© 1997 American Heart Association, Inc.
Articles |
Developmental Changes in Transient Outward Current in Mouse Ventricle
From the Department of Medicine, University of Calgary (Canada).
Correspondence to H.J. Duff, MD, FRCPC, Department of Medicine, University of Calgary, 3330 Hospital Dr, NW, Calgary, Alberta, Canada, T2N 4N1.
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Abstract |
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Abstract Developmental changes in the transient outward K+ current (Ito) in mouse ventricular myocytes were assessed by the whole-cell patch-clamp technique. The density of Ito in mouse ventricular myocytes was significantly increased from the day-1 neonate to the adult. At +50 mV, the density of Ito was 3±1 pA/pF in the day-1 neonate, 15±3 pA/pF in the day-14 neonate, and 19±4 pA/pF in the adult (P<.01). Unlike other species, the rate of Ito inactivation significantly slowed in mouse ventricular cells during development. Moreover, the time courses of inactivation and recovery from inactivation of Ito were well described by a monoexponential function in day-1 neonatal cells, whereas they were best fitted by a biexponential function in day-14 neonatal and adult cells. The characteristics of steady state inactivation were also significantly different in day-1 neonatal cells (half-inactivation potential [Vh]=-66±4 mV, slope factor [k]=12±2 mV), in day-14 neonatal cells (Vh=-40±3 mV, k=13±1 mV), and in adult cells (Vh=-34±4 mV, k=6±1 mV). Microelectrode studies revealed that action potential duration progressively decreased in mouse ventricles during normal postnatal development. In addition, 4-aminopyridine (1 mmol/L) prolonged action potential duration more in adult than in neonatal mouse ventricles, suggesting that the developmental increase in the density of Ito contributes to the age-related shortening of action potential duration in mouse ventricles. In conclusion, Ito in adult mouse ventricular myocytes exhibits a higher density, slower inactivation kinetics, and a relatively more positive half-inactivation potential. All these characteristics result in Ito being a physiologically more important repolarizing K+ current in adult than in neonatal mouse hearts.
Key Words: transient outward K+ current • ventricular myocytes, mouse • postnatal development
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The voltage-dependent Ca2+-independent Ito has been recorded in mammalian cardiac myocytes from many species.1 2 3 4 5 Because of its rapid activation kinetics, Ito is responsible for the rapid initial phase of action potential repolarization. Recent studies have shown that in addition to its important role in electrophysiological heterogeneity in the heart,4 6 7 8 expression of Ito is also profoundly species and age dependent.9 10 11 12 13 Furthermore, age-related changes in cardiac action potential configuration have been postulated to be associated with developmental alteration in Ito in many species.10 11 However, only limited studies have focused on developmental expression of Ito and its functional role in the mouse heart. Davies et al14 studied the expression of Ito in mouse cardiac myocytes only during intrauterine development. Since the type and the density of other K+ currents are remarkably altered in the mouse ventricle after birth,15 the purpose of this investigation was to study the expression of Ito in the mouse ventricle during normal postnatal development. In the present study, we show that the density of Ito increases significantly and that its inactivation properties are profoundly altered in mouse ventricular myocytes during normal postnatal development. The results of the present study provide prerequisite knowledge for studying or designing transgenic mice with altered K+ channel expression in the heart. These results are also very useful for the understanding of K+ channel regulation in the mouse heart during normal development.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Neonatal day-1, neonatal day-14, and adult CD-1 mice were used for the present study. The mice were handled in accordance with our institutional guidelines for animal use in research.
Single Ventricular Myocyte Isolation
Single ventricular myocytes from day-1 neonatal mice
were isolated and cultured by a previously described
method,16 and single ventricular myocytes from
day-14 neonatal and adult mice were isolated by a previously described
Langendorff perfusion technique.15
Whole-Cell Patch-Clamp Recording
Macroscopic K+ currents were recorded by the
whole-cell patch-clamp method with an Axopatch 200 amplifier (Axon
Instruments). Electrodes had tip resistances of 1 to 4 M
for adult,
day-14, and day-1 neonatal myocytes when filled with an internal
solution containing (mmol/L) potassium aspartate 110, MgCl2
4, K2ATP 4.2, CaCl2 1, NaCl 8, HEPES 5, and
EGTA 10, pH 7.2 adjusted with KOH. A liquid junction potential of 
10
mV (pipette negative) was corrected electrically. Mouse
ventricular myocytes were superfused at 2 mL/min at room
temperature (22°C) with a HEPES-buffered Tyrode's solution
containing (mmol/L) NaCl 140, KCl 4, MgCl2 1,
CaCl2 1, glucose 5.5, and HEPES 10, pH 7.4 adjusted with
NaOH. L-Type Ca2+ current was blocked by CdCl2
(0.3 mmol/L). For action potential recordings, mouse
ventricular myocytes were perfused with normal Tyrode's
solution in the absence of Ca2+ channel blocker. The cell
capacitance and series resistance were measured and calculated from the
uncompensated capacity current transients elicited by a 10-mV
hyperpolarizing voltage step from a holding potential of -80 mV.
