© 1998 American Heart Association, Inc.
Original Contributions |
Quinidine Interactions With Human Atrial Potassium Channels
Developmental Aspects
From the Departments of Pharmacology (N.I.N., C.W.C.), Pediatrics (W.J.C.), and Surgery (J.D.P.), Tulane University School of Medicine, and the Department of Surgery, Louisiana State University School of Medicine (L.H.H.), New Orleans, Louisiana.
Correspondence to Craig W. Clarkson, PhD, Department of Pharmacology SL83, 1430 Tulane Ave, New Orleans, LA 70112-2699. E-mail cclarks{at}tmcpop.tmc.tulane.edu
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Abstract |
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Abstract—Clinical studies have suggested that quinidine is less effective when used for the treatment of atrial arrhythmias in pediatric patients compared with its clinical effectiveness in the adult patient population. Age-related changes in the cardiac actions of quinidine on action potential duration and interaction with potassium channels in several mammalian species also have been reported. We investigated the effects of postnatal development on quinidine's interaction with major repolarizing currents (Ito, IKur, Ins, and IK1) in human atrial myocytes, using the whole-cell configuration of the voltage-clamp technique. Our results indicate that there are age-related changes in both the IC50 for quinidine blockade of Ito, as well as the mechanism of quinidine unblocking. In contrast, quinidine was found to inhibit both adult and pediatric IK1 and IKur in an age-independent manner, whereas the nonselective cation current (Ins), which contributes to the sustained outward current (Isus), was insensitive to quinidine. The results from this study help to clarify the electrophysiological mechanism by which quinidine elicits its antiarrhythmic effect in the pediatric and adult human population.
Key Words: human • atrial myocyte • development • quinidine • K+ channel
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Quinidine is one of the most commonly used drugs for treatment of both atrial and ventricular rhythm disturbances.1 Quinidine's efficacy as an antiarrhythmic agent is believed to result from its effects on conduction velocity and repolarization of the cardiac action potential.1 2 Quinidine's ability to prolong the duration of the cardiac action potential has been attributed to its ability to inhibit several different types of potassium ion channels expressed in mammalian cardiac tissue, including the transient outward K current (Ito), the inwardly rectifying K current (IK1), the rapidly activating delayed rectifier (IKr), and the ultrarapid delayed rectifier (IKur).3 However, the mechanisms by which quinidine exerts its inhibitory effects on these potassium currents are not understood fully.
Previous studies in dog, rabbit, and rat cardiac tissue have documented that the ability of quinidine and other antiarrhythmic agents to alter conduction and repolarization change significantly during postnatal development.4 5 6 7 8 Quinidine has been shown to prolong both the QT interval9 and repolarization4 of the Purkinje fiber action potential to a significantly greater extent in young canines compared with adult animals. Recent evidence suggests that developmental changes in the effects of antiarrhythmic agents on cardiac tissue may be attributed to age-related changes in drug-channel interactions.6 7 8 For example, quinidine block of rabbit ventricular Ito and IK1 has been shown to be significantly different in neonatal versus adult myocytes, with cells from neonates being more sensitive to the action of quinidine than adults.8
It seems likely that age-related differences in quinidine interaction with cardiac ion channels may also exist in man. Recent clinical studies have documented that quinidine and flecainide exhibit a markedly reduced clinical efficacy against atrial tachyarrhythmias in pediatric patients10 compared with their relatively high clinical efficacy in adults.11 Because changes in drug-channel interaction have been indicated as a potential mechanism underlying postnatal changes in the actions of antiarrhythmic agents, we initiated a study to compare the effects of quinidine on major repolarization currents (Ito, IK1, IKur, and the nonselective cation current, Ins) expressed in pediatric and adult human atrial myocytes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human Atrial Specimens and Isolation of Cardiac Myocytes
Human myocytes used in the experiments investigating the effects of quinidine on human atrial potassium channels were isolated from specimens of right atrial appendages obtained during surgery from the hearts of 23 adult patients (35 to 75 years of age) and 17 pediatric patients (4 days to 2 years of age) undergoing cardiopulmonary bypass surgery. Atrial tissue obtained from a separate group of patients was used to study the effects of age on Ito density (Figure 1
). Atrial tissue was obtained in
accordance with Tulane University School of Medicine institutional
guidelines. Specimens of atrial tissue were considered free from
pathology if all of the following criteria were met: (1) the specimen
appeared grossly normal on removal; (2) there was no evidence of right
atrial enlargement (eg, P wave amplitudes >2.5 mm); and (3) there
was no evidence for significant right atrial pressure overload (right
atrial pressure >7 mm Hg). Human atrial myocytes were isolated
enzymatically from the obtained specimens. The isolation procedure was
identical to that previously described by Crumb et al12
and typically produced an initial yield of 40% to 60% rod-shaped,
calcium-tolerant cells. Cells were used within 8 hours after isolation.
