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Vol. 285, Issue 2, 672-679, May 1998
Department of Pharmacology, Georgetown University Medical Center, Washington, DC
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Abstract |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Women are known to have a longer electrocardiographic Q-T than men,
which may contribute to their being at greater risk of developing
drug-induced polymorphic ventricular arrhythmias. However, little is
known about the underlying mechanisms. In the present study, we
evaluated potential gender differences in Q-T interval in isolated
perfused rabbit hearts using the Langendorff technique and
evaluated the density of outward potassium currents in single ventricular myocytes using the whole-cell patch-clamp technique. We
found that female hearts demonstrated a greater Q-T lengthening (
Q-T%) upon an increase in cycle length (CL), resulting in a significantly longer Q-T (301 ± 4.8 ms, CL = 2.3 s) at
a long CL in female hearts compared with male hearts (267 ± 4.0 ms, P < .01). Ventricular myocytes isolated from female hearts
showed a smaller IKtail and peak IKl outward
current density. A 50% reduction in extracellular K+ and
Mg++ shifted the I-V relationship of IKl and
Ito and reduced their amplitude. However, neither the I-V
relationship of IKr nor the gender difference in the
Q-T-CL relationship was significantly altered. We conclude that 1)
female rabbit ventricular myocytes have significantly lower
IKr and IKl outward current densities than do
male cells, which may contribute to the gender difference in Q-T, and
2) a lower base-line IKr density may contribute to the
steeper Q-T-CL relationship in female hearts.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Women
are known to have a longer, CL-dependent electrocardiographic Q-T
interval than men (Stramba-Badiale et al., 1997
). However,
little is known about the mechanism responsible for this gender
difference. Prolongation of the Q-T interval on the electrocardiogram has clinical importance because it is a common feature associated with
a complex form of ventricular arrhythmia known as TdP (Dessertenne, 1966). An acquired long Q-T syndrome secondary to drug administration has been associated with TdP and sudden death in patients treated with
antiarrhythmic drugs (Ben-David and Zipes, 1993; Carlsson et
al., 1990; Roden et al., 1986). A gender difference in
Q-T duration may therefore result in a gender difference in the
incidence of TdP. Indeed, recent clinical observations have indicated
that the occurrence of TdP displays a gender difference with a
higher-than-expected occurrence in females (Kawasaki et al.,
1995; Lehmann et al., 1996; Makkar et al., 1993).
Crucial to generation of TdP is prolongation of the Q-T interval and
APD that permits EADs to occur (Zeng and Rudy, 1995). Because potassium
currents are major determinants of cardiac repolarization, and because
shortening of the action potential suppresses EADs in isolated myocytes
(Bouchard et al., 1995), the activity of one or more
potassium channels may be critical in modulating EADs. In fact, most
drugs that are associated with TdP clinically have also been shown to
block cardiac potassium channels, especially the rapid component of
IK, IKr (Ben-David and Zipes, 1993; Carlsson et al., 1990; Roden et al., 1986; Lehmann
et al., 1996). Furthermore, overexpression of HERG, the gene
coding for IKr, has been shown to shorten APD and suppress
EAD in rabbit ventricular myocytes (Nuss et al., 1997).
In the present study, we examined the gender differences in the CL-dependent Q-T in isolated perfused rabbit hearts. In addition, we measured the density of outward potassium currents that may contribute to such a difference in single rabbit ventricular myocytes.
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Langendorff preparation.
Hearts from 35 New Zealand White
male and female rabbits (3-4 months old, weight 3-3.5 kg; HRP Inc.,
Denver, Pennsylvania) were studied using the nonrecirculating
Langendorff technique as described previously (Zabel et al.,
1995). The hearts were perfused with an oxygenated Tyrode's solution
(95% O2, 5% CO2), pH 7.4, containing (mmol/l)
NaCl 115, KCl 4.7, CaCl2 2, MgCl2 0.7, NaH2PO4 1, NaHCO3 27.9, glucose 20, and 0.04% (w/v) purified bovine albumin. The perfusate was maintained
at 37°C and delivered to the aortic inflow cannula at the constant
rate of 10 ml/min by a Masterflex pump. The AV node was cauterized to
slow the intrinsic HR for pacing at a fixed rate. Hearts were paced at
a CL of 400 ms and twice diastolic threshold intensity via a
pacing catheter positioned in contact with the right ventricular
endocardium. Experiments were conducted in accordance with the
guidelines of the Georgetown University Animal Care and Use Committee
and the American Heart Association's position statement on use of
animals in research.