Series resistance was checked regularly to ensure no variations with
time. If the series resistance increased during the course of a
recording, the data were discarded.
Action potentials from single ventricular cells were recorded at room temperature in the current-clamp mode of the whole-cell patch clamp. The membrane currents and action potentials were monitored on a storage oscilloscope, digitized, and stored on an IBM AT computer. Data acquisition was performed using a TL-1 DMA interface and pCLAMP software (Axon Instruments).
In addition, developmental changes of the action potential configuration in mouse ventricles were also assessed by a conventional microelectrode technique.15 Briefly, right ventricular myocardium was isolated from day-1 neonatal, day-14 neonatal, and adult mouse hearts. The preparations were superfused with an oxygenated Tyrode's solution at 37°C. The myocardial preparations were constantly paced at 2 Hz, and action potentials were recorded before and after exposure to an Ito channel blocker, 4-AP.
Data Analysis
Whole-cell patch-clamp data were analyzed using CLAMPFIT
software and plotted using the Fig P graphic software (Biosoft,
Cambridge, NJ). The action potential configurations recorded from
microelectrode experiments were stored, processed, and analyzed
using CELLSOFT (D. Bergman, University of Calgary [Canada]). All
averaged and normalized data were presented as mean±SE unless
otherwise indicated. Statistical significance among groups was
determined using one-way ANOVA. A value of P<.05 was
considered significantly different. To define the difference between
the subgroups compared within ANOVA, such as the day-1 neonatal group
versus the adult group, Dunnett's multiple-range test was used.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Age-Related Changes in Morphology of Mouse Ventricular Myocytes With Light Microscopy
Fig 1
shows phase-contrast photomicrographs of
mouse ventricular myocytes taken on a Zeiss Axiovert
inverted microscope equipped with a Contax SLR camera. The appearance
of mouse ventricular myocytes changes remarkably during
development. One day after birth, mouse ventricular
myocytes were spherical in appearance without visible striations (Fig 1A). After short-term cell culture (24 hours), day-1 neonatal cells
flattened and spread somewhat (Fig 1B). Two weeks after birth, mouse
ventricular myocytes were spindle-shaped, and most cells
had considerably less prominent striations than adult cells (Fig 1C).
In general, day-14 neonatal mouse ventricular myocytes were
less than half of the width of adult mouse ventricular
myocytes. Adult mouse ventricular cells were rod-shaped and
exhibited clear cross striations (Fig 1D).
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As shown in Fig 1
, in addition to changes in the shape of mouse
ventricular myocytes, changes in the size of mouse
ventricular cells also occur during development. The
average capacitance of mouse ventricular myocytes was 24±2
pF for day-1 neonatal mice, which significantly increased to 75±5 pF
for day-14 neonatal mice and 136±9 pF for adult mice
(P<.01).
Current-Voltage Relationships and Density
Fig 2 illustrates the
representative superimposed outward currents elicited
by the protocol shown in the inset. The amplitude of the peak outward
currents significantly increased from day-1 neonatal (Fig 2A) to day-14
neonatal (Fig 2B) and adult (Fig 2C) mouse ventricular
myocytes. The inactivation process of the current was incomplete in all
three age groups, suggesting that the peak outward current consists of
at least two components. Thus, the increase in the peak outward current
may be due to an increase in Ito only, an
increase in Isus only, or the combination of
both. Therefore, the amplitudes of both peak current and
Isus were measured, and then
Ito was obtained by subtracting
Isus from the peak outward current.