Currents were recorded from myocytes with characteristically normal
morphology (rod-shaped, clear striations, no surface blebs).
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Solutions and Drugs
Recordings of potassium currents were made from myocytes
bathed in an "external" solution having the following chemical
composition (in mmol/L): NaCl 137, KCl 4,
MgCl2 1, CaCl2 1.8, glucose
11, and HEPES 10 (adjusted to pH 7.4 with NaOH). All recordings
were made in the presence of 0.2 mmol/L
CdCl2 to block the L-type calcium
current (ICa).13 In most of
the experiments, cells were held at –40 mV to inactivate
the fast inward sodium current (INa). In
some cells, Ito was elicited with
depolarizing steps from a holding potential of –80 mV. As demonstrated
by Li and Keung,14 no sodium current was elicited under
these conditions, suggesting complete inactivation of Na channels.
Glass pipettes were filled with "internal" solution containing
(in mmol/L): K-aspartate 120, KCl 20,
Na2-ATP 4, EGTA 5, and HEPES 5 (adjusted to pH
7.2 with KOH). When the nonselective cation current was recorded, a
potassium-free internal solution of the following composition was used
(in mmol/L): CsCl 140, Na2-ATP 4,
Mg2Cl 1, EGTA 5, and HEPES 5 (adjusted to pH 7.2
with CsOH). Quinidine hydrochloride was obtained from Sigma Chemical Co
and dissolved in ethanol to form stock solutions of 8-, 40-, and
125-mmol/L concentrations. Pilot experiments indicated that the level
of ethanol present in the quinidine stock solution was without
effect on ionic currents when added to the bath alone. Steady-state
drug effects were typically reached 8 to 10 minutes after onset with
quinidine-containing solution. All experiments were performed at room
temperature (22°C to 24°C).
Voltage-Clamp Technique and Data Acquisition
The whole-cell patch-clamp technique was used to record
ionic currents under voltage-clamp.15 An Axopatch
amplifier (Axon Instruments) interfaced via a 333-kHz Digidata 1200
acquisition board to a personal computer running pClamp (Version 6.0+)
software was used to voltage-clamp the isolated myocytes. Borosilicate
glass pipettes were made using a horizontal pipette puller, and pipette
tips were heat-polished. Pipette tip resistance was 
1 to 2.5 M
when the electrodes were filled with the internal solution.
Capacitative transients were evoked by a 10-mV step (from -40 to
-50 mV) and well described by a single exponential function. Before
compensation, the mean 
rec of transient decay
was estimated to be 0.32±0.02 ms in adult (n=96) and 0.11±0.01 ms in
pediatric cells (n=57). Cell capacitance
(Cm) was obtained by integration of the
area under the capacitative transient. Mean values of
Cm obtained by this method were 90.2±3.14
pF and 35.7±1.07 pF for adult and pediatric myocytes, respectively.
The series resistance (Rs) for the pathway
between the pipette and cell membrane was estimated from the equation
Rs=/Cm. The
uncompensated Rs was 3.53±0.12 M for
adult and 3.1±1.01 M for pediatric cells. To minimize the duration
of the capacitative surge and voltage drop across the pipette,
Rs was compensated electronically
(typically by 30% to 60%). The amplitude of
Ito always was measured as the difference
between the peak current and the steady-state level of current
remaining at the end of the pulse (typically of 800-ms duration). To
determine the effects of quinidine on the inwardly rectifying potassium
current (IK1) and the sustained current
(Isus), a p/4 post hoc leak subtraction
procedure was used.