ECG recordings and Q-T measurements.
Four silver-silver
chloride electrode wires were positioned in a simulated "Einthoven"
configuration, with the reference and "foot" electrodes fixed
beneath the heart on the walls of a tissue bath that has the
approximate diameter of a rabbit thorax (Zabel et al.,
1995). The signals were amplified by an ECG amplifier (Colbourn
Instruments, Lehigh Valley, PA) allowing for the simultaneous recording
of the three orthogonal signals designated as X, Y and Z. The ECG
signals were filtered selectively at 60 Hz.
). After about 30 min
of continuous drive pacing at a CL of 0.4 s, the base-line Q-T
interval was recorded. To compare the gender difference in Q-T interval
at a slow rate, we switched the CL to 2.3 s and measured the Q-T interval when it was stable after 
5 min pacing at this CL. In some
experiments, Q-T was measured at multiple CLs (0.4, 0.8, 1.2 and
2.3 s) after 5 min pacing at each CL to examine the Q-T-CL relationship. Upon completion of Q-T measurements at multiple CLs in
these experiments, the CL was switched back to 0.4 s and a
modified Tyrode's solution (Liu et al., 1997) containing
50% reduced K+ and Mg++ (low K/Mg) was
perfused to study the effect of low K/Mg on the Q-T-CL relationship.
After a stable baseline Q-T interval was reached in the modified
Tyrode's solution (35-40 min), Q-T intervals were again measured at
four CLs (0.4, 0.8, 1.2 and 2.3 s) using the same procedure as in
normal Tyrode's solution.
Data were recorded on a strip chart recorder (Gould Electronics,
Cleveland, OH) at a paper speed of 100 mm/s. Four representative beats
from each set of XYZ recordings were chosen for Q-T measurement. The
end of the T wave was defined as the point of maximal change in the
slope of the T wave as it merges with the electrical base line in any
lead.
Isolation of ventricular cells.
Cells were isolated using a
modified method previously described (Giles and Imaizumi, 1988).
Briefly, rabbit hearts (four male and five female hearts) were removed
and mounted on the Langendorff perfusion system. The following
procedure was used: 1) perfusion with normal Tyrode's solution for 10 min; 2) perfusion for approximately 20 min with a Ca++-free
Tyrode's solution; 3) perfusion for 30 to 35 min with Tyrode's solution containing 40 U/ml of collagenase II (Worthington Biochemical, Freehold, NJ) and 50 µmol/l of CaCl2. The ventricles were
then minced and gently stirred in Tyrode's solution containing 100 µmol/l of CaCl2. After stirring for 5 to 10 min, a large
number of single ventricular cells were obtained. The resulting cell suspension was then filtered through a nylon mesh. Cells were collected
by centrifugation at 50 × g and then resuspended in Tyrode's solution containing 250 µmol/l of Ca++. The
cells were again collected by centrifugation and then resuspended in
Tyrode's solution containing 1 mmol/l of Ca++. After a
third centrifugation, the cells were resuspended in Dulbecco's
modified Eagle's medium supplemented with 10% bovine calf serum
(HyClone Labs, Logon, UT). The myocytes were immediately seeded onto
laminin-coated glass microcoverslips at a density of 104
rod-shaped cells/cm2 and allowed to attach. The cells were
stored in a humidified incubator in 5% CO2, 95% air at
37°C. Approximately equal numbers of cells (7-10) were studied from
each heart, and all experiments were performed within 16 h after
cell isolation.
Whole-cell patch clamp.
