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CARDIOVASCULAR
NeuroSearch A/S, Ballerup, Denmark (R.S.H., M.G.); and Danish National Research Foundation Centre for Cardiac Arrhythmia, Panum Institute, University of Copenhagen, Copenhagen, Denmark (R.S.H., S.-P.O., M.G.R.)
Received December 11, 2006; accepted February 22, 2007.
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Abstract |
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-subunit KCNE2 (Sanguinetti et al., 1995
; Trudeau et al., 1995; Abbott et al., 1999). The IKs current is mediated by KCNQ1 channels associated with KCNE1 -subunits (Barhanin et al., 1996; Sanguinetti et al., 1996). Class III antiarrhythmic compounds such as dofetilide, E-4031, and MK-499 block the IKr current and increase action potential duration, which is detected on the surface electrocardiogram (ECG) as a prolongation of the QT interval (Spector et al., 1996a; Kamiya et al., 2006). This can result in the acquired form of the long QT syndrome; however, a relatively rare form of inherited long QT syndrome also exists, named LQT1–8 according to the gene mutation that causes the phenotype. The LQT2 syndrome is associated with QT prolongation that is caused by loss-of-function mutations in the hERG channel, resulting in either altered gating properties of the channel or impairment of normal intracellular trafficking (Chen et al., 1999; Clancy and Rudy, 2001). Common for both the inherited and acquired form of long QT syndrome is an increased risk for sudden cardiac death preceded by a polymorphic ventricular tachycardia, Torsade de Pointes. The trigger of Torsade de Pointes is thought to be early afterdepolarizations in the Purkinje fibers and/or M cells, caused by reactivation of L-type calcium channels during the long plateau phase (January and Riddle, 1989). M cells and Purkinje fibers have intrinsically longer action potential than found in other regions of the ventricular myocardium, and this heterogeneity in action potential duration is accentuated during slow heart rates, which explains why Torsade de Pointes is more easily triggered during bradycardia (Antzelevitch et al., 1999). Loss-of-function mutations in the hERG channel or pharmacological block of IKr increase the transmural dispersion of repolarization, setting the substrate for ventricular fibrillation. Normal hERG channel function is likely to protect the cardiomyocytes from early afterdepolarizations as well as premature beats (Lu et al., 2001). The gating properties of the hERG channel secure a minor IKr contribution during the action potential plateau phase, while significant IKr current is observed during repolarization (Smith et al., 1996; Spector et al., 1996b). Overexpression studies performed in vitro supports this notion since it has been shown that an increase in IKr in rabbit ventricular myocytes (Nuss et al., 1999) and guinea pig ventricular myocytes (Hoppe et al., 2001) increases the refractory period and suppresses the occurrence of early afterdepolarizations. Moreover, overexpression of hERG in canine ventricular myocytes has been shown to suppress electrical alternans (Hua et al., 2004). We and others (Kang et al., 2005; Zhou et al., 2005; Hansen et al., 2006a,b) have recently presented pharmacological activators of the hERG channel. One of the compounds we investigated, NS3623, was shown to increase the macroscopic hERG channel-mediated current primarily by slowing the inactivation gate and change voltage-dependent recovery from inactivation. We believe that activating the hERG channel is an interesting new approach in the development of a new antiarrhythmic principle, here we have examined the antiarrhythmic potential of hERG channel activation using the model compound NS3623. The present study was designed to evaluate the physiological consequences of activating the hERG channel in the intact guinea pig heart. We found that hERG channel activation concentration-dependently shortens QT intervals in intact hearts. In addition, we observed significant suppression of triggered activity by activation of hERG channels, demonstrating that increased IKr current could constitute a new antiarrhythmic approach for certain types of arrhythmia. |
Materials and Methods |
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Drug Application. NS3623 (synthesized in house) and E-4031 (Wako, Osaka, Japan) were dissolved in purified water.
Adaptation to Changes in Heart Rate. After stabilization the right atrium was removed, the atrioventricular (AV) node was mechanically crushed with metal forceps, and the heart was allowed to stabilize for at least 30 min. The heart was then paced below the crushed AV node at the indicated basic cycle length. To avoid hysteresis, a fixed basic cycle length of 250 ms was kept in between changes in pacing rate.
