(Circulation. 1995;91:1799-1806.)
© 1995 American Heart Association, Inc.
Articles |
Ibutilide, a Methanesulfonanilide Antiarrhythmic, Is a Potent Blocker of the Rapidly Activating Delayed Rectifier K+ Current (IKr) in AT-1 Cells
Concentration-, Time-, Voltage-, and Use-Dependent Effects
From the Departments of Pharmacology (T.Y., D.J.S., D.M.R.) and Medicine (D.J.S., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dan M. Roden, MD, Division of Clinical Pharmacology, 532 Medical Research Building, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.
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Abstract |
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Background Ibutilide is an action potential–prolonging antiarrhythmic currently in clinical trials. The drug shares structural similarities with E-4031 and dofetilide, specific blockers of the rapidly activating delayed rectifier K+ current (IKr). However, previous in vitro studies in guinea pig myocytes have indicated that ibutilide does not block IKr but rather increases a slow inward sodium current.
Methods and Results In this study, we compared the effects of ibutilide with those of dofetilide on outward current in mouse atrial tumor myocytes (AT-1 cells), a preparation in which, unlike guinea pig, a typical IKr is the major delayed rectifier and can be readily recorded in isolation from other currents. In AT-1 cells, ibutilide and dofetilide were both potent IKr blockers, with EC50 values of 20 (n=12) and 12 (n=8) nmol/L, respectively, at +20 mV. The time and voltage dependence of IKr inhibition by the two compounds were virtually identical. The following characteristics were most consistent with open channel block: (1) block increased with depolarizing pulses; (2) block increased with longer pulses; (3) currents deactivated more slowly in the presence of drug, resulting in a "crossover" typical of open channel block; and (4) with repetitive pulsing after drug wash-in, use-dependent block was observed.
Conclusions These data suggest that the clinical actions of ibutilide are mediated at least in part by block of IKr; an effect on inward currents is not excluded. AT-1 cells are a useful model system for the study of drug block of this important repolarizing current.
Key Words: ibutilide • dofetilide • antiarrhythmic agents • myocytes
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The delayed rectifier K+ current (IK) plays an important role in controlling cardiac action potential duration, and block of IK is a major mechanism underlying action potential prolongation by antiarrhythmic drugs.1 2 3 A number of drugs with the class III action potential–prolonging attribute are currently in clinical trials. In many mammalian cardiac cells, IK is now recognized to be made up of at least two components, IKr and IKs. This distinction was first described in guinea pig cells, where IKr was defined as the component of IK blocked by the methanesulfonanilide antiarrhythmic E-4031.4 With the use of a subtraction procedure (ie, examination of the difference between baseline current and current recorded after exposure to a very high concentration of E-4031), it was possible to infer the major physiological features of IKr: rapid activation and prominent inward rectification. In other cells (eg, rabbit or cat ventricular myocytes), a prominent IKr, blocked by nanomolar concentrations of E-4031 or dofetilide, can be recorded, and no IKs is observed.5 6
A prominent IKr is also readily recorded and no IKs observed in the atria of AT-1 cells.7 These cells are derived from mice carrying a transgene in which the atrial natriuretic factor promoter drives expression of the SV40 large T antigen.8 AT-1 cells retain morphological, biochemical, and electrophysiological features of cardiac myocytes.9 10 In AT-1 cells, IKr can be studied directly, without the necessity of a subtraction procedure to eliminate overlapping currents.7 IKr recorded in AT-1 cells displays features very similar to those deduced in guinea pig cells: it activates rapidly, shows prominent inward rectification, and is blocked by nanomolar concentrations of dofetilide.
Ibutilide,
N-[4-[4-(ethylheptylamino)-1-hydroxybutyl]phenyl]-methanesulfonamide,
also prolongs cardiac repolarization in vitro and in vivo, including in
humans.11 12 13 This effect has been
attributed to activation
of a slow inward current rather than inhibition of outward potassium
current14 ; however, studies characterizing the effects of
ibutilide were performed in guinea pig myocytes, in which multiple
K+ currents are present and subtraction is required to
delineate drug effects. Since ibutilide shares the
methanesulfonanilide motif (Fig 1
) seen in other
antiarrhythmics known to block IKr (E-4031 and dofetilide),
we performed the present study in AT-1 cells to test the hypothesis
that ibutilide is a blocker of IKr. The characteristics of
the effects of ibutilide in this system were compared with those of
dofetilide.