The patch-clamp technique was used
to record the membrane currents in single ventricular myocytes. Command
voltage pulses were generated by use of PCLAMP 6.0.2 Software (Axon
Instruments, Foster City, CA) connected to an interface (Axon
Instruments), an IBM-compatible Pentium computer and an Axopatch 200A
amplifier. Membrane potentials and current signals were monitored on an
oscilloscope (5103, Tektronix, Beaverton, OR) and stored in the lab
computer. Pipettes with tip resistance of 1 to 4 M
were pulled from
borosilicate glass (World Precision Instruments, Sarasota, FL) and
filled with an intracellular solution containing (mmol/l) KCl 125, NaCl
10, CaCl2 1, Mg-ATP 5, EGTA 14, HEPES 10 and cAMP 0.1, adjusted with KOH to pH 7.2. A holding potential of 
40 mV was used to
inactivate fast sodium and T-type calcium currents. The external
solution was Tyrode's solution containing (mmol/l) NaCl 137, KCl 5.4, HEPES 10.0, MgCl2 1.0, CaCl2 2.0 and glucose
10.0 and was adjusted with NaOH to pH 7.4 (NaOH). In some experiments,
a modified Tyrode's solution containing 50% reduced K+
and Mg++ (low K/Mg) was used to study its effect on
potassium currents. Cd++ (0.2 mmol/l) was used to block the
L-type calcium channel and to shift the I-V relationship of
Ito and IKr to more positive potentials (Daleau
et al., 1997; Agus et al., 1991). This makes possible 1) separation of IKr and the outward portion of
IKl, especially at membrane potentials positive to 30 mV,
and 2) marked increase in Ito availability at a holding
potential of 40 mV.
. Junction potentials under our conditions were approximately 3
mV and were not corrected. IK currents were elicited from a
holding potential of 40 mV by a series of 1.5-s test pulses from 10
to +50 mV in 10-mV increments. Membrane potential was then returned to
holding potential or was held at 30 mV for 2 s before return to
the holding potential in order to observe IK tail currents.
The I-V relationship for IK was constructed by measuring
the tail currents. The voltage dependence of IK activation was fit to a Boltzmann distribution of the form
IKtail/IKmax = 1/{1 + exp[(V1/2 Vt)/k]} with a nonlinear
least-squares fitting routine (Origin 4.10, Microcal Software,
Northampton, MA) to estimate the half-activation potential
(V1/2) and slope factor (k) for this
relationship. Deactivation of IK can be well fit by a
single exponential function, using an equation of the form
It = As
exp(t/
s), where
It is the tail current at time t,
As is the initial amplitude of the current and
s is the time constant of deactivation. In
the presence of 0.2 mmol/l of Cd++, the same protocol for
IK also activated Ito because of the marked shift of Ito activation to more positive potentials. The
amplitude of Ito was estimated by measuring the peak of the
transient component of the current with respect to its steady-state
value.
The IKl currents were elicited from a holding potential of
40 mV by a series of 250-ms test pulses ranging from 150 to 10 mV
in 10-mV increments. The amplitude of IKl at each voltage
was determined by measuring the peak current relative to zero current.
Data analysis and statistics. Q-T intervals were interpreted in a masked fashion by two investigators. Patch-clamp data were normalized for total cell capacitance to allow comparison between cells of various sizes. Student's t test was used to assess gender differences in Q-T at a given CL and current density at a given voltage. Data were reported as mean ± S.E.M., and differences between values were considered statistically significant when P < .05.
