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(Circulation. 1996;93:407-411.)
© 1996 American Heart Association, Inc.

Articles

Extracellular Potassium Modulation of Drug Block of I_Kr

Implications for Torsade de Pointes and Reverse Use-Dependence

Tao Yang, PhD; Dan M. Roden, MD

From Vanderbilt University School of Medicine, Departments of Medicine and Pharmacology, Nashville, Tenn.

Correspondence to Dan M. Roden, MD, Director, Division of Clinical Pharmacology, 532 Medical Research Bldg, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.

	Abstract

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Background Torsade de pointes often occurs with underlying hypokalemia and bradycardia. A common effect of many drugs producing torsade de pointes is block of the rapidly activating component of the cardiac delayed rectifier (I_Kr). In this study, we evaluated the effect of changing extracellular potassium ([K⁺]_o) on I_Kr block by the nonspecific agent quinidine and by the specific I_Kr blocker dofetilide.

Methods and Results I_Kr was measured in AT-1 cells, where contaminating outward currents are absent. The drug concentration producing 50% inhibition of I_Kr tails (IC₅₀) was strikingly [K⁺]_o-dependent. Elevating [K⁺]_o from 1 to 8 mmol/L increased the IC₅₀ for dofetilide block from 2.7±0.9 to 79±32 nmol/L and for quinidine block from 0.4±0.1 to 3.8±1.2 µmol/L.

Conclusions (1) The increase in drug block with low [K⁺]_o provides a mechanism to explain the link between hypokalemia and torsade de pointes. (2) Elevations in [K⁺]_o occur with myocardial ischemia and with rapid pacing. Possible consequences of blunted drug block with high [K⁺]_o include loss of drug efficacy with ischemia and with rapid pacing; the latter may contribute to "reverse use-dependent" action potential prolongation. Extracellular potassium is a critical determinant of drug block of I_Kr, with substantial clinical implications.

Key Words: potassium • torsade de pointes • ions

	Introduction

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The rapidly activating cardiac delayed rectifier I_Kr is a common target for antiarrhythmic drugs. Some drugs, such as dofetilide or E4031, specifically inhibit this current^{1 2} and do not appear to have significant effects on any other cardiac ion current. Others, such as quinidine, suppress I_Kr as well as a range of other cardiac potassium currents.^{3 4 5 6} I_Kr blockers share the characteristic that they can, in some patients, markedly prolong the QT interval and produce polymorphic ventricular tachycardia, the torsade de pointes syndrome.^{2 7} For some drugs, this is related to high dosages and/or plasma concentrations,^{8 9} whereas for others, it is not.¹⁰ Important risk factors for the development of torsade de pointes include underlying bradyarrhythmias and hypokalemia.^{7 10}

The Nernst equation predicts that elevated extracellular potassium ([K⁺]_o) should decrease the driving force for outward current through potassium channels and hence decrease I_Kr.¹¹ However, in studies of delayed rectifier in guinea pig myocytes (in which a large I_Ks overlaps I_Kr), elevated [K⁺]_o appeared to increase I_Kr.¹² More recently, a similar effect of elevated [K⁺]_o has also been shown in Xenopus oocytes expressing HERG, the cDNA that is thought to encode the channels that carry I_Kr.¹³ Given the role of hypokalemia in clinical torsade de pointes, the present studies have been conducted to determine whether changes in [K⁺]_o modulate drug block of I_Kr.

	Methods

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Cell Preparation
These studies were conducted in AT-1 cells, in which I_Kr typical of that seen in other cardiac myocytes can be readily recorded in the absence of overlapping currents.¹⁴ The cells were kindly supplied by Loren Field (Krannert Institute, Indianapolis, Ind). Cells were injected subcutaneously into new syngeneic hosts ([C57BL/6J x DBA/2J]F₁ female mice, Jackson Laboratories, Bar Harbor, Me) to propagate tumors from which AT-1 cells were then isolated as previously described.¹⁴ The media (PC1 [Ventrex Laboratories], which included pen-strep, 10% fetal bovine serum, and 10 nmol/L dexamethasone) were changed every other day until used. Primary cultures grew to confluence and usually beat spontaneously at approximately 1 week. The electrophysiological findings described here were obtained from cells that had been in culture for 7 to 14 days. For electrophysiological studies, cells were removed from the culture dish by a 2-minute exposure to a trypsin-containing solution (0.125% in calcium-magnesium–free Hanks'), decanted into sterile culture tubes, and kept at room temperature until study the same day.

