Published online before print February 12, 2004, doi: 10.1161/01.RES.0000121102.24277.89
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© 2004 American Heart Association, Inc.
Cellular Biology |
Contribution of IKr to Rate-Dependent Action Potential Dynamics in Canine Endocardium
From the Department of Biomedical Sciences, Cornell University, Ithaca, NY.
Correspondence to Robert F. Gilmour, Jr, Department of Biomedical Sciences, T7 012 VRT, Cornell University, Ithaca, NY 14853-6401. E-mail rfg2{at}cornell.edu
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Abstract |
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Previous modeling studies have suggested that the rapid component of the delayed rectifier (IKr) may contribute importantly to action potential dynamics during tachycardia. To test this idea experimentally, IKr was measured as the E-4031–sensitive current in isolated canine endocardial myocytes at 37°C using the perforated patch-clamp technique. Command potentials were trains of action potential waveforms recorded at cycle lengths (CLs) of 1000, 500, 320, 170, and 120 ms. Action potential duration (APD) alternans occurred at CLs of 170 and 120 ms. During an action potential, IKr increased gradually to a maximum at –55 to –60 mV. Peak IKr increased initially as CL was shortened from 1000 to 500 ms (from 0.55±0.03 to 0.57±0.03 pA/pF), but decreased progressively as CL was shortened further (to 0.45±0.03 pA/pF at CL=120 ms). Baseline IKr was negligible at CLs of 1000 to 320 ms, but increased to 0.12±0.01 pA/pF at a CL of 120 ms. During APD alternans, peak IKr was larger for the short than for the long action potential (0.48±0.03 versus 0.46±0.03 pA/pF). A computer model of IKr based on these data indicated that increasing IKr suppressed alternans and decreasing IKr increased alternans. In support of the latter result, inhibition of IKr by E-4031 increased the maximal amplitude of alternans. These results indicate that IKr contributes importantly to rate-related alterations of repolarization, including APD alternans. Modifying IKr may be a promising approach to suppressing alternans and thereby preventing ventricular tachyarrhythmias.
Key Words: IKr • alternans • ventricular arrhythmias
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Introduction |
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The duration of the canine ventricular action potential (APD) decreases as the pacing cycle length (CL) decreases, until at short CL, APD alternans occurs.1,2 The rate-dependency of APD is represented by the APD restitution relation, which is the relationship between APD and the preceding diastolic interval. Previous studies have indicated that rate-dependent APD alterations are important determinants of ventricular arrhythmias and that reducing the slope of the APD restitution relation can be antiarrhythmic.3–8 However, the available options for altering APD restitution are limited, in part because the ionic mechanism for the rate-dependency of APD is not well understood.
Several lines of evidence suggest that the L-type Ca2+ current (ICa) plays an important role in APD restitution and in the development of APD alternans.9–11 In particular, blockade of ICa in a computer model and experimentally has been shown to reduce the slope of the APD restitution relation and to suppress ventricular fibrillation.4,10 The obvious drawback to this approach is that blockade of ICa also suppresses contractility. However, if reducing inward plateau current flattens the slope of the APD restitution relation, then perhaps increasing outward repolarizing current might have a similar effect. This idea has been supported by computer simulations,10 but there is little experimental data regarding the role of repolarizing currents in APD restitution. Consequently in this study, we examined the possible role of the rapid component of the delayed rectifier (IKr) in rate-dependent APD alterations, including APD alternans.
IKr plays an important role in defining ventricular repolarization, as reflected by the fact that a wide variety of drugs that inhibit IKr prolong APD and the QT interval.12–16 In addition, mutation of the gene encoding IKr (HERG) underlies one form of the long-QT syndrome.17,18 The contribution of IKr to action potential repolarization is complex, in that during an action potential, IKr initially activates at positive membrane potentials, but then rapidly inactivates during the plateau phase. As the membrane potential repolarizes, IKr recovers from inactivation before it deactivates. As a result, IKr increases to a maximum during phase 3 of the action potential and then decreases, as the electrical driving force decreases and as deactivation of the channel increases.
