
asymmetry was caused by the outward flow of
ICa in the depolarized portions of strands
when the Vm levels exceeded the
ICa reversal potential. According to
patch-clamp studies, the ICa reversal
potential in rat and rabbit myocytes is 45 to 50
mV.18 19 The magnitudes of the
nifedipine-sensitive
V+m caused by strong shocks
were higher in this study, which is consistent with the idea
that ICa was outwardly directed in these
portions of the strands. This explanation of the
Vm asymmetry is also supported by measurements
using weak shocks, which showed no sensitivity of the
Vm ratio to nifedipine when
Vms were 20%APA. Assuming that the APA was
100 mV and the plateau level was 20 mV, this level is close to the
ICa reversal potential.
In addition to the effect of Vm asymmetry,
involvement of Ca2+ current might also explain
the saturation of positive Vm observed during
strong shocks.9 11 Previously, the effect of
Vm saturation was linked to a nonspecific
increase in membrane conductance caused by membrane
electroporation.16 However, saturation of positive
Vm was observed in cardiac tissue at
Vm levels of 100 mV,9 11
whereas electroporation in voltage-clamp experiments typically occurred
at Vm >300 mV.17 Furthermore,
shocks caused no change in the diastolic potential (Figure 6), which is expected from electroporation.17
Therefore, results of this study indicate that the ionic properties of
the cell membrane reduce the likelihood of reaching very high
Vm levels, thus protecting cardiac cells from the
detrimental effects of strong electric shocks.17
Modulation of Drug Effects by Tissue Structure
An interesting feature of the effects of drugs on
Vm is that they were strongly dependent
on the tissue structure. Thus, nifedipine caused reduction
of the negative Vm in the narrow strands
(Figure 2) but not in the wide strands (Figure 4). The
decrease of V-m in the
narrow strands was likely not due to the effects of
nifedipine on the channel properties at these locations but
was rather due to the electrotonic interaction between the depolarized
and hyperpolarized areas. Because of a strong electrotonic interaction
in the narrow strands, any charge entering intracellular space on one
side of the strand should quickly redistribute across the strand,
causing equivalent shifts of Vm at all sites, as
in Figure 2. When the area of
hyperpolarization is "buffered" from the area
of depolarization, the
V-m was much less
affected by the shock (Figure 4).
Overall, these results indicate that the effects of shocks on Vm in cardiac tissue are a result of dynamic interaction among several factors, including active properties of cell membrane, myocardial structure, and passive tissue properties, as well as applied electric field.
Limitations
Extrapolation of the results of this study to the intact adult
myocardium can be potentially limited by differences in the
ultrastructural and ionic channel properties between neonatal and adult
myocytes. Particularly, the cellular distribution of gap junctions is
different in cells of these 2 types.20 21 22 This difference
might affect distribution of the shock-induced
Vm on the subcellular scale, but it should not
play a significant role in Vm measured on a
scale larger than cell size. In the context of this study, a more
important factor is the species- and age-dependent differences in
properties of ionic currents.23 24 25 26 27 Nevertheless, the fact
that the same types on nonlinear Vm were
observed both in neonatal rat10 11 and in adult guinea
pig8 9 12 preparations suggests that response of
Vm to defibrillation shocks shares common
mechanisms.
|
Acknowledgments |
|---|
This work was supported by a grant from the Whitaker Foundation (to V.G.F.) and NIH Grant HL-42760 (to R.E.I.). We thank Windy Jones for her help with preparation of the cell cultures.
|
Appendix 1 |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
|---|
Magnitude of (
V+m+V-m) in
Narrow StrandsWhen strand width, L, is much smaller than the electrotonic space constant,
, the intracellular potential,
Vi, is constant across the strand. Therefore, any
change in Vm
(Vm=Vi-Ve,
where Ve is extracellular potential) across a
strand is due to changes in Ve, or
 |
V+e+V-e,
is equal to E*L, where E is field strength. Therefore,
 |
Vm,
 |
Received June 30, 2000; revision received July 21, 2000; accepted July 21, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
|---|
1. Rattay F. Analysis of models for extracellular fiber stimulation. IEEE Trans Biomed Eng. 1989;36:676–682.[Medline] [Order article via Infotrieve]
2. Sepulveda NG, Roth BJ, Wikswo JP. Current injection into a two-dimensional anisotropic bidomain. Biophys J. 1989;55:987–999.[Medline] [Order article via Infotrieve]
3. Wikswo J. Tissue anisotropy, the cardiac bidomain, and the virtual electrode effect. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: WB Saunders Co Inc; 1995:348–361.
