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(Circulation. 2001;103:1317.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K+ Current
From the Department of Circulation, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan, and the Department of Internal Medicine, University of Utah, Salt Lake City, Utah (M.C.S.).
Correspondence to Dr Kaichiro Kamiya, Department of Circulation, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail kamiya{at}riem.nagoya-u.ac.jp
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Amiodarone is the most promising drug for the treatment of life-threatening tachyarrhythmias in patients with structural heart disease. The pharmacological effects of amiodarone on cardiac ion channels are complex and may differ for short-term and long-term administration.
Methods and Results—The delayed rectifier K+ current (IK) of ventricular myocytes isolated from rabbit hearts was recorded with the whole-cell voltage-clamp technique. IK was separated into 2 components by use of specific blockers for either IKs (chromanol 293B, 30 µmol/L) or IKr (E-4031, 10 µmol/L). Short-term application of amiodarone caused a concentration-dependent decrease in IKr with an IC50 of 2.8 µmol/L (n=8) but only a minimal reduction in IKs. The short-term effects of amiodarone were also determined in Xenopus oocytes expressing the cloned human channels that conduct IKr and IKs (HERG and KvLQT1/minK). HERG current in oocytes was reduced by amiodarone (IC50=38 µmol/L), whereas KvLQT1/minK current was unaffected by 300 µmol/L amiodarone. To study the effects of long-term drug administration, rabbits were treated for 4 weeks with oral amiodarone (100 mg · kg-1 · d-1) before cell isolation. Long-term administration of amiodarone decreased IK to 55% (n=10) in control rabbits and altered the relative density of IKr and IKs. The majority (92%) of current was IKr. mRNA levels of rabbit ERG,KVLQT1, and minK in left ventricular myocardium did not differ between control and long-term amiodarone.
Conclusions—Amiodarone has differential effects on the 2 components of IK, depending on the application period; short-term treatment inhibits primarily IKr, whereas long-term treatment reduces IKs.
Key Words: amiodarone • potassium • mRNA
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Amiodarone is an effective drug for the treatment of life-threatening ventricular tachyarrhythmias.1 Amiodarone has been referred to as a class III antiarrhythmic agent, but its pharmacological action is in fact very complex.2 It prolongs both action potential duration and refractory period when administered long term but blocks Na+ and Ca2+ channels after short-term administration.3 Amiodarone also has noncompetitive antisympathetic effects and modulates thyroid function, phospholipid metabolism, and production of certain cytokines.3 4 What specific action or combination of actions is fundamental and salutary for potent antiarrhythmic activity is not known. As recently reviewed, the short-term and long-term effects of amiodarone on action potentials and ionic currents of cardiac cells are quite different.5
Delayed rectifier K+ currents (IK) are important determinants of cardiac repolarization. IK is composed of 2 distinctive components: a rapidly activating component showing inward rectification (IKr) and a slowly activating component (IKs) with a linear current-voltage (I-V) relationship.6 K+ channel genes that encode IKr and IKs, are HERG7 and KVLQT1 plus minK,8 9 respectively. The effects of amiodarone on IK are still limited and controversial.10 11 12 13 Therefore, in the present study, we examined the short- and long-term effects of amiodarone on IKr and IKs in rabbit ventricular myocytes. In addition, we studied the short-term effects of amiodarone on human ERG and KvLQT1/minK channels expressed heterologously in Xenopus oocytes. The effects of long-term amiodarone on rabbit ERG,KVLQT1, and minK mRNA were also examined.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Rabbit Ventricular Myocytes
Japanese white rabbits of either sex weighing 1.5 to 2.2 kg were killed under anesthesia with thyamiral sodium (30 mg/kg IV), and the hearts were removed. Single myocytes were isolated enzymatically from the apical region of the left ventricle (approximately one third in the apex/base axis) as described previously.14 To observe the long-term effects of amiodarone, the rabbits were administered oral amiodarone (100 mg · kg-1 · d-1) for 4 weeks before cell isolation.11
Electrophysiological Recording
The single-pipette, whole-cell, voltage-clamp
technique was used for recording membrane currents. Cell capacitance
was measured by integrating the capacitive transient evoked by applying
a hyperpolarizing pulse to -5 mV from a holding potential of -50
mV. The cell capacitance and series resistance were electrically
compensated by 60% to 90%. Command potential generation and data
acquisition were controlled by pCLAMP software (version 6.0.3, Axon
Instruments) and an IBM-compatible computer. Current signals were
filtered at 1 kHz and digitized at a sampling frequency of 2 kHz.
