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(Circulation. 2001;104:951.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Density and Kinetics of I_Kr and I_Ks in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of I_Ks Blockade at High Heart Rate in Guinea Pig and Rabbit

Implications for Arrhythmogenesis in Humans

Zhibo Lu, MD; Kaichiro Kamiya, MD; Tobias Opthof, PhD; Kenji Yasui, MD; Itsuo Kodama, MD

From the Department of Circulation, Division of Regulation of Organ Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan (Z.L., K.K., K.Y., I.K.), and the Department of Medical Physiology, University Medical Center Utrecht, Utrecht, Netherlands (T.O.).

Correspondence to Kaichiro Kamiya, Department of Circulation, Division of Regulation of Organ Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan. E-mail kamiya{at}riem.nagoya-u.ac.jp

	Abstract

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Background—— Class III antiarrhythmic agents commonly exhibit reverse frequency-dependent prolongation of the action potential duration (APD). This is undesirable because of the danger of bradycardia-related arrhythmias and the limited protection against ventricular tachyarrhythmias. The effects of blockade of separate components of delayed rectifier K⁺ current (I_K) may help to develop agents effective at high heart rate.

Methods and Results—— We assessed the density and kinetics of the 2 components of the delayed rectifier K⁺ current, I_Kr and I_Ks, in rabbit and guinea pig ventricular myocytes. The effects of their specific blockers (chromanol 293B for I_Ks and E-4031 for I_Kr) on the action potential was studied at different heart rates by use of whole-cell patch-clamp techniques. In guinea pig ventricular myocytes only, blockade of I_Ks causes APD prolongation in a frequency-independent manner, whereas blockade of I_Ks in rabbit ventricular myocytes shows reverse frequency dependence, as does blockade of I_Kr in both species. This result can be explained primarily by the higher density of I_Ks in guinea pig ventricle and by its slow deactivation kinetics, which allows I_Ks to accumulate at high heart rate because little time is available for complete deactivation of it during diastole.

Conclusions—— Density and kinetics of components of I_K explain why blockade of I_Ks is more effective at high heart rate in the guinea pig ventricle than in the rabbit ventricle, without adverse effects at low heart rate.

Key Words: potassium • ion channels • antiarrhythmia agents • action potentials

	Introduction

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The delayed rectifier potassium current (I_K), a major determinant of action potential duration (APD), has a rapidly (I_Kr) and a slowly (I_Ks) activating component.^1,2 They differ in kinetic properties, rectification characteristics, and sensitivity to drugs.^1,2 Most of the class III antiarrhythmic drugs, such as dofetilide and E-4031, prolong APD in a reverse frequency-dependent manner by blockade of I_Kr.^2,3 Therefore, theseI_Kr blockers may act in a proarrhythmic manner during bradycardia, with minimal therapeutic potency against tachyarrhythmias.^4,5 Chromanol 293B has recently been reported to selectively block I_Ks. Moreover, it prolonged APD in a frequency-independent manner in guinea pig and human ventricular myocytes.⁶ This favorable characteristic of chromanol 293B may potentially have an antiarrhythmic effect on ventricular tachyarrhythmias without the harmful effect at low heart rate.

I_Ks has been reported to be unevenly distributed over the ventricles. It is larger in epicardium and endocardium than in midmyocardium,⁷ in the right than in the left canine ventricle,⁸ and at the base than the apex in the rabbit ventricles.⁹ The removal of these 3 types of regional inhomogeneities by pharmacological blockade may render the heart electrically more homogeneous.

From the temporal point of view, I_Kr and I_Ks display rather different activation and deactivation kinetics in ventricular myocardium of rat, guinea pig, rabbit, and dog.^9–12 Compared with guinea pigs,^2,3 I_Kr in rabbit ventricular myocardium activates 10 times more slowly, although I_Ks activates 3 times faster.⁹ Such fundamental differences in channel kinetics may be expected to have a bearing on APD prolongation and on the efficacy of different class III antiarrhythmic agents.^4,13

We compared the densities and the kinetics of I_Kr and I_Ks in guinea pig and rabbit ventricular myocytes and assessed the effects of E-4031 (I_Kr blocker) and chromanol 293B (I_Ks blocker) on APD. Specific action potential prolongation at short cycle length is feasible by I_Ks blockade in the guinea pig, but not in the rabbit. This difference is consistent with (1) the higher density of I_Ks in the guinea pig and (2) its slow deactivation, which allows little time for decrease of the current during diastole. Because I_Ks blocker produces APD prolongation at short cycle length in humans as in guinea pig,⁶ it is suggested that I_Ks is relevant in human ventricle.¹⁴