4. Muzikant A, Henriquez C. Bipolar stimulation of a three-dimensional bidomain incorporating rotational anisotropy. IEEE Trans Biomed Eng. 1998;45:449–462.[Medline] [Order article via Infotrieve]
5. Plonsey R, Barr R. Inclusion of junction elements in a linear cardiac model through secondary sources: application to defibrillation. Med Biol Eng Comput. 1986;24:137–144.[Medline] [Order article via Infotrieve]
6. Krassowska W, Pilkington T, Ideker R. Periodic conductivity as a mechanism for cardiac stimulation and defibrillation. IEEE Trans Biomed Eng. 1987;34:555–560.[Medline] [Order article via Infotrieve]
7. Sobie E, Susil R, Tung L. A generalized activating function for predicting virtual electrodes in cardiac tissue. Biophys J. 1997;73:1410–1423.[Medline] [Order article via Infotrieve]
8. Zhou XH, Rollins DL, Smith WM, Ideker RE. Responses of the transmembrane potential of myocardial cells during a shock. J Cardiovasc Electrophysiol. 1995;6:252–263.[Medline] [Order article via Infotrieve]
9.
Zhou X, Smith W, Rollins D, Ideker R. Transmembrane
potential changes caused by shocks in guinea pig papillary muscle.
Am J Physiol. 1996;271:H2536–H2546.
10.
Gillis AM, Fast VG, Rohr S, Kléber AG. Effects of
defibrillation shocks on the spatial distribution of the transmembrane
potential in strands and monolayers of cultured neonatal rat
ventricular myocytes. Circ Res. 1996;79:676–690.
11.
Fast VG, Rohr S, Ideker RE. Non-linear changes of
transmembrane potential caused by defibrillation shocks in strands of
cultured myocytes. Am J Physiol. 2000;278:H688–H697.
12.
Cheng DK, Tung L, Sobie EA. Nonuniform responses of
transmembrane potential during electric field stimulation of single
cardiac cells. Am J Physiol. 1999;277:H351–H362.
13.
Rohr S, Schölly DM, Kléber AG. Patterned
growth of neonatal rat heart cells in culture: morphological and
electrophysiological characterization.
Circ Res. 1991;68:114–130.
14. Jongsma HJ, van Rijn HE. Electrotonic spread of current in monolayer cultures of neonatal rat heart cells. J Membr Biol. 1972;9:341–360.[Medline] [Order article via Infotrieve]
15. Fermini B, Schanne OF. Determinants of action potential duration in neonatal rat ventricle cells. Cardiovasc Res. 1991;25:235–243.[Medline] [Order article via Infotrieve]
16. DeBruin KA, Krassowska W. Electroporation and shock-induced transmembrane potential in a cardiac fiber during defibrillation strength shocks. Ann Biomed Eng. 1998;26:584–596.[Medline] [Order article via Infotrieve]
17. Tung L. Detrimental effects of electrical fields on cardiac muscle. Proc IEEE. 1996;84:366–378.
18.
Yuan W, Ginsburg KS, Bers DM. Comparison of sarcolemmal
calcium channel current in rabbit and rat ventricular
myocytes. J Physiol (Lond). 1996;493:733–746.
19. Gomez JP, Potreau D, Branka JE, Raymond G. Developmental changes in Ca2+ currents from newborn rat cardiomyocytes in primary culture. Pflugers Arch. 1994;428:241–249.[Medline] [Order article via Infotrieve]
20.
Darrow BJ, Laing JG, Lampe PD, Saffitz JE, Beyer EC.
Expression of multiple connexins in cultured neonatal rat
ventricular myocytes. Circ Res. 1995;76:381–387.
21.
Darrow BJ, Fast VG, Kléber AG, Beyer EC, Saffitz
JE. Functional and structural assessment of intercellular
communication: increased conduction velocity and enhanced connexin
expression in dibutyryl cAMP-treated cultured cardiac myocytes.
Circ Res. 1996;79:174–183.
22. Peters NS. New insights into myocardial arrhythmogenesis: distribution of gap-junctional coupling in normal, ischaemic and hypertrophied human hearts. Clin Sci (Colch). 1996;90:447–452.[Medline] [Order article via Infotrieve]
23.
Cohen NM, Lederer WJ. Changes in the calcium
current of rat heart ventricular myocytes during
development. J Physiol (Lond). 1988;406:115–146.
24.
Kilborn M, Fedida D. A study of the developmental
changes in outward currents of rat ventricular myocytes.
J Physiol (Lond). 1990;430:37–60.
25.
Osaka T, Joyner RW. Developmental changes in
calcium currents of rabbit ventricular cells. Circ
Res. 1991;68:788–796.