Given the complex interactions between voltage, time, and magnitude of IKr, measurements of IKr during an action potential waveform may more faithfully represent the contribution of IKr to repolarization than measurements obtained from standard voltage clamp techniques. Therefore in this study, the possible contribution of IKr to rate-dependent alterations of APD was assessed by measuring IKr during action potentials elicited by different pacing CLs using the action potential clamp technique. Data generated by these experiments subsequently were used to construct a computer model of IKr, which was then used to test whether increasing IKr suppressed APD alternans and whether decreasing IKr had the opposite effect.
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Materials and Methods |
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This investigation conformed to the Guidelines for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication no. 85-23). Experiments were approved by the Institutional Animal Care and Use Committee of the Center for Research Animal Resources at Cornell University. All animals used in these experiments were obtained from a colony of dogs maintained by Cornell University.
Microelectrode Recordings
Adult beagle dogs of either sex were anesthetized with Fatal-Plus (86 mg/kg IV), and their hearts were excised and placed in aerated (95% O2/5% CO2) Tyrode solution containing (in mmol/L) NaCl 124, KCl 4.0, NaHCO3 24, NaH2PO4 0.9, CaCl2 2.0, MgCl2 0.7, and glucose 5.5; pH 7.4. Sections of left ventricular endocardial tissue measuring 2 cmx1 cmx2 mm were mounted in a Plexiglas chamber and superfused with Tyrode solution at 37°C. Transmembrane action potentials at different pacing CLs were recorded using standard microelectrode techniques. The recordings were sampled at 5 kHz and analyzed using programs written in Matlab 4.2c.
Isolation of Cardiac Myocytes
Endocardial myocytes were isolated by enzymatic dissociation as previously described.19 Briefly, a section of the ventricular free wall supplied by the left circumflex coronary artery was perfused with Tyrode solution at 37°C for 10 to 15 minutes. Perfusion was then switched to Ca2+-free perfusion solution containing (in mmol/L) NaCl 118, glucose 11, taurine 10, NaHCO3 25, KCl 4.8, mannitol 2, MgSO4 1.2, KH2PO4 1.2, glutamine 0.68, and pyruvate 5; adjusted to pH 7.3 with NaOH. After 3 to 5 minutes, the solution was switched to Ca2+-free perfusion solution supplemented with collagenase (0.4 mg/mL) and BSA (0.5 mg/mL) for another 10 to 15 minutes. Thin slices of tissue were then dissected from the endocardium, minced, and agitated with 95% O2/5% CO2. After digestion, the supernatant was removed and replaced with perfusion solution to which HEPES (5 mmol/L) and CaCl2 (1.0 mmol/L) had been added. The myocytes were studied during superfusion with extracellular solution containing (in mmol/L) NaCl 132, KCl 4, MgCl2 1, CaCl2 2, glucose 10, and HEPES 20; pH 7.4 at 37±1°C.
Action Potential Clamp Recordings
The perforated-patch voltage-clamp technique was used to minimize alterations of the intracellular milieu. Pipette solution contained (in mmol/L) aspartic acid 130, KCl 15, HEPES 10, MgCl2 2, and CaCl2 0.5; adjusted to pH 7.1 with KOH. Amphotericin B (0.21 mg/mL) was used as the pore-forming agent. The pipette tip resistance was 1 to 3 M
. Currents were low-pass filtered at 2 kHz and sampled at 5.5 kHz. The series resistance was approximately 20 M, but was not compensated because the maximum current never exceeded 150 pA, and the corresponding voltage error was less than 3 mV. Data acquisition and analysis were performed using pClamp 8 (Axon Instruments, Inc).
Representative action potentials recorded at CLs of 1000, 500, 320, 170, and 120 ms were applied to the myocytes as the command potentials (Figure 1). Each action potential was applied six times, or in the case of alternans, six pairs of long and short action potentials were applied. IKr was defined as the drug-sensitive current blocked by E-4031 (5 µmol/L; Wako). Baseline IKr was defined as the subtraction current immediately preceding the upstroke of the action potential. Peak IKr was defined as the absolute amplitude of the maximal subtraction current during repolarization. Conductance (gKr) was calculated according to g=I/V, where V is the membrane potential at which the current recording was obtained (Vm) minus the reversal potential for IKr (VK), where VK=–86.1 mV. Nisoldipine (2 µmol/L) was present in the extracellular solutions to block L-type Ca2+ current for all recordings.