Statistics and Data Analysis
Data are presented as mean±SEM. Data analysis
and curve fitting were performed using the software packages Clampfit
(pClamp software, Axon Instruments), Origin (Microcal Software), and
GraphPad Prism (GraphPad Software, Inc). Differences between group
means were evaluated for statistical significance using Student
t test. An unpaired t test was used to compare
statistically best-fit values of the drug concentration producing 50%
inhibition (IC50) of adult and pediatric
Ito, Isus, and
IK1 (GraphPad Prism).
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Results |
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Effect of Postnatal Development on Ito Amplitude
In a previous study, it was reported that there is an age-related difference in human atrial Ito density, with pediatric current having half the density of the adult Ito.12 Because the time course over which Ito undergoes its developmental change was not well defined, we compared values of Ito amplitude obtained for 9 different age groups ranging in age between 0 to 1 month and 56 to 75 years. As demonstrated in Figure 1A
, the amplitude of human atrial
Ito did not change significantly during the
first 2 years of life, after which it doubled in amplitude between the
ages of 2 and 11 years and then remained relatively constant until at
least 75 years of age.
Affinity of Adult and Pediatric Itofor Quinidine
To define the age-dependent change in quinidine's effect on human
Ito, cells from the 2 age groups were
exposed to 5 different concentrations of quinidine (1, 3, 10, 100, and
1000 µmol/L), and dose-response curves for quinidine's effect
on the peak Ito were constructed (Figure 1B). Because of the spontaneous time-induced shift in
Ito voltage dependence of inactivation,
individual cells were exposed to a single concentration of quinidine.
For the same reason, peak currents before and at the time of exposure
to quinidine were measured during a depolarizing step to 60 mV from a
holding potential of -80 mV. Mean values obtained at different
quinidine concentrations were fit with the equation
1/(1+(IC50/[D])N), where
[D] is the concentration of quinidine, IC50 is
the quinidine concentration producing a 50% inhibition of
Ito, and N is the Hill coefficient. The
least squares best-fit parameters for pediatric inhibition
of peak Ito were
IC50=112.2 µmol/L and N=0.82. For adult
cells, the values were IC50=21.8 µmol/L
and N=0.67. Comparison of the IC50 values
obtained for the 2 age groups using a t test (GraphPad
Prism) indicated that pediatric Ito was
significantly less sensitive to quinidine than were adult cells
(P<0.0001).
In addition to decreasing Ito density,
quinidine also accelerated the rate of Ito
decay in both adult and pediatric cells (Figure 1B), a behavior
suggesting that channel block develops after channel
opening.16 In both the absence and presence of quinidine,
the decaying phase of Ito was well fit by a
single exponential function for the 2 age groups. The effect of
quinidine on current decay kinetics was concentration-dependent but
age-independent. At 60 mV, the rec of
Ito decay in adult cells was decreased from
77.7±5 ms (n=12 to 14) under control conditions to 41.3±1.4 ms (n=5
to 7), 22.4±3.1 ms (n=12 to 14), and 14.6±2 ms (n=5 to 8) in the
presence of 1, 3, and 10 µmol/L quinidine, respectively.
Quinidine produced a similar reduction in the
rec of Ito decay
in pediatric cells. Under control conditions, the
rec for decay at 60 mV was 64.5±5.4 ms (n=15
to 18), which decreased during exposure to 1, 3, and 10 µmol/L
quinidine to 39.6±5.2 ms (n=5), 18.5±1.4 ms (n=5 to 7), and 20.1±2.4
ms (n=5), respectively.