Current measurement was started after 40-minute superfusion with normal
Tyrode’s solution to avoid possible retention of amiodarone and its
active metabolite
(desethylamiodarone)3 on the
cell surface in rabbits with oral treatment.
cRNA Injection and Voltage-Clamp of
Oocytes
Isolation and maintenance of
Xenopus oocytes and injection
with HERG cRNA were performed as described
previously.7 Stage V and VI
oocytes were injected with 10 ng
HERG cRNA.
KVLQT1 cRNA (5 ng) and
minK cRNA (1 ng) were
coinjected to induce IKs. Currents were recorded
at room temperature (22°C to 24°C) by standard 2-microelectrode
voltage-clamp techniques15 2
to 4 days after cRNA injection.
Ribonuclease Protection Assay
For the ribonuclease protection assay, rabbit
ERG,KVLQT1, and minK
subunit cDNA fragments were amplified by reverse-transcriptase
polymerase chain reaction. The nucleotide sequences of the primers and
the amplified regions are listed in
Table 1
. Gene bank accession numbers are U75212
(nucleotides187 to 456) for
ERG, U70068 (nucleotides 502 to
1133) for KVLQT1, and L41659
(nucleotides 239 to 477) for
minK. A
HindIII site (AAGCTT) was
introduced into the 5' end of the sense primers of the rabbit
ERG,KVLQT1, and minK.
The amplified cDNA was cloned into pGEM-T vector with the TA cloning
system (Promega). The ribonuclease protection assay was performed as
described
previously.16
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Solution and Drugs
The Tyrode’s solution used for cell isolation and
the single myocyte experiments was composed of (mmol/L) NaCl 143, KCl
5.4, CaCl2 1.8, MgCl2
0.5, NaH2PO4 0.25, HEPES
5.0, and glucose 5.6; pH was adjusted to 7.4 with NaOH. The glass
pipette had a resistance of 3 to 5 M
after filling with the internal
pipette solution containing (mmol/L) KOH 60, KCl 80, aspartate 40,
HEPES 5, EGTA 10, MgATP 5, sodium creatinine phosphate 5, and
CaCl2 0.65
(PCA 8.0) at pH 7.2. The
external solution used to measure K+
currents was maintained at 34°C and was composed of the following
(mmol/L):
N-methyl-D-glucamine
149, MgCl2 5, HEPES 5, and nisoldipine 0.003.
IKs and IKr were
separated by applying 2 specific blockers, chromanol 293B (30
µmol/L)17 and E-4031 (10
µmol/L),14
respectively.
Oocytes were bathed in a modified ND96 solution containing (mmol/L) NaCl 94, KCl 4, MgCl2 2, CaCl2 0.1, and HEPES 5 (pH 7.6). CaCl2 was reduced to 0.1 mmol/L to suppress endogenous Ca2+-activated Cl- current.
Amiodarone hydrochloride (Sigma Chemical Co) was dissolved in dimethyl sulfoxide to prepare a stock solution of 300 mmol/L. On the day of experiments, aliquots of the stock solution were diluted with the bath solution. Dimethyl sulfoxide at 0.1% had no significant effect on outward currents in rabbit ventricular myocytes or Xenopus oocytes. E-4031 was kindly provided by Eisai Pharmaceuticals (Tokyo, Japan); chromanol 293B, by Aventis Pharma (Frankfurt, Germany).