Bradycardia. After stabilization, the right atrium was removed, the AV node was mechanically crushed with metal forceps, and the heart was allowed to stabilize for at least 30 min. The heart was then paced below the crushed AV nodes at basic cycle length long enough (400–600 ms) to elicit extrasystoles identified as premature ventricular contractions (PVCs) occurring 40 ms or less after a previous contraction. After 15 min of sustained PVCs, perfusion with 30 µM NS3623 was initiated. Time-matched controls were performed where 15 min of sustained PVCs was followed by perfusion with Krebs-Henseleit solution.
Short-Term Variability. Short-term QT variability of the heart in the presence of 30 µM NS3623 relative to control was determined by quantification of the mean orthogonal distance to the line of identity of the corresponding Poincaré plots of 100 consecutive beats that were drawn by plotting each QT duration against the QT duration of the former beat. Quantification was done using the equation: variabilityQT = 
|QTn + 1 – QT|/[100 x
2] as described previously (Thomsen et al., 2004).
Data Analysis and Assessment of Significance. QRS duration was assessed from the beginning of the Q-wave to the end of the S-wave. QT measurements were performed from the beginning of the Q-wave to the end of the T-wave. Tpeak – Tend measurements were from the peak of the T-wave to the end of the T-wave. Duration of monophasic action potentials was measured at 30, 50, and 90% of repolarization relative to the diastolic membrane potential (APD30, APD50, and APD90). QT intervals, QRS duration, and Tpeak – Tend durations were measured using Chart 5 software (ADInstruments). Significance was assessed using one-way analysis of variance with Tukey post-test (Figs. 1 and 2) or two-way analysis of variance (Fig. 5) with Bonferroni post-test. Paired Student's t test was used in Fig. 6, C and D (*, P values of 0.01–0.05; **, P values of 0.001–0.01; and ***, P values of < 0.001).
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), this concentration-effect relationship can be attributed to an increase in the repolarizing IKr current. No significant change in QRS duration was detected after perfusion with increasing concentrations of NS3623 (Fig. 1C), although a tendency toward a prolongation after exposure to the highest concentrations was observed.
Figure 2A depicts monophasic action potentials measured in control situation (black) and in the presence of 30 µM NS3623 (gray). In the biophysical characterization of the compound, we found that NS3623 mainly affects the inactivation of the hERG channel (Hansen et al., 2006b). The inactivation gate is thought to prevent excess potassium efflux through the hERG channel during the action potential, and we therefore speculated whether the compound could cause triangulation of the monophasic action potentials. During the vulnerable period, which coincides with the repolarizing phase 3, the heart is particularly sensitive to stimuli that can induce fibrillations. We measured monophasic action potential duration at 90, 50, and 30% of repolarization shown as MAPD90, MAPD50, and MAPD30 in Fig. 2A. As can be seen from Fig. 2B, 10 and 30 µM NS3623 caused a concentration-dependent shortening of MAPD30, MAPD50, and MAPD90 (n = 4). As a measure of triangulation, we used the time interval between MAPD30 and MAPD90, and no significant change in this parameter was identified (2C).
Action potential shortening can be associated with decreased ventricular contractility due to the shorter plateau phase limiting calcium influx. After perfusion with 30 µM NS3623, we observed a time-dependent decrease in the left ventricular pressure as seen in Fig. 3. This effect was also seen after coperfusion with a 1 µM concentration of the specific hERG channel blocker E-4031, whereas E-4031 alone did not induce any change in contractility.
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Application of most class III and some class I compounds is associated with some degree of reverse use dependence with the beneficial effect of the compounds decreasing at heart rates when they are needed the most (Hondeghem and Snyders, 1990; Winslow and Campbell, 1991). We examined the effects of 30 µM NS3623 on the QT interval at different heart rates (basic cycle length, 400, 333, 270, and 200 ms) (Fig. 4). QT intervals decreased to approximately 80% of the control values at all heart rates examined (n = 5).
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). Figure 5A shows representative traces of a slowly paced heart before (black) and after (gray) treatment with 30 µM NS3623. The frequency of extrasystoles decreased significantly (P < 0.05) and time-dependently after NS3623 perfusion (n = 4) (Fig. 5B) with obtained significance both for 3 and 4 min after NS3623 perfusion relative to 1 and 2 min and also relative to the time-matched control. The time for perfusate to reach the heart in our set-up was approximately 2 min and 45 s.