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Methods |
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Cell Preparations
The transgenic animals and initial characterization of AT-1 cells have been reported by the Field and Claycomb laboratories (Steinhelper et al9 and Delcarpio et al10 ). We have used these methods to establish a self-sustaining colony of tumor-bearing mice. To isolate the cells, we used procedures described previously.7 In brief, tumors were minced and digested with collagenase-containing PC-1 medium. After gentle centrifugation, supernatants were collected, plated, and cultured for at least 1 week at 37°C. In the experiments described here, cells cultured for 7 to 14 days were disaggregated by a brief trypsinization procedure and stored until use (within 48 hours) in culture medium at room temperature (22° to 23°C). Cells that appeared round were then used for electrophysiological study.
Electrophysiological Recording
Recordings were made at room
temperature with an Axopatch-1A
patch-clamp amplifier (Axon Instruments, Inc) using the whole-cell
configuration of the voltage-clamp technique.15
Microelectrodes were pulled from starbore borosilicate glass (Radnoti
Co) and were heat-polished. Ion currents were low pass filtered at 500
Hz (Bessel filter, -3 dB), sampled at 1 kHz, and stored on the hard
disk of an IBM PC-AT for subsequent analysis. Data acquisition and
command potentials were controlled with a commercial software program
(PCLAMP, Axon Instruments). To ensure voltage-clamp
quality, microelectrode resistance (Re) was kept below 3
M
. Junction potential was zeroed with the electrode in the bath
solution. The microelectrode was then gently lowered onto the cell
surface, and gigaohm seal formation was achieved by suction (range, 5
to 50 G). After the seal was ruptured and the whole-cell
configuration established, the capacitive transients elicited by 10-mV
voltage-clamp steps from -80 to -70 mV were recorded at 50 kHz
(filtered at a bandwidth of 10 kHz, -3 dB) for subsequent calculations
of capacitive surface area, time constant, and access resistance
(Ra). Thereafter, capacitance and series resistance
compensation were optimized; approximately 80% compensation was
usually obtained.
Solutions and Drugs
The intracellular pipette filling
solution contained (mmol/L)
KCl 110, K4BAPTA 5, K2ATP 5,
MgCl2 1, and HEPES 10, and the solution was adjusted to pH
7.2 with KOH, yielding a final intracellular K+
concentration of approximately 145 mmol/L. The extracellular Tyrode's
solution contained (mmol/L) NaCl 130, KCl 4, CaCl2 1.8,
MgCl2 1, HEPES 10, and glucose 10, and the solution was
adjusted to pH 7.35 with NaOH.
Ibutilide was provided by Upjohn Pharmaceutical Co. Nisoldipine (to block L-type Ca2+ current, ICa-L) was obtained from Miles Pharmaceutical, Inc, and dofetilide was provided by Pfizer Central Research. Other chemicals were purchased from Sigma Chemical Co. In the experiments in which the use dependence of drug block was measured, INa was eliminated by an Na+-free extracellular solution (N-methyl-D-glucamine was substituted for Nao), and NiCl2 was used to block T-type Ca+ current, ICa-T. The final drug concentrations in the bath were obtained by diluting stock solutions into the extracellular solution during experiments.
Voltage-Clamp Protocols and Analysis
In this study,
INa and ICa-T were
inactivated with a holding potential of -40 mV, and cycle time between
pulses was 15 seconds unless indicated otherwise. When drug was added,
activating current was monitored by depolarizing pulses every 15
seconds, and "on-drug" data were recorded only when steady state
was reached. To obtain current-voltage relations for K+
current in AT-1 cells, activating currents were elicited with
depolarizing pulses from a holding potential of -40 to +50 mV in
10-mV
steps, and deactivating tail currents were recorded on repolarization
to -40 mV unless otherwise indicated. As we have previously
reported,7 activating current elicited under these
conditions satisfies an envelope test; ie, it is composed of a single
component. Evidence that this current is IKr includes the
relatively rapid activation of the current (eg, 
=182±27
milliseconds at +20 mV), its prominent inward rectification, and block
by nanomolar concentrations of dofetilide.7 AT-1 cells
also display INa, ICa-L, and
ICa-T, which were eliminated as described above.