Statistical Analysis
Data are presented as mean±SEM unless otherwise
specified. When relative densities of IKr and
IKs and effects of long-term amiodarone
administration on the ratio were determined, current amplitudes from 2
to 3 myocytes per each rabbit heart were averaged and served as 1 datum
point. Statistical comparisons between the different experimental
groups were obtained by ANOVA. Comparisons between multiple group means
were performed with a Bonferroni-corrected
t test for all group
comparisons. Differences were considered significant at
P<0.05. Concentration-response
relationships were fit to the Hill equation to determine the
concentration of drug required for 50% inhibition
(IC50). A nonlinear least-squares curve-fitting
program (Calmpfit 6.0) was used to analyze deactivation
kinetics.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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IKr and IKs of Rabbit Ventricular Myocytes
The relative contributions of chromanol 293B–resistant and –sensitive components of IK in rabbit isolated ventricular myocytes are illustrated in Figure 1
. Depolarizing pulses for 2 seconds from -40 to 70
mV were applied from the holding potential at -75 mV at 0.03 Hz. The
tail current (IK, tail) was measured on
repolarization back to -50 mV
(Figure 1A). Application of 30 µmol/L chromanol 293B
decreased the time-dependent outward current during depolarization and
the tail current on repolarization. Additional application of 10
µmol/L E-4031 eliminated most time-dependent current.
Figure 1B illustrates the chromanol 293B–sensitive
component obtained by subtraction of the current traces. The chromanol
293B–resistant and –sensitive components of IK
were used in this study to define IKr and
IKs, respectively.
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Figure 1C
shows a tail current-voltage
(It-V) relationship for total
IK, IKr, and
IKs in control rabbit ventricular myocytes
(n=10, 22 cells). Based on sensitivity to chromanol 293B, 71% of the
tail current amplitude after depolarization to 50 mV was attributable
to IKr and 29% to IKs.
Tail current amplitudes were normalized to peak values, and the
resulting I-V relation was fitted to a Boltzmann equation to construct
isochronal activation curves
(Figure 1D).
The time courses of activation at 50 mV and deactivation at
-50 mV were determined by exponential fitting. The time constants of
IKr and IKs in control
myocytes are summarized in
Table 2. There were no significant differences between the
2 components of IK at these
potentials.
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Short-Term Effects of Amiodarone on
IKr and IKs
The short-term effects of amiodarone on
IKr were examined in ventricular myocytes
pretreated with 30 µmol/L 293B
(Figure 2). Application of amiodarone (0.1 to 10 µmol/L)
caused a concentration-dependent inhibition of both time-dependent
outward currents and tail currents
(Figure 2A). The residual tail currents after application of
10 µmol/L amiodarone were abolished after additional application of
10 µmol/L E-4031.
Figure 2B shows averaged I-V relationships for
IKr (n=8). The tail current density after
depolarization to 50 mV was reduced by amiodarone at 1 and 10 µmol/L
by 29% and 75%, respectively, from baseline (0.53±0.12 pA/pF). The
IC50 for block of IKr was
2.8 µmol/L
(Figure 2C).
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Short-term effects of amiodarone on
IKs were examined in myocytes pretreated with 10
µmol/L E-4031
(Figure 3). Application of 10 µmol/L amiodarone to these
myocytes caused only a slight inhibition of currents. The residual
time-dependent currents in the presence of 10 µmol/L amiodarone were
abolished after additional application of 30 µmol/L 293B. To estimate
the short-term effects of amiodarone on IKs more
precisely, 293B-sensitive components were obtained by subtraction of
current traces in the absence and presence of 30 µmol/L 293B
(Figure 3B, a-c and b-c). A minimal reduction in both
time-dependent outward currents and tail currents by 10 µmol/L
amiodarone was recognized more clearly in such subtracted current
traces.
Figure 3B shows the It-V relationship
of IKs, in which the tail current amplitude in
the subtracted current was plotted against test potential (n=9).
Amiodarone (10 µmol/L) caused a slight reduction in currents that was
associated with a 15-mV shift in the It-V
relationship.
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Effects of Amiodarone on HERG and KvLQT1/minK
Currents
HERG currents were measured with a 2-step pulse
protocol at a frequency of 0.03 Hz. From a holding potential at -90
mV, a 2-second depolarization (-80 to 50 mV) was applied to activate
outward currents, followed by return of the membrane potential to -70
mV to evoke tail currents
(Figure 4A). The amplitude of outward tail currents exceeded
the amplitude of the activating currents, characteristic of HERG
channel
behavior.11 18
Bath application of amiodarone (1 to 100 µmol/L) for 30 minutes
resulted in a concentration-dependent decrease in outward currents
during depolarization and tail currents.