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Statistical Analysis
All data are presented as mean±SE. Means were compared using paired Student’s t test or 2-way ANOVA, followed by a Scheffe’s F test, where appropriate. A value of P<0.05 was considered significant.
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Results |
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Rate-Dependent Alterations of IKr
Figure 2 shows representative recordings of IKr at different CLs and a summary of the mean data (n=20). Peak IKr occurred during terminal repolarization at all CLs. Peak IKr density increased slightly, but significantly, from 0.55±0.03 to 0.58±0.03 pA/pF, as CL was reduced from 1000 to 500 ms. As CL was reduced further, peak IKr decreased progressively (Figure 2D). The membrane potentials at which peak IKr occurred were the same for CLs of 1000 ms (–55.6±1.1 mV) and 500 ms (–55.5±1.0 mV) and became slightly more negative at a CL of 320 ms (–56.1±1.1). During alternans at CLs of 170 and 120 ms, the membrane potentials at which peak IKr occurred were significantly more negative for the short action potentials than for the long action potentials (–58.9±1.0 versus –57.0±1.0 mV and –58.3±1.0 versus –57.7±1.0 mV, respectively).
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During APD alternans at a CL of 170 ms, IKr increased at a slower rate and reached its maximum value at a later time during the long action potential than during the short action potential (Figure 2B). The peak magnitude of IKr was significantly less during the long action potential than during the short action potential (0.46±0.03 versus 0.48±0.03 pA/pF, respectively), as was the peak conductance (gKr) (15.8±1.2 versus 17.6±1.4 pS/pF, respectively) (Figure 2E). At a CL of 120 ms, the amplitude of APD alternans was reduced and the difference in peak IKr density between the long and short action potentials was no longer statistically significant (Figure 2C). Similarly, there were no significant differences in gKr between the long and short action potentials (15.7±1.2 versus 16.0±1.3 pS/pF, respectively).
Baseline IKr increased significantly at CLs of 170 and 120 ms (Figure 2D). There was no difference between baseline IKr during the long and short action potentials at a CL of 170 ms, whereas at a CL of 120 ms baseline IKr was significantly smaller preceding the long action potential than the short action potential. The increase in baseline IKr at short CL may have been caused, in part, by the increased driving force resulting from depolarization of the resting membrane potential (from –85.0 mV at CL=1000 ms to –77.6 mV at CL=170 ms and to –71.1 mV at CL=120 ms). However, the increase in baseline IKr also was associated with an increase in gKr (gKr=0.14±0.01 pS/pF at CL=1000 ms; 0.15±0.01 pS/pF at CL=500 ms; 2.2±0.15 pS/pF at CL=320 ms; 3.1±0.22 and 3.4±0.23 pS/pF for the long and short action potentials, respectively, at CL=170 ms; 7.2±0.64 and 8.0±0.68 pS/pF for the long and short action potentials, respectively, at CL=120 ms). The difference in gKr between the long and short action potentials was statistically significant at a CL of 120 ms, but not at 170 ms.
Rate-Dependent Accumulation of IKr
In the experiments described, the CLs were varied and the shape of the action potential at each CL also differed. To isolate the effect of CL on IKr, a single action potential waveform was applied at different CLs (Figure 3). The action potential recorded at a CL of 500 ms (Figure 3A) was applied at CLs of 1000, 500, and 230 ms to 23 myocytes. Because APD at 90% repolarization (APD90) at a CL of 500 ms was 214 ms, the shortest CL that could be delivered without encroaching on the action potential was 230 ms. As shown in Figure 3, peak IKr increased as CL was shortened, whereas baseline IKr did not differ between CL of 1000 ms and 500 ms, but increased slightly at a CL of 230 ms. The membrane potential at which peak IKr occurred was similar for all three CLs.