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Gender difference in baseline Q-T interval. ECG recordings were made from isolated male and female rabbit hearts to determine whether there is a gender difference in the baseline Q-T interval or the Q-T-CL relationship. After about a 30-min perfusion with Tyrode's solution and continuous pacing at 0.4 s, the Q-T interval stabilized. Upon switching of the CL from 0.4 s to 2.3 s, Q-T interval lengthened, and it reached steady state after about 5 min. Figure 1A depicts the Q-T interval at CL 0.4 s, measured at the end of a 30-min perfusion with Tyrode's solution and the Q-T interval at 2.3 s, measured at least 5 min after the switch of the CL in male and female rabbit hearts. At a CL of 0.4 s, baseline Q-T was only slightly longer in female hearts (232 ± 2.0 ms) than in male hearts (223 ± 3.6 ms, P > .05). However, at CL 2.3 s, the mean Q-T was significantly longer in female hearts (301 ± 4.8 ms) than in male 267 ± 4.0 ms, P < .01). Thus female hearts demonstrated greater Q-T lengthening after the increase in CL from 0.4 s to 2.3 s (29.9% ± 3.3.3% and 19.9% ± 2.7%, female vs. male, P < .05, fig. 1B).
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Gender difference in IKr.
IKr is one
of the major repolarizing currents and has been implicated in TdP
(Carlsson et al., 1990; Lehmann et al., 1996; Roden et al., 1986). To determine whether a gender
difference in IKr may contribute to the observed gender
difference in Q-T, we first sought to establish the presence of
IKr in our rabbit ventricular myocytes. Figure
2A shows the membrane currents elicited by a 1.5-s voltage-clamp step from 40 to different test potentials ranging from 10 to +40 mV in the same cell before and after a 5-min
exposure to 5 µmol/l of E-4031 (Eisai Ltd., Ibaraki, Japan). Under
control conditions, a small and slowly activating outward current
flowed during depolarization, followed by a large outward tail current
that has been shown to represent the gradual decay of IK
(Follmer and Colatsky, 1990; Sanguinetti and Jurkiewicz, 1990). The
initial peak in the time-dependent outward current was due to the rapid
activation and inactivation of Ito. E-4031 abolished the
tail current on repolarization and also reduced the time-dependent
outward current, without affecting the initial peak. The
E-4031-sensitive current, obtained by digital subtraction of currents
in the bottom tracings from currents in the top tracings in panel A, is
shown in panel B. Compared with the tail current, the time-dependent
current demonstrated marked inward rectification at very positive
potentials. Superfusion of 1 to 2.5 µmol/l of dofetilide or removal
of extracellular K+ also abolished the tail current (data
not shown). These features (inward rectification of the time-dependent
current, inhibition by E-4031, dofetilide and removal of extracellular
K+) are consistent with the description of IKr
in rabbit and other species (Follmer and Colatsky, 1990; Sanguinetti
and Jurkiewicz, 1990; Sanguinetti et al., 1995). Similar
time-dependent and tail currents were observed in nearly all the cells
we studied. Only in 2 of 84 cells did we observe a large,
noninactivating, time-dependent current (data not shown) that resembled
the IKs described in earlier studies (Follmer and Colatsky,
1990; Salata et al., 1996; Gintant, 1996). These two cells
were not included in our analysis.
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; Sanguinetti et al., 1995). The time
constant () of IKr decay was well fit by a single
exponential function (see "Materials and Methods"). At the test
potential of +50 mV, was 527 ± 13 ms in male and 569 ± 17 ms and female cells, respectively (P > .05). The time constant
of IKr activation was obtained by studying the
E-4031-sensitive current. At the test potential of +20 mV, the
time-dependent IKr showed the highest amplitude (fig. 2B)
and can be adequately fit by a single exponential function with time
constants of 400 ± 44 ms and 392 ± 103 ms in female and
male cells, respectively (P > .05).
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Gender difference in IKl.
To determine whether
other outward potassium currents also display a gender difference, we
next examined the IKl current density in female and male
ventricular myocytes. As shown in figure
4, A and B, in rabbit ventricular
myocytes, the pulse protocol for IKl activated a current
that is largely time-independent at membrane potentials positive to
100 mV. This current had a prominent negative slope between 50 and
10 mV. A similar voltage dependence of IKl was observed
in both sexes (fig. 4B). Between 70 and 10 mV, IKl
carried an outward current that peaked at 50 mV. Because the presence
of 0.2 mmol/l of Cd++ caused a positive shift of
IKr activation, no IKr was activated within
this membrane potential range (figs. 2 and 3). Although there was no
significant difference in the inward portion of IKl between
male and female cells, the outward component of IKl was significantly smaller in female cells than in male cells. Peak outward
IKl at 50 mV was 1.46 ± 0.06 pA/pF in female cells
and 1.67 ± 0.08 pA/pF in male cells (P < .05).