As
illustrated in Fig 2, activating IKr was
defined as the difference between initial and steady-state currents
obtained at the end of depolarization within a moving window of 10 to
20 milliseconds beyond capacitive transients. The deactivating
IKr tail was the difference between peak and steady-state
currents with repolarizing pulses. Instantaneous current, which in
other cell types represents a plateau potassium current or a
chloride current,16 17 and recovery from fast
inactivation
(large arrow, Fig 2)18 were occasionally observed
but were
not further studied. After linear leak subtraction, macroscopic
currents were normalized to cell capacitance.
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The concentration dependence of drug block of IKr was determined by first normalizing on-drug current as Idrug/Icontrol and then fitting these data to the Hill equation, Idrug/Icontrol={1+[EC50/(drug)]n}, where EC50 is the concentration producing 50% block, and n is the Hill coefficient. To analyze the voltage dependence of activation and deactivation, Idrug/Icontrol versus voltage data were fit to the Boltzmann equation, Idrug/Icontrol=1/{1+exp[-(E-Eh)k]}, where k represents the slope factor and Eh the voltage at which 50% of the channels are activated or inactivated. The time course of tail currents was fit with sums of multiple exponential terms. All fitting was performed with software developed in our laboratories19 20 using nonlinear least-squares fitting procedures.
Results are expressed as mean±SEM. Student's t test was used to compare differences between mean values, with a value of P<.05 considered significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Concentration Dependence
Activating currents elicited by 1-second pulses to +20 mV and subsequent tail currents at -40 mV are shown in Fig 3
.
These data demonstrate that ibutilide, like dofetilide, is a potent
blocker of IKr in AT-1 cells. The concentration dependence
of block by the two drugs is presented in Fig 4A.
The EC50 for block with 1-second pulses to +20 mV was 20
nmol/L (n=12) for ibutilide and 12 nmol/L (n=8) for dofetilide.
Fig 4B
shows that the EC50 for drug block during 1-second
depolarizing pulses was voltage dependent, with greater drug
sensitivity at positive potentials.
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, n=12) and dofetilide
(
, n=8). Each data point represents the mean of 4 to 12
experiments. B, Line graph shows voltage dependence of EC50
values determined as in A.
Voltage and Time Dependence
Block of activating and
deactivating outward current is shown in
Figs 5 and 6. Fig 5 shows the
very
prominent inward rectification of activating IKr and
demonstrates that virtually all activating current was inhibited by 1
µmol/L of either drug. Similarly (Fig 6), deactivating
tails were
abolished by 1 µmol/L of either drug. Concentrations near the
EC50 (Figs 6 and 7) were used to
assess the
voltage dependence of tail current block. Block by both drugs was most
prominent after pulses to positive potentials, consistent with the
lower EC50 values calculated at positive potentials (Fig
4B
).
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) and presence (
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The data with intermediate drug concentrations (10
to 100 nmol/L) (Fig 3) suggest that the time course of
activation was altered by the drugs:
the depression of activating current became more prominent as the pulse
duration increased. Envelope of tails tests (Fig 8) were
also consistent with this finding. In the absence of drug, the time
course of peak currents paralleled that of activating current with a
long pulse; ie, the envelope of tails test was satisfied. When either
drug was added, two effects became apparent. First, block of activating
current was much more prominent than block of tails, and second, the
time course of activating current now displayed slow inactivation-like
behavior, again suggesting drug block of open channels. Fractional
block of deactivating tail current as a function of activating pulse
duration developed with a time constant of 289 milliseconds at +20 mV
(Fig 9). These data indicate that block increased with
increasing pulse duration, strongly suggesting block of open
channels.
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State Dependence
Further evidence in favor of open channel
block is presented
in Fig 10. Note that in these experiments, nisoldipine
was omitted from the extracellular solution, and an inward
ICa-L was recorded and unaffected by either drug. With
2-second depolarizing pulses to +20 mV, the evidence of open channel
block during the depolarizing pulse described above was again observed.