We then examined the short-term variability of QT duration in the slowly paced heart, before the occurrence of extrasystoles and after compound application. A representative Poincaré plot is shown in the absence (Fig. 6A) and in the presence of 30 µM NS3623 (Fig. 6B). The mean distance from the diagonal line was significantly different in NS3623-treated hearts compared with the control measurements (P < 0.01, n = 4), as seen in Fig. 6C. Increased dispersion of repolarization is likely to set the substrate for maintenance of ventricular arrhythmias in the bradycardic heart. It has been shown that complete repolarization of epicardial cells coincides with peak of the T-wave, and the end of the T-wave is representative of full repolarization of the M cells (Yan and Antzelevitch, 1998). We therefore used the interval between Tpeak – Tend as a measure of dispersion of repolarization (Fig. 6D). No significant change in this measure was obtained, although a strong tendency toward a shorter time interval was observed.
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). In the isolated Langendorff-perfused guinea pig hearts, NS3623 concentration-dependently decreased QT durations (Fig. 1). Termination of the action potential occurs when L-type calcium channels time-dependently inactivate and potassium channel conductance increases. NS3623 mainly change the voltage dependent release from inactivation of hERG channels. The earlier recovery of the channel population may contribute to an earlier increase in potassium conductance during the action potential. It should however be noticed that the changed voltage-dependent release from inactivation in the presence of NS3623 is only observed at potentials more negative than approximately –20 mV. The molecular mechanism of action of NS3623 is therefore in agreement with the data presented in Fig. 2. Here, an unaffected initial plateau phase was followed by a faster initiation of repolarization when NS3623 was present. The mechanism of action of NS3623 explains the observed dose-dependent QT shortening induced by the compound. We previously reported that NS3623 selectively activates the cloned hERG channels expressed in oocytes, with no effect of 30 µM of the compound on cloned KCNQ1 representing native IKs, Kv1.5 (IKur), and Kv4.3 (Ito), or native INa and a minimal effect on native ICa,L. We furthermore reported that the EC50 value for NS3623 on the cloned hERG channels expressed in oocytes was 79.4 µM. For all the present studies except the initial dose-effect experiments, we used 30 µM, which in the oocyte resulted in a current increase to approximately 120 to 130% of the control values. Given the selectivity of the compound the observed decrease in QT interval can be attributed mainly to activation of the IKr current.
Action potential shortening can be associated with a negative inotropy as a consequence of the shorter systole, and all class I and class IV compounds have cardiosuppressive features (Honerjager et al., 1986; Taira, 1987). We also observed a decrease in inotropy in the presence of the NS3623. The negative inotropy was furthermore seen in the presence of a surplus of the hERG channel antagonist E-4031 (Fig. 3) at a concentration where no monophasic action potential shortening was observed. Moreover, decrease in contractility was observed about a minute after the compound exerted its monophasic action potential shortening effect, pointing toward no direct coupling between shorter APD and compromised contractility. The negative inotropy observed after NS3623 application must therefore be an independent effect to the compounds ability to shorten the QT interval. In isolated guinea pig ventricular myocytes, we previously found that NS3623 caused a slight block of ICa,L (Hansen et al., 2006b), and whether this sufficiently explains the observed decrease in contractility remains to be examined. It might be speculated that the compound acts on intracellular effectors affecting the contractility; for example, by increasing intracellular nitric oxide concentrations, general effects on calcium mismanagement or by inducing acidosis, which all have been shown to decrease contractility. Future studies will be needed to address this question.
Malfunction in adaptation to an increase or decrease in heart rate associated with drug treatment has been shown to highly increase the risk of proarrhythmicity. Most class III agents prolong the APD only at normal or low heart rates and thereby lose their beneficial action upon sympathetic stimulation (Hondeghem and Snyders, 1990). This can lead to arrhythmia with no class III activity when needed the most. Likewise, the class IC compound flecainide has been shown to lose its beneficial effect at low heart rates (Wang et al., 1990). In contrast, we observed that NS3623-induced shortening of the QT interval is rate-independent meaning that it does not display reverse-use dependence.
Even though pharmacological activation of IKr may constitute a new antiarrhythmic concept, the idea of preventing arrhythmias by activation of cardiac potassium channels is well described. The IKATP opener nicorandil have been used clinically (Fujimoto et al., 1999; Akagi et al., 2006). KATP channels are highly expressed especially in the ventricles and activation of these channels when ATP levels are scarce, e.g., during ischemia leads to a sharp triangulation of the action potential as well as an increase in the rate of repolarization (Ashcroft and Ashcroft, 1990). Pharmacological activation of sarcolemmal IKATP has been shown to accelerate repolarization, thereby shortening the action potential duration as well as the effective refractory period (Escande et al., 1989). Activation of KATP channels leads to an early increase in potassium conductance due to the increased driving force on potassium efflux during depolarization. The pro- or antiarrhythmic outcome of application of KATP openers probably depends on the arrhythmic settings. In disease states with increased incidence of reentry, the outcome is most likely to be proarrhythmic, whereas in arrhythmic settings including prolongation of the APD and increase the risk of early after-depolarizations and premature ventricular contractions, application of KATP openers seems to lead to antiarrhythmic activities (Kondo et al., 1999; Shimizu and Antzelevitch, 2000).