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The action potentials recorded at a CL of 120 ms (Figure 3B) were applied at CLs of 1000, 500, and 120 ms to 12 myocytes. Peak IKr was similar at CLs of 1000 and 500 ms, but increased at a CL of 120 ms (Figures 3B and 3C). There was no difference in peak IKr between the long and short action potentials at any CL. Baseline IKr was similar at CLs of 1000 and 500 ms and was not different between the long and short action potentials at these CLs. However, baseline IKr increased at a CL of 120 ms and was smaller preceding the long action potential than the short action potential. The membrane potential at which peak IKr occurred was similar, regardless of CL.
Time Constant for Deactivation
To determine whether the increase in baseline IKr at short CL was caused by slow deactivation of the current, the time course of deactivation was measured using a double-pulse protocol (Figure 4). The initial pulse was stepped to +20 mV for 100 ms from a holding potential of –85 mV and then back to either –85, –70, or –55 mV, depending on the voltage at which the time constant was to be measured. The second pulse was a square-ramp pulse (to simulate the shape of an action potential) with a 15-ms square pulse to +20 mV followed by a ramp from +20 mV to –85 mV over 70 ms. Peak current was measured during the repolarization ramp. The interpulse interval was 2 ms initially and increased by 20 ms for measuring the time constant at –85 mV and by 50 ms for measuring the time constants at –70 and –55 mV.
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Figure 4B shows a representative recording used to determine the deactivation time constant at –85 mV. The current elicited by the square-ramp pulse was similar to IKr recorded during action potential clamp. The relationship between the peak current amplitude and the interpulse interval was fit by a single exponential equation. The mean time constants for deactivation at –85, –70, and –55 mV were 34.0±6.3 ms (n=7), 48.8±7.0 ms (n=7), and 116.4±7.6 ms (n=6), respectively.
Computer Simulation
A computer model for IKr was developed on the basis of the Winslow model20 and our subsequent modification of the Winslow model for the canine ventricular myocyte (CVM).10 The model was driven by the same action potentials used for the voltage clamp experiments. To fit the experimental data, the parameters for IKr used in the CVM model were modified as follows: the voltage-dependence of steady-state activation was shifted to less negative membrane potentials; the time constant for deactivation was markedly reduced; the voltage-dependence of steady-state inactivation was flattened and was shifted to more negative membrane potentials; a time constant for inactivation was introduced and; maximum conductance was increased (Figures 5A through 5D) (also see Appendix). Thus modified, the model generated a current that faithfully reproduced the IKr recorded experimentally (Figures 5E through 5F).
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The modified IKr model subsequently was used to study the mechanism for alternating peak IKr during APD alternans at CL=170 ms. Figure 6 shows changes in the open probability of the activation (Xa) and inactivation (Xi) gates. The open probability of the inactivation gate (Xi) did not vary significantly from beat to beat and followed the shape of the action potential, as expected from its fast kinetics. In contrast, the open probability of the activation gate (Xa) exhibited large beat-to-beat variations. During the long action potential, there was insufficient time for the activation gate to close completely (ie, open probability did not return to zero), which resulted in a fraction of channels remaining open before the next action potential. Consequently, Xa for the next (short) action potential was larger. In addition, the more positive plateau voltage during the short action potential activated more channels than during the long action potential. Together, incomplete deactivation at the end of the long action potential and a higher plateau during the short action potential produced a larger peak IKr during the short action potential.
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The CVM model incorporated with modified IKr also was used to test whether increasing IKr suppressed APD alternans. IKr was increased by (1) increasing conductance, (2) shifting the voltage-dependence of steady-state activation to more negative membrane potentials, (3) shifting the voltage-dependence of steady-state inactivation to less negative membrane potentials, and (4) increasing the time constant for deactivation (Figure 7A). Each of these alterations abolished APD alternans (Figure 7B), in association with minimal changes in the APD restitution relation (Figure 7D). After increasing IKr, peak L-type Ca2+ current (ICa) increased slightly during pacing at a CL of 400 ms (from 1.6 to 1.7 pA/pF), and the normal alternation of ICa during pacing at a CL of 160 (between 1.4 and 1.0 pA/pF) was suppressed (ICa was constant at 1.1 pA/pF).
