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(Circulation Research. 1996;78:499-503.)
© 1996 American Heart Association, Inc.

Articles

Class III Antiarrhythmic Drugs Block HERG, a Human Cardiac Delayed Rectifier K⁺ Channel

Open-Channel Block by Methanesulfonanilides

Peter S. Spector, Mark E. Curran, Mark T. Keating, Michael C. Sanguinetti

From the Cardiology Division (P.S.S., M.E.C., M.T.K., M.C.S.), Eccles Program in Human Molecular Biology and Genetics (M.C.S.), Department of Human Genetics (M.E.C., M.T.K.), and Howard Hughes Medical Institute (M.T.K.), University of Utah Health Sciences Center, Salt Lake City.

Correspondence to Michael Sanguinetti, PhD, Cardiology Division, University of Utah Health Sciences Center, Salt Lake City, UT 84112. E-mail mikes@gene1.med.utah.edu.

	Abstract

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Abstract We recently reported that mutations in HERG, a potassium channel gene, cause long QT syndrome. Heterologous expression of HERG in Xenopus oocytes revealed that this channel had biophysical properties nearly identical to a cardiac delayed rectifier K⁺ current, I_Kr, but had dissimilar pharmacological properties. Class III antiarrhythmic drugs such as E-4031 and MK-499 are potent and specific blockers of I_Kr in cardiac myocytes. Our initial studies indicated that these compounds did not block HERG at a concentration of 1 µmol/L. In the present study, we used standard two-microelectrode voltage-clamp techniques to further characterize the effects of these drugs on HERG channels expressed in oocytes. Consistent with initial findings, 1 µmol/L MK-499 and E-4031 had no effect on HERG when oocytes were voltage clamped at a negative potential and not pulsed during equilibration with the drug. However, MK-499 did block HERG current if oocytes were repetitively pulsed, or clamped at a voltage positive to the threshold potential for channel activation. This finding is in contrast to previous studies that showed significant block of I_Kr in isolated myocytes by similar drugs, even in the absence of pulsing. This apparent discrepancy may be due to differences in channel characteristics (HERG versus guinea pig and mouse I_Kr), tissue (oocytes versus myocytes), or specific drugs. Under steady state conditions, block of HERG by MK-499 was half maximal at 123±12 nmol/L at a test potential of -20 mV. MK-499 (150 nmol/L) did not affect the voltage dependence of activation and rectification nor the kinetics of activation and deactivation of HERG. These data indicate that MK-499 preferentially blocks open HERG channels and further support the conclusion that HERG subunits form I_Kr channels in cardiac myocytes.

Key Words: HERG • K⁺ current • class III antiarrhythmic drug • Xenopus oocytes

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
In cardiac myocytes, activation of a delayed rectifier K⁺ current, I_Kr, initiates repolarization and terminates the plateau phase of the action potential. Methanesulfonanilides (eg, E-4031, dofetilide, MK-499) block I_Kr and prolong action potential duration. Excessive prolongation of action potentials by these class III antiarrhythmic drugs, an effect exacerbated by hypokalemia and bradycardia, can cause acquired long QT syndrome (LQT). LQT is associated with torsade de pointes, an arrhythmia that can degenerate into ventricular fibrillation, and may be one cause of sudden cardiac death.

LQT can also be inherited as an autosomal-dominant disorder. We recently reported that mutations in HERG cause chromosome 7–linked LQT.¹ Heterologous expression studies revealed that HERG encodes subunits of a K⁺ channel with biophysical characteristics similar to I_Kr.² We hypothesized that a decrease in I_Kr, either by pharmacological block or by mutations in HERG, results in prolonged cardiac repolarization and LQT. However, we initially found that HERG expressed in oocytes was unaffected by 1 µmol/L MK-499 or E-4031, drugs known to be specific blockers of I_Kr in cardiac myocytes.^{3 4 5}

In this study, we demonstrate that these drugs can block HERG, but only when channels are in the open state. This condition can be achieved by repetitive pulsing or by clamping the membrane at a voltage positive to that required for channel activation. Recently, Trudeau et al⁶ reported that inward HERG current was blocked by E-4031, an effect interpreted to result from preferential block of open channels. The finding that MK-499 and E-4031 block HERG provides further evidence that HERG subunits coassemble to form functional I_Kr channels. Moreover, these findings confirm the link between acquired and chromosome 7–linked LQT and provide a molecular mechanism for their association with torsade de pointes and sudden death.