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The current-voltage relationships of Ito and
Isus from each age group are illustrated in Fig 3. As shown in Fig 3A, activation of
Ito was voltage dependent in all three age
groups. The density of Ito normalized to cell
capacitance significantly increased in mouse ventricular
myocytes during development (Fig 3A). At +50 mV, the density of
Ito increased significantly from 3±1 pA/pF in
day-1 to 15±3 pA/pF in day-14 neonatal mouse ventricular
myocytes (P<.01). In adult mouse ventricular
myocytes, Ito further increased to 19±4 pA/pF.
An increase in the density of Isus was also
significant but less dramatic (Fig 3B). Therefore, the developmental
increase in the peak outward currents is mainly due to an increase in
Ito.
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Inactivation Kinetics of Ito
The inactivation rate of Ito in mouse
ventricular cells was obviously altered during postnatal
development (Fig 4). The current in day-1 neonatal
ventricular myocytes inactivated rapidly and
reached a steady state within 250 milliseconds. In contrast,
Ito in day-14 neonatal and adult mouse
ventricular myocytes inactivated slowly and did
not reach the steady state at the end of a 1000-millisecond
depolarization pulse.
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fast and
P<.05 for day-14 Neo vs adult cells. Panel
D displays the slow inactivation time constants of
Ito in day-14 Neo and adult mouse
ventricular myocytes. NS denotes no significant
differences.
The inactivation time constants of Ito in day-1
neonatal, day-14 neonatal, and adult mouse ventricular
myocytes were determined by an exponential fitting program in CLAMPFIT
software. The inactivation kinetics of Ito in
day-1 neonatal mouse ventricular myocytes were well
described by a monoexponential function, suggesting
that only one inactivation component contributes to the
Ito at this age stage (Fig 4A). However, the
inactivation time course of Ito in day-14
neonatal mouse ventricular myocytes was not well described
by a monoexponential equation, suggesting that there is
more than one inactivation component in day-14 neonatal and adult mouse
ventricular myocytes (Fig 4B). The inactivation time course
of Ito in adult mouse ventricular
cells did not fit to a monoexponential function either,
whereas the data from both neonatal day-14 and adult myocytes were very
well fitted with a biexponential function. The inactivation time
constants of Ito obtained from each of the age
groups were averaged and displayed in Fig 4C and 4D. Both fast and slow
inactivation time constants of Ito were voltage
independent at test potentials from +10 mV to +50 mV.
Steady State Inactivation of Ito
A two-pulse protocol was used to assess the voltage dependence of
steady state inactivation of Ito. The prepulses
were used to depolarize the cell to different membrane voltages ranging
from -100 to 0 mV for 5 seconds. Each prepulse was followed by a
single test pulse, which depolarized the cell to +50 mV.
Representative current traces elicited by this
double-pulse protocol from day-1 neonatal (Fig 5A),
day-14 neonatal (Fig 5C), and adult (Fig 5E) mouse
ventricular myocytes are shown. The peak currents evoked
from the prepulses of -90 to 0 mV were measured and normalized to the
value obtained from a prepulse of -100 mV. The amplitude of the peak
currents was reduced substantially when a prepulse progressively
depolarized the cell membrane from -100 to 0 mV, suggesting that the
number of available channels was decreased with membrane
depolarization. In Fig 5, panels B, D, and F are plots of the
normalized data obtained from day-1 neonatal, day-14 neonatal, and
adult mouse ventricular myocytes, respectively, as a
function of prepulse voltage. The curves through each data point
represent the best fit by the Boltzmann equation. The mean
values of Vh and k obtained by the Boltzmann equation for
day-1 neonates were -66±4 and 12±2 mV, respectively (n=6). Although
the k value of the steady state inactivation curve was unchanged in the
day-14 neonate (13±1 mV), its Vh was significantly shifted
to -40±3 mV (P<.05). Adult mouse ventricular
myocytes underwent steady state inactivation at a much more positive
potential, with a Vh value of -34±4 mV
(P<.05) and a steeper k value of 6±1 mV
(P<.05, n=5). These results indicate that in day-1 neonatal
mouse ventricular myocytes, Ito undergoes
substantially steady state inactivation at potentials close to the
resting membrane potential. For example, at -66 mV, at least 50% of
the available channels have been inactivated in day-1
neonatal mouse ventricular myocytes. In contrast, at -66
mV, almost 100% of the channels are still available in adult mouse
ventricular myocytes.
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20% at prepulse
potentials between -100 and -70 mV, indicating that the currents
undergo little steady state inactivation over these potentials in adult
mouse ventricular myocytes. In contrast, the amplitudes of
the currents in day-1 Neo mouse ventricular myocytes
decreased remarkably from the prepulse potentials between -100 and
-70 mV. At -70 mV, approximately half of the peak currents
inactivated.