Electrophysiological Recording
Recordings were performed using an Axopatch-1A patch clamp amplifier (Axon Instruments, Inc) in the whole-cell configuration of patch clamp technique.^{14 15} After the whole-cell configuration was established, the capacitive transients elicited by symmetrical 10-mV voltage clamp steps from -80 mV were recorded at 50 kHz (filtered at a bandwidth of 10 kHz, -3 dB) for calculation of capacitive surface area. Thereafter, capacitance and series resistance compensation were optimized; 80% compensation was usually obtained. The extracellular solution was normal Tyrode's that contained (in mmol/L): NaCl 130, CaCl₂ 1.8, MgCl₂ 1, HEPES 10, and glucose 10; KCl was added in varying concentrations (1 to 8 mmol/L), and the pH of the solution was adjusted to 7.35 with NaOH. The intracellular pipette filling solution contained (in 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 145 mmol/L. In these experiments, L-type calcium current was eliminated using nisoldipine (1.0 µmol/L). Sodium current and T-type calcium current were eliminated by holding at -40 mV. Salts and quinidine were purchased from Sigma Chemical Co. Nisoldipine was obtained from Miles Pharmaceutical, Inc., and dofetilide was provided by Pfizer Central Research. Stock solutions were stored at 4°C, and the final concentrations in the bath were obtained by diluting the stock solutions in the external solution during experiments.

Voltage Clamp Protocols and Data Analysis
In this report, a holding potential of -40 mV was used. One-second depolarizing pulses (to -30 to +50 mV) were then followed by repolarization back to -40 mV. The cycle time between clamp pulses was 15 seconds. Currents after exposure to drug were recorded after apparent steady state was reached. Each experiment consisted of recordings at baseline, followed by exposures to one to three (sequentially increasing) drug concentrations, at a constant [K⁺]_o. To compare current densities among cells, currents are reported as current per unit capacitance (pA/pF) after linear leak subtraction and normalization relative to cell surface area determined by measurement of capacitance, as described above. The drug concentration blocking 50% of current, IC₅₀, was determined using a Hill function y=1/(1+([D]/IC₅₀)^-N), where [D] is the drug concentration. In addition, at each drug concentration, the extent of drug block at varying [K⁺]_o was compared using one-way ANOVA. If the hypothesis of equal means could be rejected at the .05 level, the Bonferroni correction was used for pairwise comparisons. Results are expressed as mean±1 SE.

	Results

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Current traces during 1-second depolarizing pulses from a holding potential of -40 mV are shown in the top panels of Fig 1 for [K⁺]_o of 1, 4, and 8 mmol/L in three separate cells. The effect of [K⁺]_o on current activated during a pulse is evident and consistent with previous reports: Elevated [K⁺]_o was associated with increased activating current. The bottom panels in Fig 1 show currents after exposure to 10 nmol/L dofetilide, which we have previously established produces 50% block of I_Kr at a [K⁺]_o of 4 mmol/L.¹⁶ It is apparent that activating current and deactivating current tails are suppressed by much more than 50% at [K⁺]_o of 1 mmol/L (left) and by considerably less than 50% at [K⁺]_o of 8 mmol/L (right).

View larger version (25K): [in this window] [in a new window]   Figure 1. Effect of varying [K+]o on IKr. Top panels show IKr elicited by 1-second depolarizing pulses from -40 mV with [K+]o=1 (left), 4 (middle), and 8 mmol/L (right). Effect of 10 nmol/L dofetilide in each cell is shown in the bottom panels. Arrows indicate examples of rapid recovery from inactivation, as discussed in the text.

Tail current magnitudes were normalized to those at baseline in each experiment and then analyzed as a function of concentration (Fig 2). Fig 2 (left) shows the effect of dofetilide as a function of [K⁺]_o on tail currents. The IC₅₀ for dofetilide block at a [K⁺]_o of 1 mmol/L was 2.7±0.9 nmol/L, whereas at 4 mmol/L [K⁺]_o it was 11.2±1.9 nmol/L and at 8 mmol/L [K⁺]_o it was 79±32 nmol/L. Fig 2 (right) shows the concentration-response relationships for quinidine inhibition of tail current. The IC₅₀ for quinidine block at [K⁺]_o 1 mmol/L was 0.4±0.1 µmol/L, at [K⁺]_o 4 mmol/L it was 1.0±0.4 µmol/L, and at [K⁺]_o 8 mmol/L it was 3.8±1.2 µmol/L.

View larger version (18K): [in this window] [in a new window]   Figure 2. Concentration-response relations for drug block of IKr. Number of cells evaluated at each data point is indicated in brackets. Inhibition of tail current measured after a 1-second depolarizing pulse to +20 mV is shown. Effects of dofetilide are shown on the left. Data analysis, conducted as described in the text, showed that block at 10 and 100 nmol/L was significantly less (P<.05) at 8 mmol/L [K+]o than at 1 and 4 mmol/L. The effects of quinidine are shown on the right. Block by 1 and by 10 µmol/L quinidine was significantly less at 8 mmol/L [K+]o than at 1 or 4 mmol/L. At 0.1 µmol/L, the difference between 1 and 8 mmol/L was statistically significant.