With repolarization to -20 mV, the magnitude of the deactivating tails
was reduced, but their time courses appeared similar to those recorded
before drug. At -20 mV, deactivation was well characterized by a
monoexponential function, and the time constants were very similar
before and during drug (Table). However, with subsequent
repolarization to -50 mV, deactivation was slower in the presence of
drug than in control, resulting in a tail current "crossover"
that, as discussed below, has been taken as indicating open channel
unblocking. At -50 mV, deactivation was fit with a biexponential
function, and both time constants were prolonged by the drugs
(Table).
In addition, whereas IKr was reduced 41±6% by ibutilide
at -20 mV, block was much less prominent at -50 mV (22±5%,
n=4),
consistent with the voltage dependence shown in Fig 7.
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Pulses at frequencies of 0.2 to 5.0 Hz in the presence of either drug
did not reveal any steady-state frequency dependence of block (Fig
11). However, when preparations were studied after
prolonged quiescence while drug was washed in, further evidence for
activation-dependent block was observed (Figs 12 and
13). With pulsing after 5 minutes of
quiescence in control, tail currents following successive
depolarizations at 0.66 Hz were superimposable (Figs 12A and
13A).
However, when the same protocol was repeated after drug wash-in, two
effects were observed. First, block was use dependent, supporting the
likelihood of open channel block. The time constant for onset of drug
block was 3.8±0.2 pulses with ibutilide (Fig 12D) and
2.8±0.3 pulses
with dofetilide (Fig 13D). Second, even with the first pulse,
tail
current was reduced 30±3% with ibutilide and 32±3% with
dofetilide.
This is consistent with rest-state block or with development of
open-state block during the first pulse. However, activating outward
current during the first pulse was reduced 24±5% at 20 mV with
ibutilide and 26±4% at 20 mV with dofetilide (Figs 12C
and 13C),
suggesting that rest-state block need not be involved to explain the
reduction in the first tail current during these trains. Block by
ibutilide or dofetilide was not reversible with washout.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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A challenge to contemporary electrophysiology is to determine the relation between specific ion channel blocking effects and drug actions in the whole heart.12 21 22 Thus, the initial description that ibutilide appeared to exert a novel ion channel–activating behavior has led to its being used as a probe to determine the effect of this drug action in cells and in the intact heart.22 However, the data we present here demonstrate convincingly that ibutilide does block IKr and that the block is qualitatively very similar to that produced by dofetilide. Moreover, ibutilide block occurs at relatively low concentrations, raising the possibility that block of IKr is one mechanism whereby the drug exerts its in vivo effects. In previous experiments in guinea pig myocytes, Lee14 reported that ibutilide activated a slow inward current with a Kd of 1 to 2 nmol/L; the concentrations during treatment in humans have not yet been reported.
The methanesulfonanilide moiety is common to a number of compounds thought to prolong cardiac action potentials by blocking IKr. These include not only dofetilide6 23 but also E-4031,5 24 sotalol,24 sematilide,21 and L691,121.25 Although some of these (eg, sotalol26 ) may exert other actions, IKr block appears to be an important component of their clinical actions. In the present study, we did not undertake a comprehensive reevaluation of the effect of ibutilide on other ion currents, including the slow inward sodium current described by Lee.14 Thus, we cannot rule out the possibility that ibutilide exerts additional effects that will contribute to its clinical actions.
Prolongation of cardiac action potentials, by specific IKr block or by nonspecific effects, appears to exert a number of potentially important and desirable effects on whole heart electrophysiology. These include facilitated defibrillation27 and efficacy in animal models of ischemic ventricular fibrillation (in contrast to sodium channel block).28 29 On the other hand, marked QT prolongation and torsades de pointes have occurred with many new IKr blockers (not all of which have the methanesulfonanilide structure), including dofetilide,30 almokalant,31 sotalol,32 sematilide,33 and ibutilide.13 However, many of the reported episodes have occurred with intravenous administration during initial dose-finding studies, so the overall incidence of this problem during treatment with ibutilide or many other new IKr blockers remains to be determined. The initial clinical data do suggest that at least some torsades de pointes during treatment with this group of drugs is concentration dependent, in contrast to the well-recognized "idiopathic" nature of the syndrome with quinidine, a drug with a multiplicity of electrophysiological effects.