Recovery From Inactivation
A double-pulse protocol was used to measure recovery of
Ito from inactivation. The first pulse
depolarized the membrane from -80 to +50 mV, which was followed by a
second pulse from -80 to +50 mV at variable interpulse intervals
to determine the fraction of available Ito at a
given recovery time. The representative examples of
such recordings from each age group are shown in Fig 6A (day 1), 6C (day 14), and 6E (adult). The recovery
time course of Ito from inactivation was best
fit by a monoexponential equation in day-1 neonatal
cells with a time constant of 133 milliseconds (Fig 6B). However, a
biexponential fit was required to adequately describe the recovery time
course of Ito in day-14 neonatal and adult
myocytes (Fig 6D and 6F, respectively). The fast recovery time
constants were 26 milliseconds for day-14 neonatal cells and 41
milliseconds in adult cells. The slow recovery time constants were 900
milliseconds for day-14 neonatal cells and 1620 milliseconds for adult
cells. In order to determine if the fast and slow components of
inactivation recover independently, the magnitudes of the peak current
and the fast and slow components derived from biexponential fits were
measured for the different interpulse intervals. For example, when the
interpulse interval was 275 milliseconds the fast component had
recovered completely, whereas the magnitude of the slow component had
recovered to only 60% of the control pulse in 14-day-old neonatal
myocytes. The finding that complete recovery of the fast component
occurred independent of the complete recovery of the slow component
suggests that the fast and slow components function independently.
Further molecular biological studies are required to confirm the
working hypothesis that different gene products underlie the
different components of Ito.
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Effects of 4-AP on Ito in Mouse
Ventricular Myocytes
4-AP is widely used as a blocker of
Ito.17 To examine effects of 4-AP
on Ito in day-1 neonatal, day-14 neonatal, and
adult mouse ventricular myocytes, a single depolarization
pulse was applied to mouse ventricular myocytes from -80
to +50 mV for 1000 or 3500 milliseconds. The current elicited by this
protocol was recorded drug free and after application of 4-AP
(1 mmol/L). As shown in Fig 7, 4-AP profoundly
decreased Ito in all three age groups. The
inhibition effect of 4-AP on Ito could be
reversed by washout with normal Tyrode's solution.
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) and then measured again after application of 4-AP (1
mmol/L) (
). Similar results were obtained in five cells in day-1
neonates, six cells in day-14 neonates, and eight cells in
adults.
Relations Between Developmental Changes in
Ito and Action Potential Configuration
The higher density, slower inactivation rate, and relatively more
positive Vh values of Ito in adult
mouse ventricular myocytes led to the hypothesis that these
developmental changes in Ito contribute to the
age-related shortening of cardiac action potential in mouse ventricles
during development. To test this hypothesis, Ito
and the action potential were recorded in the same cell before and
after application of 4-AP (2 mmol/L). When
Ito was inhibited by 4-AP, 4-AP also
significantly prolonged the action potential duration in adult mouse
ventricular cells (Fig 8A and 8B). In some
adult cells, after application of 4-AP, the cell failed to repolarize,
and early afterdepolarizations occurred (Fig 8C). The effects of 4-AP
on action potential duration in mouse ventricles were also assessed by
using the conventional microelectrode technique under more
physiological conditions. The right
ventricular myocardium from day-1 neonatal,
day-14 neonatal, and adult mice were perfused with normal Tyrode's
solution at 37°C and continuously paced at 2 Hz. As shown in Fig 9, the action potentials in each age group were
recorded before (open circle) and after (solid circle) the
application of 1 mmol/L 4-AP. In the absence of 4-AP, the action
potential recorded from day-1 neonatal myocardium
displayed a relatively small amplitude of phase-1 repolarization,
followed by a clear plateau. Action potential duration significantly
shortened in day-14 neonatal and adult myocardium.