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Effect of low K/Mg on IKl, Ito and
IKr.
We have previously shown that a modified
Tyrode's solution containing reduced Mg++ and
K+ lengthens the Q-T interval (Liu et al.,
1997), which suggests an inhibition of potassium channels. To explore
the possibility that different cardiac potassium channels have
differential sensitivity to low K/Mg, and using low K/Mg as a tool to
elucidate the differential roles of different potassium channels in
repolarization, we further characterized the effect of low K/Mg on
three major outward potassium currents. Figure
5 shows the currents in the same cell
recorded before (panel A) and after (panel B) a 5-min superfusion of
low-K/Mg Tyrode's solution. Reducing the extracellular K+
and Mg++ reduced the amplitude of Ito. Also,
less quasi-instantaneous inward current was observed because of the
shifting of the negative slope of IKl to more negative
potentials and the reduction of peak IKl amplitude. Figure
5C shows the difference currents obtained by digital subtraction of the
currents in panel B from those in panel A. It clearly demonstrates the
inhibition of Ito during depolarization. A large
IKl outward current (the time-independent outward current
at 40 and 30 mV) was also inhibited at these potentials, but
IKr was not affected (absence of time-dependent, activating
current and deactivating tail). Figure 5, D, E and F show the I-V
relationships for IKl, Ito and IKr,
respectively, before and after reduction of extracellular
K+ and Mg++. In the presence of low K/Mg, the
I-V curve of IKl was characterized by a marked shift (about
18 mV) to more negative potentials and by a reduction in the peak
amplitude (fig. 5D). A marked reduction in Ito by low K/Mg
is also clearly demonstrated in figure 5E. No significant change in the
I-V relationship of IKr was observed (fig. 5F). The data
shown in Figure 6, D and E are pooled from both male (2-5) and female
(2-11) cells. No significant gender difference was observed in the
response of current to low K/Mg.
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Effect of low K/Mg on the Q-T-CL relationship.
Because low
K/Mg Tyrode's solution preferentially inhibited IKl and
Ito without significantly affecting IKr, we
next examined the gender difference in the Q-T-CL relationship in
normal and low K/Mg Tyrode's solution. In both normal and low-K/Mg
Tyrode's solution, as the CL increased from 0.4 s to 0.8, 1.2 and
2.3 s, Q-T progressively lengthened in male and female hearts.
After perfusion of Tyrode's solution with low K/Mg, both the absolute Q-T interval and its variability increased, but a consistent, statistically significant gender difference in the absolute Q-T value
was not observed (Liu et al., 1997). However, as the CL increased from 0.4 s to 0.8, 1.2 and 2.3 s, female hearts
still demonstrated greater Q-T lengthening (fig.
6). As shown in figure 6, the
Q-T%-CL relationship was not significantly altered by perfusion of
low K/Mg in either male or female hearts. In the presence of low K/Mg,
as the CL increased from 0.4 s to 2.3 s, Q-T lengthened by
29.1% ± 2.7% and by 20.5% ± 2.1% in female and male hearts,
respectively (P < .05)
an outcome very similar to the results
obtained in normal Tyrode's solution (29.9% ± 3.3% and 19.9% ± 2.7%, female vs. male, P < .05).
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Although the rate-corrected Q-T interval of women is known to be
longer than that of men, which suggests that women have a slower
repolarization process (Stramba-Badiale et al., 1997), few
experiments have been performed to examine the basis for this difference or its potential consequences. The current study was designed to examine the ionic mechanisms that contribute to gender differences in repolarization.