	Discussion

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These studies demonstrate that the I_Kr blocking properties of quinidine and of dofetilide are strikingly dependent on extracellular potassium. This effect was observed at potassium values representing the range of those that might be observed clinically.

Quinidine blocks other potassium channels, but usually at concentrations well above 1 µmol/L. For example, the approximate blocking concentration for the transient outward current was 3 to 10 µmol/L,⁴ for the inward rectifier 10 µmol/L,^{4 17} for I_Ks 30 to 50 µmol/L,⁵ and for the cloned potassium channel Kv1.5 expressed in mammalian cells, 6 µmol/L.⁶ The sodium channel–blocking properties of quinidine are similarly evident only at concentrations of 10 µmol/L.¹⁸ Carmeliet³ has previously suggested an IC₅₀ of 0.6 µmol/L for I_Kr block in rabbit cardiac myocytes, and Woosley et al⁹ noted similar suppression of I_Kr by low concentrations of quinidine in feline myocytes. Thus, these very low IC₅₀ values for I_Kr block suggest that a major effect of low-dose quinidine is to block this current. Dofetilide, on the other hand, is thought to target I_Kr specifically and is devoid of other significant pharmacological activities. Specific I_Kr blockers such as dofetilide are known to exert antiarrhythmic effects in preclinical models and in some clinical studies.² However, a risk with dofetilide and similar I_Kr blockers, as well as with quinidine, is the occasional and often unpredictable development of torsade de pointes. Thus, a model system in which to study I_Kr and its block by drugs is desirable.

We have previously reported that the characteristics of I_Kr in AT-1 cells strongly resemble those observed in other cardiac cells.^{13 19} These characteristics include rapid activation, prominent deactivating tails, inward rectification, and nanomolar sensitivity to dofetilide.¹⁴ AT-1 cells are derived from mouse atrium, while long QT–related arrhythmias originate in the ventricle. However, the activation, deactivation, rectification, and drug sensitivity of I_Kr in AT-1 cells are similar to those observed in cells from neonatal mouse ventricle²⁰ and from cardiac cells in other species (rabbit ventricle,²¹ cat ventricle,²² guinea pig atrium and ventricle,^{19 23} dog ventricle,²⁴ and human atrium²⁵ ). In addition, I_Kr has been directly compared in atrial and ventricular cells in guinea pigs, and the only difference was a greater amplitude in the atrium.²³ Recent studies have identified mutations in a human cardiac potassium channel gene, HERG, in some cases of the long QT syndrome, and electrophysiological evaluations have demonstrated that expression of HERG results in a current with properties virtually identical to those of I_Kr, including sensitivity to [K⁺]_o.^{13 26 27} We have recently found that mRNA transcripts hybridizing to a HERG-derived probe are even more abundant in AT-1 cells than they are in the human heart,²⁸ further adding validity to the use of this cell line as a model system to study the physiology of I_Kr and its response to blockers.

Possible Mechanisms
The mechanisms whereby extracellular potassium modulates activating I_Kr, and whereby changes in [K⁺]_o modulate drug block of I_Kr, remain speculative and will require extensive further study. One possibility is that a [K⁺]_o-induced change in the conformation of the channels responsible for I_Kr could alter access of a blocking drug to its target site on the channel. A starting point for such an analysis is an understanding of the normal gating behavior of this channel. It is now generally appreciated that with depolarization, the channels responsible for I_Kr move from closed to open and inactivated states^{13 27 29} :

In this scheme, only open channels conduct. With pulses to moderate depolarizing potentials (eg, +10 to +20 mV), channels distribute preferentially to the open state, and large activating currents are seen. On the other hand, with pulses to very depolarized potentials (eg, +50 to +60 mV), channels distribute preferentially to the inactivated state so that activating current is much smaller. This rectifying behavior was readily apparent at all [K⁺]_o values examined here (Fig 1, top panels). With strong or weak depolarizations, a deactivating pulse is followed immediately by fast recovery from inactivation and then slow deactivation from open to closed states. This behavior accounts for the typical "hook" observed at the beginning of the deactivating pulse and is indicated with an arrow in Fig 1. Increased [K⁺]_o might lead to preferential occupancy of the open state as opposed to the inactivated state during depolarization. If this were the case, then the present data with dofetilide and quinidine would suggest that the drugs bind preferentially to the inactivated state. This would also be consistent with our previous finding that dofetilide block is voltage dependent, increasing at very positive potentials.¹⁶ Alternatively, the drugs could bind to open channels in a voltage-dependent (but not state-dependent) fashion. In this case, increasing potassium permeating through the channel might impair binding of a blocking drug to a site in the pore.