	Methods

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Isolation of Ventricular Myocytes
Japanese White rabbits (1.5 to 2.0 kg) or guinea pigs (200 to 300 g) were euthanized under anesthesia with thiamylal sodium or pentobarbital sodium after being heparinized. Single myocytes were isolated enzymatically from the middle of the left ventricular free wall by a procedure described previously.⁹ All animal procedures were approved by the Animal Care and Use Committee, Research Institute of Environmental Medicine, Nagoya University.

Electrophysiological Recordings
A single-pipette whole-cell patch-clamp method was used to record the action potential and current. The resistance of the glass pipette was 4 to 6 M after it was filled with an internal pipette solution. The cell capacitance was determined by applying a ramp voltage pulse of 0.5 V/s at a potential ranging between -50 and +70 mV. The cell capacitance and series resistance were electrically compensated by 70%. Action potentials were recorded in Tyrode’s solution and were elicited by application of a 5-ms depolarizing pulse through the pipette and recorded at cycle length from 333 to 10 000 ms. The APD was measured at 90% repolarization (APD₉₀). Voltage and current signals (filtered at 2 kHz) were stored on an IBM personal computer with PCLAMP software (version 6.0, Axon Instruments) for analysis.

Solutions and Drugs
Tyrode’s solution, used for cell isolation and the recording of action potentials, was composed of (in mmol/L) NaCl 143, KCl 5.4, MgCl₂ 0.5, NaH₂PO₄ 0.25, HEPES 5.0, CaCl₂ 1.8, and glucose 5.6 (pH 7.35 adjusted with NaOH). The internal pipette solution was composed of (in mmol/L) KOH 60, KCl 80, aspartate 40, HEPES 5.0, EGTA 10, MgATP 5.0, sodium creatinine phosphate 5.0, and CaCl₂ 0.65 (pH 7.2 adjusted with NaOH; pCa 8.0). When I_K was measured, cells were superfused with a Na⁺- and K⁺-free solution (NMG solution) composed of (in mmol/L) N-methyl-D-glucamine 149, MgCl₂ 5, CaCl₂ 0.9, HEPES 5, and nisoldipine 0.003 (pH 7.35 adjusted with HCl). The bath temperature in all experiments was 35°C to 37°C.

I_Ks was measured during blockade of I_Kr by 10 µmol/L E-4031 added to the superfusate, and I_Kr was measured during blockade of I_Ks by 30 µmol/L chromanol 293B. Action potentials were measured before and after perfusion of 10 µmol/L of each drug for 10 minutes. E-4031 was dissolved in distilled water. Chromanol 293B was dissolved in dimethyl sulfoxide (DMSO) as 100 mmol/L stock solutions and diluted in superfusates to achieve a final concentration immediately before each application. The final concentrations of DMSO (0.01% to 0.03%) had no significant intrinsic effects on the current traces and action potential configuration.

Statistical Analysis
Data were expressed as mean±SEM. Results were compared by Student’s t test for paired and unpaired data to evaluate statistical significance, and differences were considered significant at P<0.05. In analysis of activation and deactivation kinetics of I_Kr and I_Ks, the double-exponential fit was accepted as the fit of choice whenever it had a mean square error that was at least one third that obtained with a single exponential.

	Results

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Effects of 293B and E-4031 on Action Potentials
Action potentials were measured in the presence and absence of 10 µmol/L of the 2 agents in guinea pig and rabbit ventricular myocytes at the shortest cycle length (333 ms) and at a longer cycle length (1000 ms) (Figure 1). Obviously, both blockers prolonged the action potential in both species and at both cycle lengths. Blockade of I_Ks caused a larger increase in APD in the guinea pig at 333 ms than at 1000 ms and the opposite in the rabbit. Blockade of I_Kr caused virtually no increase in APD in the rabbit at 333 ms. In both species, the increase in APD during blockade of I_Kr was larger at 1000 ms than at 333 ms.