A drug-induced reduction in peak current amplitude could result from a drug-induced shift in voltage dependence of inactivation, as well as open channel block. Equilibration in the presence of 10 µmol/L quinidine for 8 to 10 minutes resulted in a hyperpolarizing shift in the midpoint for Ito inactivation by 7.9±1.9 mV in pediatric cells (n=6) and 9±1.9 mV in adult cells (n=11). However, the amplitude of the shift in the midpoint was not significantly different from the amplitude of the spontaneous shift observed for cells exposed to quinidine-free solutions for the same time interval (at 1 to 5 minutes, Vmid=-22.9±1.3 mV; at 20 to 25 minutes, Vmid=-32.7±1.7 mV). This suggests that quinidine itself does not produce a significant shift in the voltage dependence of inactivation and that the change in the midpoint of the inactivation curve measured during quinidine perfusion is due to perfusion (time) alone. The slope of adult and pediatric voltage dependence of Ito inactivation was not affected by quinidine either (adult: n=8, control k=-5.2±0.2 mV, 10 µmol/L quinidine k=-6.1±0.3 mV; pediatric: n=6, control k=-6.3±0.6, 10 µmol/L quinidine k=-7.8±1.5 mV).
Voltage Dependence of Ito Recovery From
Quinidine Block
Recovery from quinidine block was defined using a paired-pulse
protocol (Figure 2A). Channel block was
initially produced using an 800-ms–long pulse, and the time course for
recovery from block then was defined using a second pulse evoked after
a variable recovery time, ranging from 3 to 8000 ms. Under
drug-free conditions, the recovery of channels from inactivation at
-40 mV could be well described by a single exponential equation having
a rec significantly smaller in adult cells
(292±27 ms) compared with pediatric cells (450±49 ms; Figure 2A through 2C). This difference in rec
decreased progressively as the recovery potential was made more
hyperpolarized, with rec becoming nearly
identical at -80 mV (adult, 62±5 ms; pediatric, 71±7 ms; Figure 2C). In the presence of quinidine, the recovery of
Ito from block was a double-exponential
process (Figure 2A and 2B). The fast
rec was similar to the recovery
rec observed during control conditions and was
assumed to reflect the recovery of drug-free channels from
inactivation. The rec for the slow phase of
Ito recovery observed in quinidine
(quin) was assumed to reflect the time course
of quinidine unbinding from channels. Pediatric
Ito was found to recover significantly
slower from quinidine block at -40 mV
(quin=2938±454 ms) compared with adult
channels (quin=1628±187 ms;
P<0.007; Figure 2D). We also observed a marked
developmental difference in the voltage dependence of the
rec for quinidine unblocking. In adult cells,
the unblocking rec increased significantly
with hyperpolarization from -40 to -80 mV,
whereas in pediatric cells, the unblocking rec
underwent an apparent, although not statistically significant decrease
with hyperpolarization (Figure 2D). The
marked difference in voltage sensitivity suggests that the mechanisms
for quinidine unblocking are different in pediatric versus adult
myocytes. The voltage dependence for quinidine unblocking (Figure 2D) in both age groups was also significantly different from
that observed for recovery from channel inactivation under control
conditions. In the absence of quinidine, the recovery
rec changed e-fold (2.7) for a 10.7-mV
change in the membrane potential for pediatric cells and e-fold for
every 12.6 mV for adult Ito (Figure 2C). In contrast, quin changed by
<20% over a 40-mV voltage range in pediatric cells and displayed a
voltage dependence opposite of control rec in
adult cells. This suggests that the mechanism underlying the slow
interpulse recovery of Ito in the presence
of quinidine does not result from a simple slowing of recovery from
inactivation.