	Materials and Methods

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cRNA Injection and Voltage Clamp of Oocytes
The HERG cDNA expression construct in the pSP64 transcription vector (Promega) and synthesis of cRNA were as previously described.²

Isolation and maintenance of Xenopus oocytes and injection with cRNA were performed as described.² Stage V and VI oocytes were injected with 60 nL of cRNA encoding HERG (0.25 ng/nL). Currents were recorded with a Dagan TEV-200 amplifier using standard two-microelectrode voltage-clamp techniques, as described,² 2 to 4 days after injection. Oocytes were bathed in a modified ND96 solution, containing (in mmol/L) NaCl 94, KCl 4, MgCl₂ 2, CaCl₂ 0.1, and HEPES 5 (pH 7.6). In some experiments, [KCl] was changed to 2 or 16 mmol/L; osmolarity was maintained by an equimolar change in [NaCl].

Data Analyses
pCLAMP software (version 6.2, Axon Instruments) was used to measure current amplitudes and fit current tracings to exponential functions. The voltage dependence of HERG current activation was determined for each oocyte by fitting peak values of tail current (I_tail) versus test potential (V_t) to a Boltzmann function:

where I_tail-max is maximum tail current. The voltage at which the current was half activated (V_1/2) and the slope factor (k) were calculated from these data.

The voltage dependence of HERG rectification was determined for each oocyte as described.² Tail currents were measured at potentials ranging from -130 to -40 mV after a 1.5-second pulse to 0 mV to fully activate HERG current. At voltages -10 mV, fully activated HERG currents were measured using 4-second pulses applied from a holding potential of -80 mV. The rectification factor (R) at each voltage was defined as:

where I_HERG is fully activated current, G is maximal conductance of I_HERG, n is activation variable at +20 mV (n=1), V_t is test potential, and E_rev is reversal potential. The relationship between R and V_t was fit with a Boltzmann function. Data are expressed as the mean±SEM (n=number of oocytes).

The percent block of HERG by different concentrations of MK-499 was fit with a Hill equation: relative current=1/{([drug]/IC₅₀)^h+1} to determine the concentration required for half block (IC₅₀) and the Hill coefficient (h).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
MK-499 and E-4031 Are Open-Channel Blockers of HERG
We previously reported that 1 µmol/L MK-499 and E-4031 had no effect on HERG expressed in oocytes. In those experiments, oocytes were voltage clamped at -70 mV and not pulsed during a 10-minute equilibration with drug. MK-499 did not significantly affect HERG when measured with 3-second test pulses to potentials ranging from -40 to +60 mV (n=6). We subsequently discovered that MK-499 can block HERG current, but only if the oocytes are repetitively pulsed, or clamped at a membrane potential positive to the threshold for channel activation. As before, MK-499 at 1 µmol/L had no effect (4±4% increase, n=5) on HERG current measured after a 10-minute pulse-free equilibration period. However, application of repetitive (0.1 Hz, 30 pulses) voltage steps (+20 mV, 4 seconds' duration) caused a cumulative decrease in HERG. A test pulse to 0 mV was then applied 10 to 30 seconds after the pulse train. The current during this pulse was 63±6% smaller than the control pulse recorded before exposure to drug (n=5; Fig 1A and 1C). If shorter conditioning pulses were used, a greater number of pulses were required to achieve equivalent block. Block of HERG could also be achieved in the absence of pulsing if the membrane was voltage clamped at -50 mV during drug equilibration (10 minutes). At -50 mV, a fraction of HERG channels are in the open state. When oocytes were held at this potential, 1 µmol/L MK-499 blocked HERG current by 83±3% (n=5; Fig 1B and 1C). Thus, MK-499 does not block HERG channels when the membrane is held at potentials negative to that required for channel activation.