Moreover, the initial phase of repolarization was considerably larger
and more rapid without a discernible plateau phase in day-14 neonatal
and adult mouse ventricular preparations. Although 4-AP
prolonged the action potential duration in all three age groups, the
percent prolongation of the action potential duration (relative to drug
free) increased during development. In review, our data show that
developmental changes in Ito are
physiologically relevant and contribute to
developmental changes in action potential configuration in the mouse
ventricle.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study shows that developmental changes in the morphology of mouse ventricular myocytes are temporally associated with profound increases in the density of Ito and changes in its inactivation properties. The inactivation rate of Ito slows during normal postnatal development in mouse ventricular myocytes, which is substantially different from previously reported data in other species. In addition, Vh of steady state inactivation occurs at a relatively negative potential (-66 mV) in day-1 neonatal cells compared with a relatively more positive Vh in adult mouse ventricular myocytes (-34 mV). These observations indicate that Ito is more physiologically important in adult than in neonatal mouse ventricles.
Developmental Changes in Ito
Age-related changes in the expression of cardiac
Ito have been investigated in many species,
including rats, rabbits, dogs, and humans.1 2 3 4 5 Recently,
Davies et al14 examined the age-related expression of
Ito in mouse hearts during embryonic
development. The present study extends this work by reporting a
progressive increase in Ito expression in mouse
ventricular myocytes from postnatal to adult development.
The inactivation kinetics of Ito from neonatal
to adult mouse ventricular myocytes display a different
pattern of Ito inactivation from previous
studies in other species.9 10 Generally, the inactivation
time course in the neonatal heart is much slower than that in the
mature heart. For example, Jeck and Boyden10 have shown a
rapidly activating, slowly inactivating outward current in 23% of
all neonatal canine epicardial cells. They reported that such a slowly
inactivating current was never observed in adult myocytes. In contrast,
the present study has shown that Ito
inactivated more rapidly in newborn than in adult mouse
ventricular myocytes. Nuss and Marban18 have
also shown rapid inactivation of Ito in neonatal
mouse ventricular myocytes. In addition, a developmental
increase in Isus was noted in the present
study. However, the magnitude of the age-related increase in
Isus was less than that of
Ito. Developmental increase in
Isus was also reported in human atrial myocytes
by Gross et al.13
Physiological Relevance of Developmental
Increase of Ito in Mouse Ventricles
Although Ito is present in newborn
mouse ventricular myocytes, at a membrane potential of -66
mV, at least half of the available Ito channels
are unavailable because of steady state inactivation. In addition, the
inactivation kinetics were faster in newborn than in adult myocytes. As
a result, Ito is expected to be less available
for action potential repolarization in early neonatal than in adult
mouse ventricles. In contrast, Ito in adult
mouse ventricular myocytes exhibits a larger amplitude and
slow inactivation kinetics. At resting membrane potential, almost 100%
of Ito channels would be expected to be
available for action potential repolarization in adult mouse
ventricular cells. From these voltage-clamp data, it was
expected that Ito would be a more important
repolarizing current in adult compared with early neonatal mouse
ventricles. This prediction was supported by our microelectrode
studies. The extent of action potential prolongation by 4-AP was
significantly greater in adult than in day-1 neonatal mouse
ventricular myocardium.
Adult Myocytes: Comparison With Previous Findings of
Ito
A voltage-dependent 4-AP–sensitive Ito in
adult mouse ventricular myocytes was first described by
Benndorf and Nilius.2 In the present study, we show a
similar current in adult mouse ventricular myocytes;
however, differences also exist. First, Ito was
elicited from different holding potentials: -50 mV in the study of
Benndorf and Nilius versus -80 mV in the present study. Second,
the duration of the depolarization pulses in the study of Benndorf and
Nilius was only 50 milliseconds. Given such a short depolarizing pulse,
the inactivation of Ito in adult mouse
ventricular myocytes would be far from complete. Third, the
experiments were carried out at different temperatures. All these
factors may result in the different inactivation kinetics of
Ito in adult mouse ventricular cells
between the two studies.
The characteristics of Ito inactivation in adult mouse ventricular myocytes are different from those in other species.1 4 8 19 Typically, Ito activates and inactivates rapidly in adult ventricular myocytes. In addition, the inactivation time course of Ito is best fit by a single exponential function in ventricular myocytes isolated from rats.19 In contrast, the inactivation kinetics of Ito in adult mouse ventricular myocytes were much slower and were composed of two inactivation components: a fast inactivation component (69±7 milliseconds at +50 mV) and slow inactivation component (903±66 milliseconds at +50 mV). Two inactivation components of Ito were reported in rat atrial but not ventricular myocytes.20 Similar to that found in rat atrial cells, the time course of the recovery of the fast inactivation component in mouse ventricular cells (day 14 and adult) is independent of the recovery of the slow component. This result suggests that the fast and slow components are functionally independent currents. The molecular biological studies are required to determine whether independent gene products underlie these two components.