IKr can be dissected from IKs in guinea pig
myocytes by using pharmacological probes such as E-4031, dofetilide, or
lanthanum.4 19 23 34 However,
for the study of time or
voltage dependence of block, multiple subtraction procedures (eg,
[control versus high concentration] versus low concentration) are
required. Moreover, if IKr happens to be absent from a
particular cell or isolation, erroneous conclusions may be drawn
regarding the presence or mechanism of drug block. Thus, the study of
drug block of ion channels requires systems in which specific currents
can be readily isolated from potentially overlapping components. For
IKs, guinea pig myocytes may still be appropriate.
For IKr, on the other hand, more suitable
preparations are those in which IKs is absent, allowing
IKr to be studied in isolation; these include
cat5 and rabbit6 myocytes as well as AT-1
cells. AT-1 cells are derived from an atrial tumor in a transgenic
animal and so might not truly represent normal cardiac cells.
However, they do retain morphological, biochemical, and
electrophysiological characteristics of atrial
myocytes,7 9 10 and in particular the
IKr seen
in this preparation shares all the important characteristics for
IKr in guinea pig: inward rectification (Fig 5),
rapid
activation and deactivation (eg, Figs 3 and 8),
and block by
dofetilide, which is thought to be IKr specific. Thus, AT-1
cells are well suited for the further study of IKr
physiology and pharmacology.
The characteristics of IKr block by dofetilide in rabbit
myocytes have been reported previously.6 The data were
quite similar to those we observed here, and the EC50 for
dofetilide block found here (12 nmol/L) is well within the range of
other reports (3 to 39 nmol/L). The voltage dependence (Figs 6
and 7)
and time dependence (Figs 8 through
10) of block are similar to
those
observed previously and argue for open channel block. The tail current
"crossover" presented in Fig 10 also supports this
idea. A crossover has also been observed with quinidine block of
IKs,35 quinidine block of the cloned
channel Kv1.5,20 and E-4031 block of IKr in
cat myocytes.5 The interpretation is that as the
drug-blocked channel protein deactivates, it shuttles transiently into
a conducting state before closing: drug · open
openclosed.
If
drug unblocking is slow compared with channel closing, macroscopic
deactivation slows and a crossover occurs. The lack of steady-state
frequency-dependent block (Fig 11) has been observed by
another
researcher6 and is still consistent with very slow
recovery from open channel block. Indeed, with specifically designed
protocols, strong evidence for open channel block was observed. Drug
effects could not be washed out. However, a simple time-dependent
change in IKr cannot account for the observed drug effects,
particularly since IKr consistently remains stable for more
than 60 minutes in the absence of drug intervention. There is a paradox
in these data: the crossover phenomenon implies relatively rapid
unblocking, but we are unable to even partially wash out the effect of
either drug, even after holding at -40 or -80 mV for 5 minutes.
This
suggests to us that ibutilide and dofetilide block IKr
through at least two mechanisms: one a readily reversible one that
could account for the crossover phenomenon, and one in which the
channel is trapped in a drug-associated, nonconducting state from which
recovery is very slow. The latter could account for the apparent
frequency independence of block (Fig 11).
Block of IKr is under active clinical investigation as an antiarrhythmic mode of action. The greatest obstacle to the widespread use of this strategy appears to be the occasional development of torsades de pointes.1 2 3 AT-1 cells are a convenient model system in which factors that modulate drug block of IKr can be determined. The further use of this or similar preparations may now allow a systematic evaluation of the characteristics of IKr block by individual drugs. In this way, features of block that maximize efficacy and minimize risk may be identified.
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Acknowledgments |
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This study was supported in part by grants from the US Public Health Service (HL-46681, HL-47599, and HL-49989). Dr Roden is the holder of the William Stokes Chair in Experimental Therapeutics, a gift from the Daiichi Corp. The authors wish to thank Holly Waldrop for maintaining the AT-1 cells and Patricia James for preparing the manuscript.
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Footnotes |
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Previously presented in abstract form (Biophys J. 1994;66:A83).
Received August 25, 1994; accepted October 31, 1994.
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