Figure 4B and 4C shows the I-V relationship for currents at
the end of the depolarization step and at the peak of the tail after
repolarization, respectively (n=5). The IC50 for
amiodarone block of the HERG channel tail current was 37.9 µmol/L
(Hill coefficient=0.61; n=5).
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) and 30 minutes after amiodarone at 3 µmol/L (
), 30 µmol/L (
), and 100 µmol/L (•). C, It-V relationship for peak tail currents. D, Representative current traces recorded from oocyte expressing KvLQT1 and minK subunits before and after application of 300 µmol/L amiodarone. E, I-V relationship for currents measured at end of 7.5-second depolarization step (n=5). Data were obtained before (
Injection of oocytes with cRNA encoding KVLQT1 and minK
subunits induced IKs, characterized by a linear
I-V relationship
(Figure 4D).8 9
Currents were measured during a 7.5-second depolarizing pulse to
potentials ranging from -80 to 40 mV, with tail currents measured at
-80 mV. Pulses were applied at a frequency of 0.03 Hz. Bath
application of amiodarone did not affect the time-dependent currents
even at the highest concentration tested (300 µmol/L).
Figure 4E and 4F shows the I-V relationships for currents
during the test pulse (step) and for tail currents. Unlike what was
observed for IKs in rabbit myocytes, the
averaged I-V curve was not shifted by 300 µmol/L
amiodarone.
Long-Term Effects of Amiodarone on
IKr and IKs
Figure 5 shows IKr and
IKs in ventricular myocytes isolated from
rabbits treated with oral amiodarone (100
mg · kg-1 · d-1)
for 4 weeks. Averaged current densities of total
IK in these myocytes were significantly less
than total IK measured in cells isolated from
control rabbits. The tail current density after depolarization to 50 mV
was 0.81±0.13 pA/pF in controls (n=10; 22 cells) and 0.45±0.04 pA/pF
in cells isolated from rabbits treated long term with amiodarone (n=9;
26 cells). Application of 30 µmol/L 293B caused no substantial change
in both time-dependent outward currents and tail currents
(Figure 5A). Additional application of 10 µmol/L E-4031
resulted in complete elimination of the time-dependent currents. These
findings indicate that IKs was very small in
cells isolated from rabbits treated long term with
amiodarone.
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Figure 5B shows It-V relationships
for total IK, IKr, and
IKs in myocytes treated with long-term
amiodarone (n=9; 26 cells). After depolarization to 50 mV, 92% of the
tail current was 293B resistant (IKr), and only
8% was chromanol 293B sensitive (IKs). The tail
current density of IKr in the amiodarone-treated
myocytes (0.41±0.04 pA/pF at 50 mV) was reduced by 29%
(P<0.05) compared with control
myocytes (0.58±0.11 pA/pF at 50 mV). In contrast, the tail current
density of IKs in the amiodarone-treated
myocytes (0.04±0.02 pA/pF at 50 mV) was reduced by 83%
(P<0.05) compared with control
(0.23±0.02 pA/pF at 50 mV).
Figure 5C shows isochronal activation curves for total
IK and its 2 components.
V1/2 of total IK and
IKr did not differ significantly from the
corresponding values in control myocytes. The amplitude of
IKs was too small to analyze precisely, but its
activation curve
(Figure 5C, dotted line) was apparently shifted toward more
positive potentials compared with those of IK
and IKr. There were no significant differences
between control and amiodarone-treated myocytes in the activation and
deactivation time constants of IKr
(Table 2).