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We also tested whether decreasing IKr increased the magnitude of APD alternans in the modified model, as was shown previously in the original CVM model.10 As IKr was decreased progressively by reducing maximal conductance, APD increased, and the magnitude of APD alternans increased as well. Figure 7C shows an example of the effects of decreasing IKr conductance from 0.0541 to 0.0441 mS/µF on steady-state APD and the magnitude of APD alternans. In this particular case, the magnitude of APD alternans was increased despite a small reduction in the slope of the dynamic APD restitution relation (from 1.170 to 1.147) (Figure 7D).
Effect of Blocking IKr on Action Potential Dynamics
The prediction that decreasing IKr increases the magnitude of APD alternans was tested by evaluating the effects of the IKr antagonist E-4031 on rate-dependent changes of APD. The effects of E-4031 on action potential morphology of endocardial tissue (n=5) at a CL of 400 and 120 ms are shown in Figure 8. E-4031 had minimal effect on the plateau phase of the action potential, but markedly prolonged terminal repolarization. At the longer CL, both APD90 and APD50 were significantly prolonged by E-4031. At a CL of 120 ms, E-4031 did not alter APD50 for either the long or the short action potential (Figure 8B). However, E-4031 significantly prolonged APD90 of the short action potential (from 88.8±1.7 to 96.5±3.0 ms) and tended to prolong APD90 of the long action potential (from 99.8±2.0 to 105.5±1.2 ms), but the latter effect was not statistically significant (P=0.1) (Figure 8B). The maximum amplitude of APD alternans was increased by approximately 50% in the presence of E-4031, from 13.5±3.2 to 19.2±2.4 ms for APD90 (Figure 8C), in concert with an increase in the slope of the dynamic APD restitution relation from 1.2±0.03 to 1.54±0.07. An example of the effects of E-4031 on the APD restitution relation is shown in Figure 8D.
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Discussion |
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Inherited or drug-induced abnormalities of IKr have been linked to a variety of cardiac arrhythmias,17,21,22 most of which are thought to be precipitated by bradycardia-induced prolongation of repolarization. The potential mechanisms by which IKr may facilitate the induction of arrhythmias at slow heart rates have been studied extensively.12,23,24 However, the contribution of IKr to repolarization during tachycardia, which might also be important for the development of cardiac arrhythmias, has not been well characterized. In this study, we measured IKr during action potentials elicited by pacing at normal to high frequencies. The results indicate that the magnitude of IKr is determined by multiple factors, including (1) the membrane potential during the action potential plateau, (2) the duration of the plateau, (3) the membrane potential during the diastolic interval, and (4) the duration of the diastolic interval. Interactions between these factors are complex, precluding straightforward relationships between stimulation rate, APD, and IKr amplitude. In general, peak IKr amplitude is smaller at faster stimulation rates, yet during APD alternans IKr is larger during the shorter action potential than during the longer action potential.
Rate-Dependent Alterations of IKr
As CL was decreased progressively, peak IKr increased initially and then decreased (Figure 2). The mechanism for the small initial increase of peak IKr is unclear, given that action potential morphology for CLs of 1000 and 500 ms was the same. On the other hand, the more marked reduction of peak IKr at short CL appeared to be caused by decreased channel activation, secondary to the shorter action potential plateau duration and a less positive membrane potential during the plateau.
During progressive reduction of CL, baseline IKr during the diastolic interval remained constant before increasing at the shortest CLs. The increase in baseline IKr was associated with depolarization of the resting membrane potential. Although IKr did not activate at membrane potentials more negative than –60 mV (Figure 5A), significant IKr was detected at –71.1 mV (the resting potential for CL=120 ms). The presence of IKr at this membrane potential can be attributed to incomplete deactivation, secondary to the slow time course of deactivation and the short diastolic intervals that occur at short CLs.