Outward potassium channels are the major determinants of the
repolarization phase of the cardiac action potential. Three major potassium currents, Ito, IK and
IKl, mediate different phases of the repolarization process
(Giles and Imaizumi, 1988; Litovsky and Antzelevitch, 1988; Sanguinetti
and Jurkiewicz, 1990). The contribution of IK and
IKl to the APD is well established, and reduction in
IK or IKl causes APD and Q-T prolongation (Clay
et al., 1995; Salata et al., 1995; Surawicz,
1992). On the other hand, although Ito has been shown to
play an important role in determining phase 1 repolarization, there is
still some uncertainty about its contribution to normal APD. Except in
rats, where Ito is the major repolarizing current, it is
still uncertain whether reduction of Ito leads to
prolongation or shortening of the entire APD (Giles and Imaizumi, 1988;
Litovsky and Antzelevitch, 1988; Kaab et al., 1996).
The present study demonstrates that female rabbit hearts have a steeper
Q-T-CL relationship than male hearts, which results in a significantly
longer Q-T interval at a long CL in female rabbit hearts. This is
consistent with the clinical observation of a steeper Q-T-CL
relationship in women (Stramba-Badiale et al., 1997). In
whole-cell patch-clamp studies, we found a major gender difference in
the current density of IKr and also a small, yet
statistically significant gender difference in the peak IKl outward current. Both IKr and IKl outward
current densities are significantly smaller in ventricular myocytes
isolated from female rabbit hearts, with no apparent difference in the
voltage dependence and activation/deactivation kinetics compared with
male hearts.
A reduction of either IKr or IKl could contribute to the slower repolarization process and longer Q-T interval at a given CL in female hearts. Our observation of no consistent, statistically significant gender difference in the absolute Q-T value in the presence of low K/Mg, conditions that affect IKl but not IKr, suggests that IKl may play a role in causing these gender differences. However, because only IKr demonstrates a strong time dependence during both the plateau and final phases of the action potential, it is more likely that the gender difference in the Q-T-CL relationship results from the gender difference in IKr current density, although the contribution of other currents (such as ICa) cannot be excluded. An increase in CL is followed by an increase in APD, so a greater IKr is activated at long CLs. A gender difference in baseline IKr should therefore become more pronounced at a long CL, which may in turn contribute to a more pronounced gender difference in Q-T. This interpretation is supported by the finding that, although low K/Mg preferentially reduced the contribution of IKl and Ito to APD by shifting their I-V curves and reducing the current amplitude, the gender difference in the Q-T-CL relationship was preserved (fig. 6).
IK has been reported to consist of two components,
IKr and IKs, in guinea pig, dog and human
ventricles (Sanguinetti and Jurkiewicz, 1990; Gintant, 1996; Li
et al., 1996). In the rabbit ventricular myocytes,
IK has been reported to be absent (Giles and Imaizumi, 1988), to consist of only one component (Clay et al., 1995)
and to consist of two components (Salata et al., 1996). In
our experiments, IK can be consistently recorded with a
clear tail current with no appreciable rundown in all the cells we
studied. Our results indicate that the major delayed rectifier current
in normal rabbit ventricular myocytes seems to be IKr,
which is evident from the complete inhibition of the tail current by 1 to 5 µmol/l of E-4031, 1 to 2.5 µmol/l of dofetilide and removal of
extracellular potassium. IKs was not detected in most cells
even though we included cAMP, an agent that has been shown to increase
IKs without affecting IKr, in the pipette
solution (Sanguinetti et al., 1995; Salata et
al., 1996). It has been reported that IKs is strongly
dependent on isolation methods and recording temperature (Salata
et al., 1996; Walsh et al., 1989), so it is
possible that our experimental conditions were not optimal for
recording IKs. However, recent studies by Waldegger
et al. (1996) demonstrated that acute administration of
estradiol directly inhibits the minK current expressed in
Xenopus oocytes, yet we observed no APD or Q-T prolongation
after acute estradiol perfusion at concentrations that caused more than
50% inhibition of minK current in Waldegger's studies (Knollman
et al., 1996). Because the minK current in
Xenopus oocytes results, in a manner similar to
IKs, from coassembly of minK and an endogenous KvLQT1-like
protein (Sanguinetti et al., 1996), these observations would
certainly argue against the possibility that a gender difference in
IKs could account for the gender difference in Q-T in
rabbits. Further studies are needed to determine whether
IKs significantly contributes to the repolarization process
in the rabbit heart and, if so, whether there is any gender difference
in IKs.