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t) at 4 different
potentials (-40, -50, -60, and -80 mV). A and B, Recovery of adult
(A) and pediatric (B) Ito from block at
Vh=-40 mV (n=7 and 12, respectively). Currents during the
test pulse have been normalized to the amplitude of
Ito after a long rest. In the absence of
quinidine, recovery of pediatric and adult
Ito was a monoexponential
process, with pediatric Ito recovering
almost twice as slow as the adult (pediatric
Effects of Quinidine on IK1,
Isus, and Ins
Previous work by Wang et al17 reported that quinidine
significantly suppressed the sustained current left after inactivation
of Ito with an estimated
IC50 of 5 µmol/L. Initial experiments
suggested that this sustained current (designated
IKur) resulted from the expression of the
gene Kv1.5.18 However, it was found later that the
sustained outward current (Isus) is carried
by a combination of at least 2 currents (70%
IKur and 30% by a nonselective current,
Ins).19 Figure 3A and 3B shows the effect of 100
µmol/L quinidine on the total steady-state current. The steady-state
current measured at the end of an 800-ms pulse to 60 mV was suppressed
by 57±6% in the presence of 100 µmol/L quinidine. The
quinidine-sensitive (difference) current was an outwardly rectifying
current (Figure 3B, inset), suggestive of a selective blockade
of IKur.
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To further test this hypothesis, we defined the effect of quinidine on
the nonselective cation current (Ins) using
potassium-free (cesium-containing) pipette solutions, an experimental
condition that rapidly eliminated other K-selective currents (eg,
IK1, IKur, and
Ito), allowing us to define selectively
quinidine's effect on Ins. As demonstrated
in Figure 3C, Ito was abolished
within 3 minutes after rupturing the membrane when using a pipette
filled with potassium-free solution. The current left
represented the nonselective cation current.19
As shown in Figure 3C and 3D, 100 µmol/L quinidine had no
definable effect on Ins. This supports the
conclusion that quinidine's inhibitory effect on the total
steady-state current (Figure 3B) is exclusively due to
quinidine-induced block of IKur, whose
density is known not to be age-independent.12
Dose-response curves defining the inhibitory effect of
quinidine on the total sustained outward current
(Isus=IKur+Ins)
in pediatric and adult myocytes also were defined from measurements of
quinidine's effect on the sustained current at the end of an 800-ms
pulse during a step to 60 mV. The IC50 values
obtained after fitting the data to the Hill equation were not
significantly different between the 2 age groups (adult
IC50=6.6 µmol/L; pediatric
IC50=5.1 µmol/L; P>0.76).
Similarly, the maximal level of inhibition of the steady-state current
by quinidine was 70% for both age groups, which is
consistent with previous observations that 70% of the total
sustained outward current is carried by
IKur and that the amplitude of
Ins is age-independent.19
Previous work by Wu et al7 in rabbit myocytes has shown
that age-related changes in the sensitivity of
IK1 to quinidine may also occur. Although
no developmental change in the characteristics of
IK1 has been reported for human cardiac
tissue,12 it was difficult to rule out the possibility
that postnatal changes in IK1 sensitivity
to quinidine sensitivity may not also exist in human tissue. To define
the effects of quinidine on IK1 in
human atrial myocytes, currents were evoked by pulses ranging between
-100 and -20 mV from a holding potential of -40 mV. Current
amplitudes were measured at the end of an 800-ms pulse. Because the
nonselective current exhibits a linear current-voltage relationship
over this voltage range, a p/4 post hoc leak subtraction method was
used to isolate IK1 from other currents
(eg, Ins).19 Figure 4A shows representative
current traces of IK1 before and after
exposure to 100 µmol/L quinidine, as well as the drug-sensitive
current. The current-voltage relationship for
IK1 before and after exposure to quinidine,
and the quinidine-sensitive current are shown in Figure 4B.