View larger version (17K): [in this window] [in a new window]   Figure 1. The class III antiarrhythmic drug MK-499 blocks only open HERG channels. A, Use-dependent block of HERG by MK-499. Current was recorded during a 2-second pulse to 0 mV in the control (con), then again after a 10-minute exposure to 1 µmol/L MK-499 (MK 1st). The oocyte was held at -80 mV without pulsing during the equilibration period. In the absence of pulsing, MK-499 had no effect on HERG. The holding potential was -80 mV. The oocyte was then pulsed repetitively (30 pulses at 0.1 Hz, 4 seconds' duration) to a potential of +20 mV. Ten to 30 seconds after the pulse train, another single test pulse, to 0 mV, was applied (MK 2nd). B, Voltage-dependent block of HERG by MK-499. In another oocyte, current was recorded before (con) and after a 10-minute exposure to 1 µmol/L MK-499 (MK). When the oocyte was held at -50 mV but not pulsed during the equilibration period, block was observed. C, Bar graph summarizing use- and voltage-dependent block of HERG by MK-499. Data are from a series of experiments similar to those illustrated in A and B. [KCl] was 2 mmol/L. D, Onset of open-channel block by MK-499 measured with long pulses. The oocyte was held at -80 mV, prepulsed to -70 mV, then pulsed to 0 mV for 20 seconds. Current was recorded before and 10 minutes after exposure of oocyte to 10 µmol/L MK-499. The onset of block in the presence of drug had a time constant of 3.3 seconds. [KCl] was 4 mmol/L.

The onset of open-channel block by a high concentration (10 µmol/L) of MK-499 or E-4031 was assessed using a single 20-second pulse to 0 mV. The oocyte was equilibrated with drug for 10 minutes (V_h=-80 mV) and the test pulse repeated. The initial amplitude of the current was unchanged but declined slowly as channel block developed (Fig 1D). The rate of block onset was well described by a single exponential function with a time constant of 5.3±1.1 seconds (n=7) for MK-499 and 6.6±1.2 seconds (n=4) for E-4031. These data indicate that MK-499 and E-4031 block HERG channels only in the open state and provide further evidence that HERG is the major component of cardiac I_Kr channels.

Steady State Block of HERG Is Independent of Extracellular [K⁺] and Voltage
The concentration-dependent effect of MK-499 (0.03 to 10 µmol/L) on HERG was determined after achieving steady state block at each concentration. Oocytes were pulsed repetitively with 4-second pulses to 0 mV until steady state block was achieved. The current-voltage relationship was then determined using 4-second test pulses to potentials ranging from -40 to +20 mV, applied in 10-mV increments. The concentration required to reduce tail-current amplitude by 50% (IC₅₀) did not vary significantly with test potential. For example, the IC₅₀ at -40, -20, and +20 mV was 121±11, 123±12, and 151±29 nmol/L, respectively (Fig 2). Steady state block of HERG was independent of direction of current flow. Outward current activated with a pulse to 0 mV was followed by a pulse to -120 mV to activate inward current. MK-499 (150 nmol/L) blocked outward current at 0 mV by 43±15% and inward current at -120 mV by 38±7% (n=4). To determine whether extracellular [K⁺] modulates the effect of drug on HERG, oocytes were bathed in a solution containing 16 mmol/L KCl and exposed to 150 nmol/L MK-499. After steady state conditions were achieved by repetitive pulsing, HERG was blocked by 54±8% at test potentials of both -20 and +20 mV (n=6). Thus, the potency of MK-499 was not dependent on voltage, direction of current, or extracellular [K⁺] when assessed under steady state conditions.