Finally, because of the variability of Ito amplitude in
this study, we were not able to determine the gender difference in baseline Ito current density. This variability is probably
caused by the marked variation in the regional distribution of
Ito among the different layers of the ventricle (Litovsky
and Antzelevitch, 1988). Ongoing studies in our lab will further
examine potential gender differences in Ito by using cells
isolated from different layers of the ventricle. However, the
observation that 4-aminopyridine, at concentrations that specifically
block Ito, caused similar Q-T prolongation in female and
male hearts (X.K. Liu, W. Wang, S.N. Ebert, M.R. Franz and R.L.
Woosley, unpublished observation, 1997) would argue against the
possibility that a gender difference exists in Ito.
Moreover, in the presence of low K/Mg that inhibited Ito,
female hearts still demonstrated a steeper Q-T-CL relationship, which
suggests that a gender difference in Ito is less likely to
contribute to the gender difference in the Q-T-CL relationship.
Clinical relevance and implications.
A lower density of
IKr in female hearts could contribute to the clinically
observed steeper Q-T-CL relationship in women. This, together with a
smaller IKl outward current, may contribute to a longer Q-T
interval in women and place them at a higher risk of developing
drug-induced TdP, especially at slow HRs. Interestingly, a higher
incidence of TdP was found in women during complete heart block, where
HRs were very slow (Kawasaki et al., 1995). In addition, because IKr current density in female hearts is already
reduced compared with that in male hearts, further IKr
reduction by administration of IKr blockers may cause
exaggerated Q-T prolongation in female hearts. This may contribute to
the greater Q-T prolongation by D-sotalol in female rabbit
hearts (X.K. Liu, W. Wang and R.L. Woosley, unpublished observations,
1997) and to the higher incidence of TdP in female patients treated
with D,L-sotalol (Lehmann et al.,
1996). These results suggest that drugs that block IKr
should be administered with special caution in female patients.
Limitations.
In our experiments, cells were isolated from the
whole ventricular mass; different channel configurations between the
left and right ventricles (Verduyn et al., 1997) and among
different layers of the same ventricle may have confounded our data.
Also, by using Cd++ as the L-type calcium
channel blocker, we were able to markedly increase the availability of
Ito at a holding potential of 40 mV and separate the I-V
curves of IKr and the outward portion of IKl.
However, the very ability of Cd++ to shift the I-V
relationship of IKr to more positive potentials also
limited our interpretation of IKr kinetics (Daleau et
al., 1997). Finally, there is the issue of species differences
between rabbit and human, although the parallel between the
CL-dependent gender difference in the Q-T interval in the rabbit and
that in the human suggests that the isolated rabbit heart may be
clinically relevant as an experimental model.
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Footnotes |
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Accepted for publication January 30, 1998.
Received for publication November 22, 1996.
1 This work was supported in part by a grant from the National Institutes of Health (Grant #RO1 HL54590 to R.L.W.).
Send reprint requests to: Raymond L. Woosley, M.D., Ph.D., Department of Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC 20007.
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Abbreviations |
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TdP, torsades de pointes; APD, action potential duration; IKr and IKs, rapid and slow components, respectively, of the delayed rectifier; IKl, inward rectifier; Ito, transient outward current; CL, cycle length; EAD, early afterdepolarization; HERG, human ether-a-go-go-related gene.
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References |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Does IKs play a role in the reverse rate dependence of class III agents?
Cir Res
78:
26-37
estradiol and dihydrotesterone on action potential duration and QT-interval in isolated rabbit hearts (Abstract).
J Investigative Med
44 (3):
209A.differential sensitivity to block by class III antiarrhythmic agents.
J Gen Physiol
96:
195-215-Adrenergic modulation of cardiac ion channels. Differential temperature sensitivity of potassium and calcium currents.
J Gen Physiol
93:
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