View larger version (15K): [in this window] [in a new window]   Figure 1. Rate dependence of APD prolongation by chromanol 293B (10 µmol/L) and E-4031 (10 µmol/L) in guinea pig and rabbit ventricular myocytes. Representative action potentials were recorded at cycle length of 333 and 1000 ms under control conditions, in presence of 293B, and in presence of E-4031.

Figure 2 shows cycle length (333 ms to 10 seconds) versus APD before and after administration of 10 µmol/L of the blocker in both species. As in Figure 1, reverse frequency dependence is obvious for I_Kr blockade in both species and for I_Ks blockade in the rabbit, but not the guinea pig. It may further be appreciated that APD shortens at excessively long cycle lengths in the rabbit, a well-known phenomenon due to the slow recovery from inactivation of rabbit transient outward current (I_to). Figure 3 addresses the issue of reverse frequency dependence in more detail by comparison of the increase in APD in the 2 species under the influence of both blockers and at 3 selected cycle lengths. Obviously, only I_Ks block in the guinea pig fulfills the criterion of substantial increase in APD without excessive increase at long cycle length.

View larger version (23K): [in this window] [in a new window]   Figure 2. Quantitative data of rate dependence of APD in guinea pig and rabbit ventricular myocytes under control conditions, in presence of 10 µmol/L 293B, and in presence of 10 µmol/L E-4031. Data are mean±SEM. *P<0.05 for difference between drug effect and control value at each frequency. n=12 and 10 in 293B- and E-4031–treated guinea pig ventricular myocytes; n=10 and 8 in 293B- and E-4031–treated rabbit ventricular myocytes, respectively.

View larger version (17K): [in this window] [in a new window]   Figure 3. APD prolongations as a function of cycle length (333, 1000, and 10 000 ms) in guinea pig and rabbit ventricular myocytes. Data are mean±SEM. n=12 and 10 in 10 µmol/L 293B– and 10 µmol/L E-4031–treated guinea pig ventricular myocytes; n=10 and 8 in 10 µmol/L 293B– and 10 µmol/L E-4031–treated rabbit ventricular myocytes, respectively.

Density of I_Ks and I_Kr
Figure 4A shows the representative total I_K and the separated I_Ks and I_Kr, as the E-4031–resistant and chromanol 293B–resistant currents, respectively, elicited from a holding potential of -50 mV to a step potential of 3 seconds’ duration from -40 mV to +50 mV at 0.1 Hz. Figure 4B shows the current-voltage relationship of the time-dependent outward (step) current at the end of the step potential (top) and the tail currents after stepping back to the holding potential (bottom) for I_Ks and I_Kr. Inward rectification of I_Kr is obvious in both species. The total I_K current is substantially larger in the guinea pig than in the rabbit, because I_Ks is larger in guinea pig than in rabbit. In fact, at the relevant potential range of +20 to +30 mV, which occurs during repolarization, I_Ks in guinea pig is still larger than I_Kr and I_Ks together in rabbit.

View larger version (31K): [in this window] [in a new window]   Figure 4. IK, IKs, and IKr in guinea pig and rabbit ventricular myocytes. Currents were elicited by applying depolarizing potentials to various levels ranging from -40 to +50 mV for 3 seconds from a holding potential of -50 mV. IKs and IKr were obtained as E-4031 (10 µmol/L)–resistant current and chromanol 293B (30 µmol/L)–resistant current. A, Representative current traces for guinea pig and rabbit ventricular myocytes. B, I-V relationships for step current and tail current of IKs and IKr in guinea pig (left) and rabbit (right) ventricular myocytes. n=10 for guinea pig and n=12 for rabbit.

Activation and Deactivation Kinetics of I_Ks and I_Kr
Figure 5 shows the voltage-dependent activation properties of total I_K and I_Ks and I_Kr tails of guinea pig and rabbit ventricular myocytes. Figure 5B shows that the voltage at which half activation is achieved (V_h) for I_Kr is similar in rabbit and in guinea pig (-21.9±1.4 and -20.6±2.5 mV, respectively). Figure 5C, however, shows a substantially more negative V_h for I_Ks in rabbit (-1.2±1.7 mV) than in guinea pig (+18.2±1.7 mV). Consequently, total I_K was activated at more negative potential in rabbit than in guinea pig (Figure 5A: rabbit V_h -8.6±1.1 mV; guinea pig V_h +8.1±3.5 mV).