Slow deactivation is one of the most prominent characteristics of IKr, both in the dog25,32 and in other species.26,27,33 However, in previous studies, the deactivation kinetics of IKr was evaluated at membrane potentials less than –60 mV, primarily because at more negative voltages the amplitude of the current is small, secondary to a reduced driving force near the reversal potential. In our study, a two-pulse protocol was used to elicit larger currents, which enabled us to measure the deactivation time constant at more negative potentials. Those measurements indicated that the deactivation time constants of IKr at –85 and –70 mV were on the order of 35 to 50 ms, which were sufficiently slow to prevent complete deactivation during pacing at short CLs. The primary manifestation of incomplete deactivation was increased baseline IKr during pacing at short CLs. The presence of significant IKr during the diastolic interval suggests that IKr may help to offset the depolarization of resting membrane potential that typically occurs during rapid pacing.
IKr During APD Alternans
During APD alternans at a CL of 170 ms, peak IKr was larger during the shorter action potential, in part because the plateau voltage during the short action potential was more positive than during the long action potential, resulting in activation of more IKr. In addition, the rate of repolarization was faster for the shorter action potential, which provided less time for the channel to deactivate. Finally, the short action potential was preceded by a short diastolic interval, during which deactivation of IKr may have been incomplete, resulting in a fraction of channels being activated before the onset of the short action potential. However, the contribution of baseline IKr to the peak current apparently was small, given that at a CL of 120 ms, baseline current was greater than at a CL of 170 ms, yet peak IKr was smaller.
Potential Implications
Decreasing IKr, both in the computer model and pharmacologically, increased the magnitude of APD alternans. Conversely, increasing IKr in the computer model, either by increasing channel conductance or by altering channel kinetics, suppressed alternans. Given that APD alternans has been linked to the development of ventricular fibrillation,6,8,28,29 modifications of IKr might be expected to alter the risk of sudden death. In that regard, the results of this study may provide at least a partial explanation for the proarrhythmic effects of certain IKr blockers12–16 and a rationale for the development of a new class of putative antiarrhythmic agents, IKr agonists.
Questions remain, however, regarding whether augmentation of IKr or other K currents selectively reduces APD alternans magnitude or whether the effects of such drugs relate to a nonspecific shortening of APD.10,30 Recent theoretical studies have suggested that K current, IKr in particular, may contribute to so-called cardiac memory, as it exists on a beat-to-beat time scale.31 Modest increases in IKr eliminate APD alternans with little or no attendant shortening of APD and tend to increase, rather than flatten, the slope of the APD restitution relation.10,31 These observations suggest that titration of K channel agonism may produce a selective inhibition of alternans. Unfortunately, tests of this idea must await the development of a selective IKr agonist, as none currently exists.
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Appendix |
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IKr in the CVM model was modified to fit the experimental data. The formulations and parameters for modified IKr are as follows:
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where XKr and YKr are the time- and voltage-dependent open probabilities of activation and inactivation gates, GKr is the maximum conductance of IKr, V is the membrane potential, and EKr=–85 mV is the reversal potential of IKr channel with physiological ionic concentrations both inside and outside the cell. X
Kr and YKr are the steady-state voltage-dependent open probabilities of the activation and inactivation gates; 
xKr and yKr are the voltage-dependent activation and inactivation time constants.
To obtain the same amplitude of APD alternans as in the original CVM model, PKr was increased to 0.000028 cm/ms. All of the other equations and parameters were unchanged from the original CVM model.
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Acknowledgments |
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These studies were supported by a predoctoral fellowship from the American Heart Association, New York State Affiliate, Inc, and NIH grant HL 62543. We thank Dr Jeffrey J. Fox for advice regarding the computer model, Dr Andrew Zygmunt for assistance with the perforated patch-clamp technique, and Dr Lisa C. Freeman for a critical and constructive review of the manuscript.
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Footnotes |
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This manuscript was sent to Michael R. Rosen, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Original received February 28, 2003; resubmission received October 15, 2003; revised resubmission received January 5, 2004; accepted January 29, 2004.
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References |
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