View larger version (37K): [in this window] [in a new window]   Figure 2. Block of HERG by MK-499 is concentration dependent. A, Currents recorded at test potentials of -40, -20, and +20 mV in control (top) and after treatment with 0.1 µmol/L (middle) and 1.0 µmol/L MK-499 (bottom). Currents were recorded after achieving steady state block by repetitive pulsing to 0 mV. B, Percent block of HERG tail current plotted as a function of [MK-499]. Data were fit with a Hill equation. The IC50s (and Hill coefficients) were 121±11 nmol/L (1.3), 123±12 nmol/L (1.3), and 151±29 nmol/L (1.4) for test potentials of -40, -20, and +20 mV, respectively. [KCl] was 4 mmol/L.

MK-499 Does Not Alter Gating of HERG
Drugs that block ion channels often alter the voltage dependence or kinetics of channel gating. Therefore, we examined the effects of MK-499 on the voltage dependence of activation and rectification and the kinetics of activation and deactivation of HERG. A single concentration of MK-499 (150 nmol/L) that blocked currents by 50% was used for these experiments.

The voltage dependence of HERG activation was determined using 4-second test pulses to potentials ranging from -60 to +30 mV. For each oocyte, tail-current amplitudes were measured at -60 mV, plotted as a function of test potential, and fit with a Boltzmann function. In the control experiment, the isochronal activation curve had a half-point of -39.9±1.0 mV and a slope factor of 8.8±0.3 mV (n=7). This relationship was unaffected by MK-499, where the half-point was -38.4±2.0 mV and the slope factor was 7.7±0.4 mV (Fig 3A). The half-point of activation was more negative than in our previous study of HERG² because extracellular [Ca²⁺], which screens negative surface charge, was reduced from 1.8 to 0.1 mmol/L.

View larger version (22K): [in this window] [in a new window]   Figure 3. MK-499 does not affect voltage dependence or kinetics of HERG channel gating. A, Normalized isochronal activation curves determined before and after treatment of oocytes with 150 nmol/L MK-499 (n=7). Smooth curves are best fits of the data to a Boltzmann function. B, Voltage dependence of rectification determined before and after treatment with 150 nmol/L MK-499 (n=5). Smooth curves are best fits of the data to a Boltzmann function. C and D, Lack of effect of MK-499 on HERG activation or deactivation kinetics. Activation of HERG was measured at membrane potentials -50 mV; deactivation was measured at potentials -60 mV. The relationship between voltage and time constants of the fast (C) and slow (D) phases of activation (n=5) and deactivation (n=6) was the same in the control and after treatment with 150 nmol/L MK-499. [KCl] was 4 mmol/L.

The voltage dependence of HERG rectification was also unaffected by MK-499. In the control experiment, rectification was half maximal at -52±4 mV and had a slope factor of 27±1 mV (n=5). In the presence of 150 nmol/L MK-499, this relationship had a half-point of -59±4 mV and a slope factor of 28±3 mV (Fig 3B).