Triangulation. A premature impulse has a higher risk of precipitating arrhythmias if it coincides with the vulnerable period for induction of fibrillation of the myocardium, which has been demonstrated to coincide with phase 3 repolarization (Kirchhof et al., 1997). Triangulation of the action potential, measured as an increase in the APD30-APD90 time interval, increases the time spent in this particularly vulnerable window, and although this has only been assessed for class III drugs (Hondeghem, 2005), the same can be speculated to be true for compounds that decrease APD. In contrast to activation of IKATP, hERG channel activation did not lead to a triangulation of the monophasic action potential in the Langendorff-perfused heart (Fig. 2C). Monophasic action potentials recorded in the presence of NS3623 were superimposable with monophasic action potentials recorded in the control situation, only with an earlier repolarization (Fig. 2). The lack of triangulation in the presence of the NS3623 indicates that pharmacological hERG channel activation may be safer than KATP activation.
Bradycardia. The ventricular myocardium consists of three cell layers that are electrophysiologically distinct: endocardial cells, M cells, and epicardial cells. M cells have particularly long action potentials due to smaller IKs (Liu and Antzelevitch, 1995) and larger late INa (Zygmunt et al., 2001) and INa-Ca (Zygmunt et al., 2000). Ectopic foci of impulse formation can originate from early afterdepolarizations in the M cells caused by drugs or other pathological conditions that further prolong the action potential. This regional prolongation of action potential duration interval augments the normal transmural heterogeneity of ventricular repolarization, setting the substrate for re-entrant arrhythmias. At concentrations that abbreviated the QT durations and MAP90 durations to 80% of control values NS3623 significantly decreased the occurrence of premature ventricular contractions provoked by acute bradycardia (Fig. 5). Early afterdepolarizations originating from Purkinje or M cells probably underlie these extrasystoles, and the NS3623-induced increase in IKr current very likely contribute to a decrease in action potential duration also in the M cells. IKr is homogenously expressed in the ventricular myocardium, and augmentation of the current probably influences all three myocardial layers. The selective augmentation of repolarizing reserve induced by the compound showed a tendency, although not significant, toward a decrease in the transmural dispersion induced by acute bradycardia (Fig. 6D). Zhou et al. (2005) directly demonstrated a decrease in transmural dispersion in the rabbit wedge preparation in the presence of the hERG agonist PD118057. This decrease in transmural dispersion was more prominent in the presence of dofetilide-provoked augmented dispersion. Short-term beat-to-beat variability has been shown to increase the risk of arrhythmias and predispose for Torsade de Pointes (Shah and Hondeghem, 2005). The variability of QT duration during bradycardia was dramatically reduced by the compound as seen in Fig. 6, A to C, indicating that IKr activation has the ability to decrease the risk of arrhythmic events as well as suppress extrasystoles.
In summary, the available data suggest that pharmacological activation of IKr in the mammalian myocardium shortens the QT interval and that this decrease in the QT interval is able to suppress the occurrence of extrasystoles elicited by acute bradycardia. It is therefore likely that IKr activation constitutes a new antiarrhythmic approach that might prevent arrhythmias originating from triggered activity.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: IKr, rapid delayed rectifier potassium current; IKs, slow delayed rectifier potassium current; hERG, human ether a-go-go potassium channel; E-4031, N-(4-{1-[2-(6-methyl-pyridin-2-yl)-ethyl]-piperidine-4-carbonyl}-phenyl)-methane-sulfonamide; MK-499, (+)-N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2,4'-piperidin)-6-yl]methanesulfonamide] monohydrochloride; ECG, electrocardiogram; NS3623, N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N'-(3'-trifluoromethylphenyl) urea; MAP, monophasic action potential; AV, atrioventricular; PVC, premature ventricular contraction; APD, action potential duration; MAPD, monophasic action potential duration; PD118057, 2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid.
Address correspondence to: Morten Grunnet, NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark. E-mail: mgr{at}neurosearch.dk
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80% of the control value. Values are mean ± S.D. (n = 5).