Exposure to 100 µmol/L quinidine inhibited
IK1 by 47±4%. The dose-response curve for
quinidine inhibition of IK1 in pediatric
and adult cells is shown in Figure 4C. As indicated by the low N
value for current blockade (0.27 for pediatric cells, 0.25 for adult
cells), IK1 displayed a shallow
concentration dependence for blockade by quinidine. Although the
IC50 for quinidine blockade of
IK1 was apparently lower for pediatric
cells (IC50=4.1 µmol/L) compared with
adult cells (IC50=42.5 µmol/L), these
values were not significantly different, based on comparison of the
best fit parameters using an unpaired t test
(P>0.16).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Quinidine's Interaction With Human ItoIs Age-Dependent
We investigated the effects of age on the interactions of quinidine with potassium channels expressed in human atrial myocytes obtained from pediatric and adult patients. Our results indicate that there are significant developmental changes in both quinidine's affinity for human atrial Ito, as well as its mechanism of unblocking. Pediatric Ito had a
5-fold higher IC50 for inhibition by
quinidine compared with adult cells (P<0.0001; Figure 1B). In addition, adult and pediatric cells displayed a
difference in their voltage dependence of recovery from quinidine
blockade, with the voltage dependence of recovery from quinidine block
being slowed with hyperpolarization in adult cells
and relatively independent of voltage in pediatric cells (Figure 2D). The voltage dependence of quinidine unblocking in adult
cells seems most consistent with an activation trapping
mechanism.20 21 According to this mechanism, the charged
form of quinidine becomes trapped within the channel lumen by a closed
activation gate, and recovery from block then is determined by the rate
of spontaneous channel opening, which becomes progressively smaller
with increasing hyperpolarization. The lack of
significant voltage dependence of quinidine unblocking in pediatric
cells (Figure 2D) suggests that either quinidine is not trapped
by the activation gate or it is trapped equally at all voltages between
-40 and -80 mV in pediatric cells. Additional experiments will be
needed to distinguish between these possibilities. Possible
explanations for the age-dependent difference in inactivation recovery
kinetics and quinidine unblocking kinetics (Figure 2C and 2D)
include age-related changes in the mixture of multimeric
proteins that constitute a functional channel (eg, due to subunit
switching during development, as has been reported to occur between
Kv1.4 and Kv4.2/4.3 in developing rat ventricular
myocytes),22 changes in post-translational modification of
the channel, or changes in the expression of an accessory subunit (eg,
ß) that modulates channel function. Further experiments will be
required to distinguish between these possible mechanisms.
Effects of Quinidine on IKur,
Ins, and IK1
The lack of effect of quinidine on the nonselective
component (Ins) of the sustained current
(Isus) (Figure 3D) indicates that
quinidine's effect on the total steady-state current in human atrial
myocytes is a result of selective inhibition of
IKur. Quinidine's effect on
IKur was found to be age-independent with
an IC50 of 5 to 7 µmol/L
(P>0.76) in pediatric and adult atrial myocytes. Our study
also showed that quinidine inhibited the human atrial
IK1 at therapeutically relevant
concentrations. Although the estimated IC50
values for quinidine inhibition of pediatric and adult
IK1 differed by a factor of 10
(IC50=4.1 µmol/L in pediatric versus
IC50=42.6 µmol/L in adult), the
concentration dependence of quinidine blockade was extremely shallow
(N=0.25 and 0.27; Figure 4C), and the 95% confidence intervals
for the estimated IC50 values for the 2 age
groups overlapped (0.07 to 25 700 µmol/L in adult versus 0.0003
to 65 850 µmol/L for pediatric cells). Consequently, the
estimated IC50 values for quinidine
block of IK1 in pediatric and adult cells
were not significantly different.
Comparison of Results With Previous Studies
Our data on the effects of age on Ito
sensitivity to quinidine are opposite of those reported by the study on
quinidine's effects on rabbit cardiac
Ito,7 suggesting the existence of
species variations in the effects of antiarrhythmic drugs on
Ito. Interestingly, the postnatal
changes in gating behavior of rabbit Ito
are also opposite to those observed in human atrial
Ito,12 23 indicating that
significant species and/or tissue differences in the pattern of
postnatal changes in ionic currents also exist.
There are conflicting reports on the effect of quinidine on the inwardly rectifying potassium current (IK1) in different animal species, including results suggesting both inhibition7 24 or lack of effect of quinidine on IK1.25 26 27 Quinidine's effect on IK1 also has been reported to be age-dependent in rabbits, with the neonatal current being more sensitive to inhibition by the quinidine when compared with the adult current.7 However, rabbit IK1 has been shown to undergo significant developmental changes,28 29 whereas no such developmental changes have been demonstrated for human IK1.12
These results indicate that species-related differences in channel expression and the pattern of postnatal changes exist for both Ito and IK1 in mammalian cardiac tissue. In support of this hypothesis, Dixon et al30 have suggested that the Kv4.3 channel may underlie the bulk of the Ito in canine and human cardiac myocytes, whereas both Kv4.2 and Kv4.3 are likely to contribute to Ito in rat. A recent study also indicates that significant regional diversity of K channel expression also may exist between cells present in different areas of the heart (eg, atrial versus ventricular).31 For this reason, extrapolation of data on the pharmacology of ion channels from one species to another, or from one region of the heart to another, should be done with caution.