In addition to the fast and slow inactivation components of Ito, a rapidly activating, noninactivating current, Isus, was also present in adult mouse ventricular myocytes. Thus, the total outward current recorded in adult mouse ventricular myocytes appears to be the sum of at least three components. The slow inactivation component is unlikely to be due to the Ca2+-activated K+ channel, because we have used CdCl2 in external perfusion and EGTA (10 mmol/L) in the internal solution to block ICa2+ and buffer intracellular Ca2+, respectively.
Limitations
The present study has a number of limitations. The regional
and transmural differences in Ito distribution
during development were not assessed. The day-1 neonatal mouse heart is
too thin to accurately isolate epicardial versus endocardial myocytes.
Since the present study mainly focuses on time-dependent expression
of K+ current in mouse hearts, a parallel design was used
to sample the whole ventricles at the different periods of
development.
In the present study, Ito was measured at room temperature rather than at a more physiological temperature. Therefore, the properties of Ito observed in the present study may differ from those recorded at 37°C. Most previously reported biophysical studies of Ito were also recorded at room temperature, probably because Ito activates so rapidly and its amplitude is so large that potential problems of voltage-clamp control would be more likely at 37°C. Therefore, our data can be compared with those of previous investigations.
Different dispersion methods were used to isolate myocytes in day-1 neonates than were used in day-14 neonates or adult mice in the present study. A previous study has compared the characteristics of measured K+ currents in day-10 neonatal rat ventricular myocytes obtained by Langendorff perfusion versus the chunk method and found that the currents were qualitatively very similar.1 Even so, we cannot completely exclude the possibility that the differences in the properties of the currents in day-1 neonatal cells versus day-14 and adult cells may in part relate to the different isolation methods, although this seems unlikely.
Significance
With the advances in molecular techniques, transgenic mouse models
will facilitate the mechanistic analysis of the range of
K+ channel gene products that are expressed at
different stages of development or by certain heart diseases. From this
point of the view, the results obtained from present study not only
illustrate the characteristics of K+ currents in mouse
ventricular myocytes during normal postnatal development
but also provide prerequisite knowledge for designing future studies of
K+ currents in transgenic mice.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We thank Drs W.R. Giles and R. Clark for their many helpful comments and suggestions and Dr R. Clark's careful and critical reading of the manuscript. We also thank Dr Zhong-Ping Feng for taking the photographs of the mouse ventricular myocytes.
Received December 3, 1996; accepted April 22, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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J. Brouillette, R. B. Clark, W. R. Giles, and C. Fiset Functional properties of K+ currents in adult mouse ventricular myocytes J. Physiol., September 15, 2004; 559(3): 777 - 798. [Abstract] [Full Text] [PDF]
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V. E. Bondarenko, G. P. Szigeti, G. C. L. Bett, S.-J. Kim, and R. L. Rasmusson Computer model of action potential of mouse ventricular myocytes Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1378 - H1403. [Abstract] [Full Text] [PDF]
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K. Banach, M. D. Halbach, P. Hu, J. Hescheler, and U. Egert Development of electrical activity in cardiac myocyte aggregates derived from mouse embryonic stem cells Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2114 - H2123. [Abstract] [Full Text] [PDF]
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C. I. Berul Electrophysiological phenotyping in genetically engineered mice Physiol Genomics, May 13, 2003; 13(3): 207 - 216. [Abstract] [Full Text] [PDF]
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B. D Stuyvers, A. D McCulloch, J. Guo, H. J Duff, and H. E D J ter Keurs Effect of stimulation rate, sarcomere length and Ca2+ on force generation by mouse cardiac muscle J. Physiol., November 1, 2002; 544(3): 817 - 830. [Abstract] [Full Text] [PDF]
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S. Danik, C. Cabo, C. Chiello, S. Kang, A. L. Wit, and J. Coromilas Correlation of repolarization of ventricular monophasic action potential with ECG in the murine heart Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H372 - H381. [Abstract] [Full Text] [PDF]