The kinetics of HERG activation were determined by fitting the onset of currents in response to 4-second test pulses. The kinetics of deactivation were determined by fitting the time-dependent decay of tail currents after activation of channels with a 1.5-second pulse to 0 mV. Both activation and deactivation were best fit with biexponential functions. MK-499 did not alter the time course of the fast phase (Fig 3C) or slow phase (Fig 3D) of activation and deactivation.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The biophysical properties of HERG expressed in oocytes are very similar to I_Kr recorded from cardiac myocytes.² However, we initially found that HERG was not blocked by MK-499 or E-4031, potent blockers of I_Kr in cardiac myocytes.^{3 5} In our previous experiments, the effects of 1 µmol/L MK-499 were determined in oocytes voltage clamped at a negative potential and not pulsed during equilibration with drug. In the present study, we demonstrate that MK-499 blocks only open HERG channels. Open-channel block of HERG expressed in oocytes was previously proposed to explain the observation that outward HERG current was relatively resistant to block by E-4031.⁶ However, we found that inward and outward HERG currents were equally sensitive to block. The block of I_Kr in cardiac myocytes by several class III antiarrhythmic drugs is also state dependent but may not be exclusively dependent upon channel opening. The use-dependent block and unblock of I_Kr by almokalant,⁷ dofetilide,^{8 9} and ibutilide⁹ indicate that these drugs preferentially block open I_Kr channels. In our study, we found that MK-499 at a concentration of 1 or 10 µmol/L did not block HERG if the membrane was held at a potential negative to that required for channel activation (eg, -80 mV). The equivalent experiment has been conducted with AT-1 cardiac myocytes.⁹ Cells were held at -80 mV while exposed to ibutilide or dofetilide during a 5-minute pulse-free equilibration period. I_Kr was reduced 25% by 10 nmol/L drug when assessed with a single pulse following the equilibration period, and further block was achieved by subsequent pulsing. This apparent discrepancy may be due to differences in channel characteristics (HERG versus mouse I_Kr), tissue (oocytes versus myocytes), or specific drugs. It remains to be determined whether MK-499 also blocks closed I_Kr channels in myocytes or whether ibutilide and dofetilide are pure open-channel blockers of HERG.

Other differences exist between methanesulfonanilide block of I_Kr in myocytes and HERG in oocytes. For example, dofetilide, almokalant, and ibutilide block I_Kr tail current more at positive potentials than at negative potentials (<-10 mV), resulting in a voltage-dependent decrease in the IC₅₀ for block of I_Kr.^{7 8 9} In rabbit myocytes, Carmeliet^{7 8} found that low concentrations of dofetilide and almokalant shifted the voltage dependence of I_Kr activation by about -6 mV. These results are in contrast with our findings with MK-499; the IC₅₀ for block of HERG expressed in oocytes was the same at all potentials examined, and the voltage dependence of activation was not shifted. These differences may be related to specific features of drug (MK-499 versus other methanesulfonanilides) or to preparation (oocytes versus myocytes). In addition, the concentration of drug required for block was greater in oocytes than in cardiac myocytes. MK-499 and E-4031 block I_Kr by 50% in guinea pig myocytes at concentrations of 44 nmol/L and 397 nmol/L, respectively.^{3 5} The IC₅₀ for block of HERG expressed in oocytes was 125 nmol/L for MK-499 and 588 nmol/L for E-4031.⁶ The difference in drug potency may be related to drug absorption by the oocyte yolk sac.

MK-499 did not alter kinetics or voltage dependence of gating under steady state conditions. This observation suggests that drug binds to the channel pore. The block of HERG by MK-499 was irreversible. Block of I_Kr in AT-1 myocytes by dofetilide and ibutilide was also irreversible.⁹ Carmeliet^{7 8} reported that block of I_Kr in rabbit ventricular myocytes by dofetilide and almokalant was partially reversible if myocytes were slowly pulsed and held at a potential of -50 mV during drug washout. The very slow or irreversible block of I_Kr and HERG by methanesulfonanilides explains the lack of rate-dependent drug effects when studied at physiologically relevant frequencies.^{8 9 10 11} An ideal class III antiarrhythmic agent would selectively prolong ventricular action potentials at high heart rates. A drug that blocked open I_Kr (HERG) channels with a slow onset and allowed rapid recovery from block at diastolic potentials would preferentially prolong action potential duration during tachycardia.¹² Currently available class III antiarrhythmic drugs do not possess this desired rate dependence.

The biophysical properties of HERG are nearly identical to the delayed rectifier I_Kr recorded from cardiac myocytes.² On the basis of currents measured in 100 mmol/L KCl and preceded by activating prepulses, a recent study⁶ of HERG expressed in oocytes concluded that it was an inwardly rectifying K⁺ channel. Intense inward rectification has been shown to be a property of cardiac I_K when studied under similar experimental conditions.¹³ Our present finding that HERG current is reduced by specific blockers of cardiac I_Kr provides further evidence that HERG is the major component of I_Kr channels.