A study comparing human atrial action potentials from pediatric and adult patients was the first to suggest the existence of developmental difference in the contribution of Ito to action potential repolarization.21 Later work12 32 demonstrated age-related differences in both the density and inactivation recovery kinetics of human atria Ito, a finding confirmed by this study, as well. In contrast to the results from these 2 studies, work by Gross et al33 suggested that the amplitude and Ito inactivation recovery kinetics do not change as a function of age. The reason for the differences in the findings of these groups is unclear. Although in the study by Mansourati and Le Grand,32 Ito was recorded from cells obtained only from dilated atria, the specimens used in the study by Crumb et al,12 as well as the tissue used in this study, came only from nondilated atria (see Materials and Methods). The lack of Ito in some pediatric cells, as well as its smaller magnitude, also could contribute to the observed age-related difference in the antiarrhythmic properties of quinidine in humans.
Clinical Relevance
Clinical studies have suggested that there are age-related
differences in the effectiveness of quinidine when used for the
treatment of atrial arrhythmias, with quinidine being less
effective in the pediatric population compared with the adult
population.10 11 In theory, age-dependent differences in
the pharmacokinetics of quinidine, as well as differences in the
pharmacodynamic interaction of quinidine with heart tissue, could
contribute to the clinically observed developmental differences in the
antiarrhythmic effectiveness of quinidine. Previous studies have shown
that quinidine is cleared by both hepatic and renal mechanisms.
Approximately 60% to 85% of quinidine administered is cleared by
hepatic metabolism, with hepatic clearance in pediatric
patients being 2 to 3 times as rapid as the clearance in
adults.1 Renal clearance involves both
glomerular filtration and active tubular secretion and
accounts for 15% to 40% of total clearance.1 When renal
clearance is taken into account, the total quinidine clearance is
independent of age. The plasma concentration of quinidine has been
found to be significantly affected by the dose administered and by the
time at which the plasma sample is obtained, but not by the age of the
patients.34 This information suggests that the difference
in the antiarrhythmic effectiveness of quinidine in pediatric and adult
population cannot be accounted for by an age dependence of the
disposition kinetics of quinidine.
To our knowledge, this work is the first to investigate the effect of postnatal development on quinidine's interactions with human cardiac potassium channels. Potassium currents play an important role in regulating the shape of the cardiac action potential and the duration of the electrical refractory period. Our results indicate that quinidine produces significant age-related differences in its ability to inhibit the transient outward current. Developmental changes in quinidine's affinity for the transient outward current, as well as a developmental change in Ito density, may contribute to the reported difference in quinidine's antiarrhythmic effectiveness in pediatric and adult patients by making pediatric tissue less sensitive to quinidine-induced changes in repolarization and refractoriness.
Quinidine was observed to inhibit the sustained outward current
(IKur) at relatively low concentrations
(IC50=5 to 7 µmol/L) and in an
age-independent manner, suggesting that inhibition of this current also
may contribute to its antiarrhythmic activity in both age groups.
Quinidine was also observed to reduce the amplitude of
IK1 by 20% to 30% at therapeutic
concentrations, an effect that could contribute to drug effects on
diastolic excitability. These results help to clarify the
electrophysiological mechanisms by which
quinidine elicits its antiarrhythmic effect in pediatric and adult
patients.
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Acknowledgments |
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This study was supported by a Graduate Student Research Fellowship from the American Heart Association, Louisiana Affiliate, Inc (Dr Nenov) and NIH grant RO1-HL-36096 (Dr Clarkson).
Received May 11, 1998; accepted September 18, 1998.
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