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A. E. Belevych, R. Beck, P. Tammaro, L. Poston, and S. V. Smirnov Developmental changes in the functional characteristics and expression of voltage-gated K+ channel currents in rat aortic myocytes Cardiovasc Res, April 1, 2002; 54(1): 152 - 161. [Abstract] [Full Text] [PDF]
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M. J. Hernandez-Benito, R. Macianskiene, K. R. Sipido, W. Flameng, and K. Mubagwa Suppression of Transient Outward Potassium Currents in Mouse Ventricular Myocytes by Imidazole Antimycotics and by Glybenclamide J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 598 - 606. [Abstract] [Full Text] [PDF]
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G. Lande, S. Demolombe, A. Bammert, A. Moorman, F. Charpentier, and D. Escande Transgenic mice overexpressing human KvLQT1 dominant-negative isoform Part II: Pharmacological profile Cardiovasc Res, May 1, 2001; 50(2): 328 - 334. [Abstract] [Full Text] [PDF]
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Y.-G. Wang, M. B. Wagner, R. Kumar, W. N. Goolsby, and R. W. Joyner Fast pacing facilitates discontinuous action potential propagation between rabbit atrial cells Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2095 - H2103. [Abstract] [Full Text] [PDF]
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S. P. Thomas, L. Bircher-Lehmann, S. A. Thomas, J. Zhuang, J. E. Saffitz, and A. G. Kleber Synthetic Strands of Neonatal Mouse Cardiac Myocytes : Structural and Electrophysiological Properties Circ. Res., September 15, 2000; 87(6): 467 - 473. [Abstract] [Full Text] [PDF]
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S. Mitarai, T. D. Reed, and A. Yatani Changes in ionic currents and beta -adrenergic receptor signaling in hypertrophied myocytes overexpressing Galpha q Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H139 - H148. [Abstract] [Full Text] [PDF]
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V. S. Chauhan, S. Tuvia, M. Buhusi, V. Bennett, and A. O. Grant Abnormal Cardiac Na+ Channel Properties and QT Heart Rate Adaptation in Neonatal AnkyrinB Knockout Mice Circ. Res., March 3, 2000; 86(4): 441 - 447. [Abstract] [Full Text] [PDF]
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L. Wang, S. Swirp, and H. Duff Age-dependent response of the electrocardiogram to K+ channel blockers in mice Am J Physiol Cell Physiol, January 1, 2000; 278(1): C73 - C80. [Abstract] [Full Text] [PDF]
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H. Xu, H. Li, and J. M Nerbonne Elimination of the transient outward current and action potential prolongation in mouse atrial myocytes expressing a dominant negative Kv4 {alpha} subunit J. Physiol., August 15, 1999; 519(1): 11 - 21. [Abstract] [Full Text] [PDF]
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L. Wang, Z.-P. Feng, and H. J. Duff Glucocorticoid Regulation of Cardiac K+ Currents and L-Type Ca2+ Current in Neonatal Mice Circ. Res., July 23, 1999; 85(2): 168 - 173. [Abstract] [Full Text] [PDF]
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S. Kupershmidt, T. Yang, M. E. Anderson, A. Wessels, K. D. Niswender, M. A. Magnuson, and D. M. Roden Replacement by Homologous Recombination of the minK Gene With lacZ Reveals Restriction of minK Expression to the Mouse Cardiac Conduction System Circ. Res., February 5, 1999; 84(2): 146 - 152. [Abstract] [Full Text] [PDF]
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J. Zhou, A. Jeron, B. London, X. Han, and G. Koren Characterization of a Slowly Inactivating Outward Current in Adult Mouse Ventricular Myocytes Circ. Res., October 19, 1998; 83(8): 806 - 814. [Abstract] [Full Text] [PDF]
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D. M. Barry, H. Xu, R. B. Schuessler, and J. M. Nerbonne Functional Knockout of the Transient Outward Current, Long-QT Syndrome, and Cardiac Remodeling in Mice Expressing a Dominant-Negative Kv4 {alpha} Subunit Circ. Res., September 7, 1998; 83(5): 560 - 567. [Abstract] [Full Text] [PDF]
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B. London, D. W Wang, J. A Hill, and P. B Bennett The transient outward current in mice lacking the potassium channel gene Kv1.4 J. Physiol., May 15, 1998; 509(1): 171 - 182. [Abstract] [Full Text] [PDF]
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D. Vaidya, H. S. Tamaddon, C. W. Lo, S. M. Taffet, M. Delmar, G. E. Morley, and J. Jalife Null Mutation of Connexin43 Causes Slow Propagation of Ventricular Activation in the Late Stages of Mouse Embryonic Development Circ. Res., June 8, 2001; 88(11): 1196 - 1202. [Abstract] [Full Text] [PDF]
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