	Acknowledgments

 
This study was supported by grants from the National Heart, Lung, and Blood Institute (P50-HL52338-01 and R01-HL48074) and grants-in-aid from the American Heart Association.

Received September 26, 1995; accepted November 21, 1995.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 
1. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80:795-804. [Medline] [Order article via Infotrieve]

2. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the I_Kr potassium channel. Cell. 1995;81:299-307. [Medline] [Order article via Infotrieve]

3. Sanguinetti MC, Jurkiewicz NK. Two components of delayed rectifier K⁺ current: differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol. 1990;96:195-215. [Abstract/Free Full Text]

4. Sanguinetti MC, Jurkiewicz NK. I_K is comprised of two components in guinea pig atrial cells. Am J Physiol. 1991;260:H393-H399. [Abstract/Free Full Text]

5. Lynch JJ, Wallace AA, Stupienski RF, Baskin EP, Beare CM, Appleby SD, Salata JJ, Jurkiewicz NK, Sanguinetti MC, Stein RB, Gehret JR, Kothstein T, Claremon DA, Elliot JM, Bitcher JW, Remy DC, Baldwin JJ. Cardiac electrophysiologic and antiarrhythmic actions of two long-acting spirobenzopyran piperidine class III agents, L-702,958 and L-706,000 [MK-499]. J Pharmacol Exp Ther. 1994;269:541-554. [Abstract/Free Full Text]

6. Trudeau M, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269:92-95.[Abstract/Free Full Text]

7. Carmeliet E. Use-dependent block and use-dependent unblock of the delayed rectifier K⁺ current by almokalant in rabbit ventricular myocytes. Circ Res. 1993;73:857-868. [Abstract/Free Full Text]

8. Carmeliet E. Voltage- and time-dependent block of the delayed rectifier K⁺ current in cardiac myocytes by dofetilide. J Pharmacol Exp Ther. 1992;262:809-817. [Abstract/Free Full Text]

9. Yang T, Wathen MS, Felipe A, Tamkun MM, Snyders DJ, Roden DM. K⁺ currents and K⁺ channel mRNA in cultured atrial cardiac myocytes (AT-1 cells). Circ Res. 1994;75:870-878. [Abstract/Free Full Text]

10. Jurkiewicz NK, Sanguinetti MC. Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent: specific block of rapidly activating delayed rectifier K⁺ current by dofetilide. Circ Res. 1993;72:75-83. [Abstract/Free Full Text]

11. Spinelli W, Moubarak IF, Parsons RW, Colatsky TJ. Cellular electrophysiology of WAY-123,398, a new class III antiarrhythmic agent: specificity of I_K block and lack of reverse use dependence in cat ventricular myocytes. Cardiovasc Res. 1993;27:1580-1591. [Abstract/Free Full Text]

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				S. Diochot, E. Loret, T. Bruhn, L. Beress, and M. Lazdunski APETx1, a New Toxin from the Sea Anemone Anthopleura elegantissima, Blocks Voltage-Gated Human Ether-a-go-go-Related Gene Potassium Channels Mol. Pharmacol., July 1, 2003; 64(1): 59 - 69. [Abstract] [Full Text] [PDF]

				D. Thomas, W. Zhang, K. Wu, A.-B. Wimmer, B. Gut, G. Wendt-Nordahl, S. Kathofer, V. A.W. Kreye, H. A. Katus, W. Schoels, et al. Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein Cardiovasc Res, July 1, 2003; 59(1): 14 - 26. [Abstract] [Full Text] [PDF]

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				M. E O'Leary Inhibition of HERG potassium channels by cocaethylene: a metabolite of cocaine and ethanol Cardiovasc Res, January 1, 2002; 53(1): 59 - 67. [Abstract] [Full Text] [PDF]

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