Clinical Implications
We believe our data have important clinical implications. First, the [K⁺]_o dependence of activating I_Kr would help explain why cardiac action potentials are shorter at higher [K⁺]_o and longer at low [K⁺]_o, a well-recognized phenomenon¹¹ that may be important for the genesis of bradycardia-dependent arrhythmias such as torsade de pointes.^{18 30} Second, the development of hypokalemia in a patient receiving these drugs would be expected to result in disproportionate action potential prolongation due to the striking increase in sensitivity to drug block at low [K⁺]_o; this further reinforces the dangers of hypokalemia in patients receiving these I_Kr blockers and perhaps others. As well, these data suggest correction of even modest hypokalemia is critical in treating torsade de pointes due to I_Kr block. Third, the relative resistance to I_Kr block at high [K⁺]_o suggests that the action potential–prolonging properties of the drugs would be blunted when [K⁺]_o is elevated, eg, during myocardial ischemia. Few data are available on action potential prolongation by dofetilide or by quinidine under these conditions; one report suggests preserved dofetilide effect with high [K⁺]_o³¹ and another indicated a blunted effect.³² Cobbe and colleagues have presented data that the action potential–prolonging effects of sotalol (a blocker of I_Kr¹⁹ and other cardiac potassium currents³³ ) were virtually completely abolished by coronary occlusion in an isolated Langendorff preparation,³⁴ although further studies suggested only a minor role for hyperkalemia.³⁵ Finally, we propose that the [K⁺]_o dependence of dofetilide and of quinidine block may play an important role in determining the normal rate dependence of the action potential and the "reverse use-dependent" effects of the drugs. With rapid stimulation, it is recognized that the restricted size of the extracellular space causes accumulation of extracellular potassium even in the absence of an elevation in serum potassium.³⁶ Thus, at rapid rates, the increase in I_Kr resulting from increased [K⁺]_o would shorten the action potential, as is usually observed. Moreover, rapid stimulation in the presence of dofetilide or quinidine would result in an apparent loss of drug block and thus shortening of action potential duration at rapid rates. This scheme does not rule out a role for other channels (such as I_Ks) in action potential control³⁷ ; in fact, it seems likely that given the multiple currents that control cardiac repolarization, more than one factor will be involved in controlling the rate dependence of the action potential and its response to drugs. If this hypothesis is correct, the observed [K⁺]_o dependence of I_Kr and its response to block will be most important when homeostatic mechanisms such as sodium-potassium pumping have not yet maximally compensated for increased [K⁺]_o. Changes in [K⁺]_o resulting from initiation of rapid stimulation in canine cardiac Purkinje fibers peak within seconds and are then slowly compensated, probably by electrogenic sodium potassium pumping.^{38 39} Thus, the effect of changing [K⁺]_o on drug block may be greatest in modifying the onset of very rapid tachycardias such as ventricular fibrillation. The extent to which [K⁺]_o accumulates in the extracellular space, during rapid stimulation or during ischemia, is difficult to establish and may vary with the size and restricted nature of the extracellular space among species.

Our data strongly suggest that extracellular potassium is a major factor modulating not only the physiology of I_Kr but also its response to blocking drugs. With the identification of a cDNA encoding I_Kr will come the possibility of identifying the molecular mechanisms underlying this form of modulation of drug block. The identification of mutations in the HERG gene in some patients with the congenital long QT syndrome speaks to the importance of I_Kr in the maintenance of normal cardiac electrophysiology. It remains to be determined whether increased understanding of the molecular determinants of HERG function can result in the identification of a drug that modulates the activity of I_Kr and yet does not cause torsade de pointes. As pointed out by others,³⁰ drugs that only interact with channels at rapid rates but do not affect normal channel function at slow rates (where torsade de pointes develops) should produce this effect.

	Acknowledgments

 
This study was supported in part by grants from the United States Public Health Service (HL-49989 and HL-46681). Dr Roden is the holder of the William Stokes Chair in Experimental Therapeutics, a gift from the Daiichi Corporation. The assistance of Holly Waldrop in the maintenance of the AT-1 cell line and of Patricia James in preparation of the manuscript are gratefully acknowledged. We are also grateful for the critical advice of Paul Bennett and Dirk Snyders.

Received October 5, 1995; revision received November 13, 1995; accepted November 19, 1995.

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