View larger version (18K): [in this window] [in a new window]   Figure 5. Voltage-dependent activation of IK, IKs, and IKr in guinea pig and rabbit ventricular myocytes. Protocol was same as in Figure 4. Tail current amplitudes were normalized to current amplitude at most positive potential. Relative activation curves were drawn by fitting averaged data as a function of test potential to Boltzmann distribution (I/Imax=1/{1+exp[(Vh-Vt)/k]}), where Vt is test potential and k is slope factor. n=10 for guinea pig and n=12 for rabbit.

Figure 6 illustrates the results of envelope-of-tails tests performed in guinea pig and rabbit ventricular myocytes. Envelopes of tail currents were evoked by applying depolarizing pulses to +50 mV from a holding potential of -50 mV, with duration ranging from 100 to 1900 ms for I_Ks (in the presence of E-4031) and from 25 to 2100 ms for I_Kr (in the presence of chromanol 239B). Tail currents after each pulse were measured on return to -50 mV. Figure 6A shows representative tracings of I_Ks and I_Kr in guinea pig and rabbit ventricular myocytes. Figure 6B shows the averaged time courses of tail envelopes obtained by fitting the tail current amplitude to a single exponential function of the pulse duration with numerical data in the Table.

View larger version (37K): [in this window] [in a new window]   Figure 6. Time-dependent activation of IKs and IKr in guinea pig and rabbit ventricular myocytes. Envelopes of tail current were obtained by applying depolarizing pulses of variable duration to +50 mV from holding potential of -50 mV. A, Representative recordings of IKs and IKr. B, Time constant of activation. n=8 for guinea pig ventricular myocytes; n=12 for rabbit ventricular myocytes. Activation time constants of IKs were approximated by single-exponential function with a time constant of 447±12 ms in guinea pig and 239±20 ms in rabbit. Activation time constants of IKr were approximated by single-exponential function in guinea pig and double-exponential function in rabbit. Time constants were 72±4 ms for guinea pig, 78±4 ms (fast component, 87%) and 624±42 ms (slow component, 13%) for rabbit.

View this table: [in this window] [in a new window]   Table 1. Time Constants of the Activation and Deactivation Kinetics of IKs and IKr in Guinea Pig and Rabbit Ventricular Myocytes

The deactivation time constants were examined by double-exponential fit of tail currents recorded on repolarization to a potential of -50 mV after a 3-second pulse to +50 mV. The Table summarizes the fast and slow time constants (_f and _s) for the deactivation of each component in guinea pig and rabbit ventricular myocytes. Average values of both deactivation time constants (_f and _s) of guinea pig I_Ks were longer than those of rabbit, although the difference reached statistical significance only for _f.

Slow deactivation will presumably result in accumulation of the activated state during rapid pacing. Figure 7 compares frequency dependence of I_Ks and I_Kr at high heart rate in guinea pig and rabbit ventricular myocytes. A train of 30 depolarizing-clamp pulses of 200 ms to +30 mV to mimic the configuration of the ventricular action potential was applied at a rate of 3.0 Hz. After 30 depolarizing pulses, the amplitude of I_Ks tail was augmented markedly in guinea pig ventricular myocytes (from 2.32±0.71 to 3.54±1.01 pA/pF) but little in rabbit (from 0.45±0.11 to 0.57±0.19 pA/pF). No difference between the 1st and the 30th traces for I_Kr was observed in either species (0.99±0.27 to 1.01±0.26 pA/pF for guinea pig and 0.36±0.06 to 0.34±0.08 pA/pF for rabbit). These frequency responses on I_Ks and I_Kr are well explained by the kinetics of currents in both species.

View larger version (16K): [in this window] [in a new window]   Figure 7. Frequency dependence of IKs and IKr in guinea pig and rabbit ventricular myocytes. A train of 30 depolarizing clamp pulses of 200 ms to +30 mV from holding potential of -50 mV were applied at a rate of 3 Hz. Tail currents were measured at -50 mV step (top) at 1st, 2nd, and 30th depolarizing pulses. Horizontal dotted lines in current traces indicate zero current level.

	Discussion

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In the present study, blockade of I_Ks by 10 µmol/L chromanol 293B prolonged APD in guinea pig ventricular myocytes independently of heart rate (Figures 1 to 3). This effect may be understood if (1) the high density of I_Ks in guinea pig ventricle is considered (Figure 4) as well as (2) its slow deactivation (Table 1). Thus, at high heart rate, I_Ks tends to accumulate in guinea pig ventricle because little time is available for complete deactivation of the current between 2 action potentials.