26.
Huynh TV, Chen F, Wetzel GT, Friedman WF, Klitzner TS.
Developmental changes in membrane Ca2+ and
K+ currents in fetal, neonatal, and adult rabbit
ventricular myocytes. Circ Res. 1992;70:508–515.
27.
Wahler GM. Developmental increases in the inwardly
rectifying potassium current of rat ventricular myocytes.
Am J Physiol. 1992;262:C1266–C1272.
This article has been cited by other articles:
 |
|
 |
|
  E. Vigmond, F. Vadakkumpadan, V. Gurev, H. Arevalo, M. Deo, G. Plank, and N. Trayanova Towards predictive modelling of the electrophysiology of the heart Exp Physiol, May 1, 2009; 94(5): 563 - 577. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Raman, A. E. Pollard, and V. G. Fast Shock-induced changes of Cai2+ and Vm in myocyte cultures and computer model: Dependence on the timing of shock application Cardiovasc Res, January 1, 2007; 73(1): 101 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Pollard and R. C. Barr Cardiac microimpedance measurement in two-dimensional models using multisite interstitial stimulation Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1976 - H1987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Trayanova Defibrillation of the heart: insights into mechanisms from modelling studies Exp Physiol, March 1, 2006; 91(2): 323 - 337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Y. Sidorov, M. C. Woods, P. Baudenbacher, and F. Baudenbacher Examination of stimulation mechanism and strength-interval curve in cardiac tissue Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2602 - H2615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. P. Nikolski and I. R. Efimov Electroporation of the heart Europace, January 1, 2005; 7(s2): S146 - S154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ashihara and N. A. Trayanova Cell and tissue responses to electric shocks Europace, January 1, 2005; 7(s2): S155 - S165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. F. Sharifov, R. E. Ideker, and V. G. Fast High-resolution optical mapping of intramural virtual electrodes in porcine left ventricular wall Cardiovasc Res, December 1, 2004; 64(3): 448 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. G. Fast, E. R. Cheek, A. E. Pollard, and R. E. Ideker Effects of Electrical Shocks on Cai2+ and Vm in Myocyte Cultures Circ. Res., June 25, 2004; 94(12): 1589 - 1597. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. F. Sharifov and V. G. Fast Intramural Virtual Electrodes in Ventricular Wall: Effects on Epicardial Polarizations Circulation, May 18, 2004; 109(19): 2349 - 2356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Cheek and V. G. Fast Nonlinear Changes of Transmembrane Potential During Electrical Shocks: Role of Membrane Electroporation Circ. Res., February 6, 2004; 94(2): 208 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. P. Nikolski, A. T. Sambelashvili, V. I. Krinsky, and I. R. Efimov Effects of electroporation on optically recorded transmembrane potential responses to high-intensity electrical shocks Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H412 - H418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. T. Sambelashvili, V. P. Nikolski, and I. R. Efimov Nonlinear effects in subthreshold virtual electrode polarization Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2368 - H2374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y-M Song and R Ochi Hyperpolarization and lysophosphatidylcholine induce inward currents and ethidium fluorescence in rabbit ventricular myocytes J. Physiol., December 1, 2002; 545(2): 463 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. G. Fast, O. F. Sharifov, E. R. Cheek, J. C. Newton, and R. E. Ideker Intramural Virtual Electrodes During Defibrillation Shocks in Left Ventricular Wall Assessed by Optical Mapping of Membrane Potential Circulation, August 20, 2002; 106(8): 1007 - 1014. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. G. Fast and E. R. Cheek Optical Mapping of Arrhythmias Induced by Strong Electrical Shocks in Myocyte Cultures Circ. Res., April 5, 2002; 90(6): 664 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. P. Nikolski, A. T. Sambelashvili, and I. R. Efimov Mechanisms of make and break excitation revisited: paradoxical break excitation during diastolic stimulation Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H565 - H575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Mowrey, Y. Cheng, P. J. Tchou, and I. R. Efimov Kinetics of defibrillation shock-induced response: design implications for the optimal defibrillation waveform Europace, January 1, 2002; 4(1): 27 - 39. [Full Text] [PDF]
|
|
|
|
|
|
I. R. Efimov A Shocking Experience : Ionic Modulation of Virtual Electrodes in Defibrillation Circ. Res., September 15, 2000; 87(6): 429 - 430. [Full Text] [PDF]
|
|
|
|
|
|
V. G. Fast and E. R. Cheek Optical Mapping of Arrhythmias Induced by Strong Electrical Shocks in Myocyte Cultures Circ. Res., April 5, 2002; 90(6): 664 - 670. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||