Channel Subunit Expression
The effects of long-term treatment of amiodarone on
mRNA encoding ERG, KVLQT1, and minK subunits were measured with the
ribonuclease protection assay using hearts obtained from control and
amiodarone-treated rabbits killed after 28 days. Cyclophilin mRNA
expression levels were used for the internal control. As shown in
Figure 6, the levels of rabbit
ERG,KVLQT1, and minK
mRNAs did not exhibit a significant difference between control and
amiodarone-treated rabbits.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Short-Term Effects of Amiodarone on IKr and IKs
We used myocytes isolated from the apical region of the left ventricle to minimize cell-to-cell variation of IKr and IKs resulting from their regionally different distribution.14 The activation-deactivation kinetics of IKr (chromanol 293B–resistant component) and IKs (chromanol 293B–sensitive component) in control rabbits were similar to those in our previous reports,14 19 in which IKr and IKs were estimated as E-4031–sensitive and –insensitive components, respectively. Unlike other animal species, activation-deactivation kinetics of IKr and IKs in rabbits are similar (Table 2
). Therefore, it was difficult to discriminate
between the 2 components on the basis of kinetics, necessitating a
pharmacological approach to distinguishing between
IKr and IKs. Short-term application of amiodarone to rabbit isolated ventricular myocytes resulted in a concentration-dependent decrease in the 293B-resistant component of IK (IKr) with minimal change in the 293B-sensitive component (IKs). This confirms our previous findings, also in rabbit ventricular myocytes, that short-term amiodarone (1 to 10 µmol/L) inhibited the E-4031 (10 µmol/L)–sensitive component of IK (IKr) without affecting the E-4031–resistant component (IKs).11 However, these results are at odds with a previous report on guinea pig ventricular myocytes by Balser et al.10 Differences in animal species and experimental conditions might explain the discrepancy.
The study of heterologously expressed human channels in Xenopus oocytes confirmed the short-term effects of amiodarone observed in isolated rabbit cardiac myocytes. We confirmed the findings of a recent study by Kiehn et al18 that HERG channels can be blocked by short-term amiodarone (IC50, 9.8 µmol/L) and demonstrated a lack of effect of the drug on KvLQT1/minK current.
Long-Term Effects of Amiodarone on
IKr and IKs
The most prominent effect of long-term amiodarone on
cardiac muscles is a moderate and frequency-independent prolongation of
action potential duration.5
Information available to explain the mechanism underlying the action
potential duration prolongation is limited. It was shown in our
previous study in ventricular myocytes isolated from rabbits treated
with oral amiodarone (100
mg · kg-1 · d-1
for 4 weeks) that the current densities of IK,
tail and Ito (transient outward
current) were decreased significantly compared with control rabbits (by
50% and 30%, respectively), without any appreciable changes in
their voltage
dependence.5 11
Qualitatively similar findings have been reported by Varró et
al.12 In these reports,
IK was not separated into the 2 components
IKr and IKs. In the
present study, the tail current density of total
IKr in amiodarone-treated rabbits was decreased
by 29%, whereas the tail current density of IKs
was reduced by 83% from controls. This indicates that
IK inhibition by long-term amiodarone is
predominantly due to a reduction in
IKs.
Recently, Bosch et
al13 reported that long-term
treatment of guinea pigs with intraperitoneal amiodarone (80
mg · kg-1 · d-1
for 7days) caused a substantial reduction in the current density of
IKr and IKs of
ventricular myocytes to a similar extent (60% reduction) without
affecting their voltage-dependence or kinetics. Different periods of
amiodarone administration (4 versus 1 week), different experimental
protocols, and different animal species (rabbits versus guinea pigs)
may underlie the discrepancy between our data and their
observations.
Study Limitations
We focused our investigation on the short- and
long-term effects of amiodarone on IKr and
IKs because block of these currents is an
obvious candidate mechanism for the class III properties of this drug.
However, the antiarrhythmic action of amiodarone likely results from
inhibition of multiple channels and
receptors.3 5 In
addition, long-term effects of amiodarone on the heart are modulated by
plasma and tissue accumulation of the parent drug and its active
metabolite desethylamiodarone, which would impose their direct
effects.3 5
mRNA levels of ERG, KVLQT1, and minK potassium channel subunits were not affected by long-term amiodarone, indicating that the reduction in IKs density cannot be ascribed to reduced transcription of mRNA. The mechanism of reduced IKs is unknown but may be due to an effect on the posttranscriptional processes of channel protein synthesis.
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Acknowledgments |
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This work was supported in part by grants-in-aids from the Ministry of Education, Science, Sports, and Culture.
Received July 12, 2000; revision received September 20, 2000; accepted September 29, 2000.
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References |
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