Comparison Between the Effects of Chromanol 293B and Other Class III Drugs
Amiodarone was the first drug reported to have class III actions.¹⁵ It prolongs APD by blocking not only I_Kr, but also I_Ks,¹⁶ I_to,¹⁷ I_K1, and sodium channels.^18,19 As with chromanol 293B in guinea pig, considerable prolongation of APD remains at short cycle length.²⁰ The extent of APD prolongation by chromanol 293B (23% to 31%) is comparable to that reported in single ventricular myocytes of guinea pig and humans⁶ but much greater than that observed in multicellular ventricular tissue preparations of guinea pig,²¹ rabbit,²² and dog.²³ Different intracellular milieus might be involved in the discrepancy.

E-4031 and dofetilide are recently developed, pure class III drugs. They selectively inhibit I_Kr, as did E-4031 in this study, and show reverse frequency dependence in the prolongation of APD in canine,¹² guinea pig,³ and rabbit ventricular myocytes.^13,20 Use dependence has been reported for the effect of E-4031 on I_Kr in rabbit ventricular myocytes, although reverse frequency dependence has been demonstrated for its effects on APD.²⁴

Relevance for the Human Ventricle
In human ventricular myocytes, the presence of I_Ks is still a debated issue.^14,25–27 The evidence for the relevance of its blockade by chromanol 293B is indirect and based on the similarity of action potential prolongation in guinea pig and human ventricular myocytes at high heart rate.⁶ In right ventricular myocytes isolated from explanted human hearts with primarily left heart failure, Li et al¹⁴ demonstrated the presence of I_Ks with relatively slow activation kinetics (_f of 360 ms and _s of 8.5 seconds at +50 mV). Recently, Virág et al²⁷ showed I_Ks in undiseased human left ventricular myocytes with slow activation ( of 903 ms at +50 mV) and relatively rapid deactivation ( of 122 ms at -40 mV). Recent developments in the research field of the congenital long-QT (LQT) syndrome indicate that dysfunction of both I_Kr and I_Ks may be the cause of some forms of the LQT syndrome. One (LQT2) results from mutations in the HERG gene, and another (LQT1) results from mutations in the KVLQT1 gene. These studies strongly suggest roles for I_Kr and I_Ks in the repolarization of the human ventricular action potential.²⁸ It is essential to determine the kinetic properties of I_Kr ad I_Ks as well as their relative densities in human ventricle to understand the repolarization process and the mechanism underlying tachyarrhythmias.

Limitations
E-4031 at 10 µmol/L completely inhibited I_Kr. The concentrations of chromanol 293B (10 and 30 µmol/L) were comparable to that used by Bosch et al.⁶ Chromanol 293B blocked I_Ks by 70% at 10 µmol/L and by 100% at 30 µmol/L, at which concentration it also blocks >50% of I_to. Therefore, we used 10 µmol/L chromanol 293B to assess the effects of I_Ks blockade on APD. It can thus not be ruled out that the effect of blockade of I_Ks on APD prolongation was underestimated. We used 30 µmol/L chromanol 293B to block I_Ks completely during the assessment of I_Kr. After application of 30 µmol/L 293B, a current with obvious rectifying properties was left. An additional 10 µmol/L E-4031 blocked this current completely (data not shown). This implies that I_Kr can be defined as chromanol 293B–resistant current. The activation and deactivation time constants of rabbit I_Ks in the present study are shorter than those we reported previously.⁹ This could be due to slightly different experimental conditions in bath temperature and E-4031 concentrations.

It should be emphasized that the mechanism responsible for the frequency dependence of APD prolongation is not caused only by I_Ks and I_Kr. Other currents, such as the inward rectifier current (I_K1), Ca²⁺ inward current, Na⁺-K⁺ pump current, Na⁺-Ca²⁺ exchanger current, and slowly inactivating Na⁺ current, also contribute to frequency dependence of APD.^29,30 In addition, the contribution of these currents may be different in atrium and ventricle. Further experimental studies, especially in human tissues, are of prime importance to elucidate the issue.

Received February 1, 2001; revision received April 23, 2001; accepted April 24, 2001.

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