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(Circulation. 2004;110:904-910.)
© 2004 American Heart Association, Inc.
Original Articles |
From the Masonic Medical Research Laboratory, Utica, NY (C.A., A.C.Z., A.B., J.M.D., J.M.F., J.M.C., G.T.), and CV Therapeutics, Inc, Palo Alto, Calif (L.B.).
Correspondence to Dr Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501. E-mail ca{at}mmrl.edu
Received February 19, 2004; de novo received March 29, 2004; revision received May 12, 2004; accepted May 21, 2004.
| Abstract |
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Methods and Results Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited IKr (IC50=11.5 µmol/L), late INa, late ICa, peak ICa, and INa-Ca (IC50=5.9, 50, 296, and 91 µmol/L, respectively) and IKs (17% at 30 µmol/L), but caused little or no inhibition of Ito or IK1. In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K+]o=4 mmol/L, 10 µmol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+]o. Ranolazine (5 to 20 µmol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective IKr blocker d-sotalol.
Conclusions Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced IKr, IKs, late INa, and ICa). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.
Key Words: ischemia ion channels intervals depolarization
| Introduction |
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| Methods |
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| Results |
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Figure 3 shows the superimposed concentration-response curves for all of the currents for which such a relationship could be obtained. The plot highlights the overlap between the inhibition by ranolazine of IKr, late INa, and late ICa at clinically relevant therapeutic concentrations (2 to 6 µmol/L), suggesting that the effect of the drug to block outward repolarizing current, which prolongs action potential duration (APD), is substantially counterbalanced by its effect to inhibit the inward current, which is expected to abbreviate the action potential.
Effect of Ranolazine in Isolated Canine Ventricular Tissues
Ranolazine caused no change in resting membrane potential, action potential amplitude, or overshoot in either midmyocardial (M) or epicardial cells, except at very high concentrations (100 µmol/L), considerably above the plasma concentrations encountered in clinical use (Table 1).
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Figure 4 illustrates the effect of ranolazine on the maximal rate of increase of the upstroke (Vmax) of the action potential recorded from free-running canine Purkinje fibers. Significant inhibition, presumably because of the effect of ranolazine to block peak INa, was observed only at concentrations
50 µmol/L. Similar inhibition was observed in canine ventricular M cells (not shown). Shown in the bottom panel of Figure 4 is the effect of ranolazine on the APD of canine Purkinje fibers. At a basic cycle length (BCL) of 2000 ms, ranolazine produced a concentration-dependent abbreviation of APD that was greater at 50% than at 90% repolarization. At a BCL of 500 ms, the drug produced little change in APD90, but a concentration-dependent depression of the action potential plateau.
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The effects of ranolazine on the action potential of canine ventricular M cell and epicardial tissues are illustrated in Figure 5. The drug caused a small concentration-dependent prolongation of APD in epicardium but an abbreviation or biphasic effect in M cell preparations. Thus, ranolazine caused a concentration-dependent reduction of transmural dispersion of APD. Higher concentrations of the drug produced a depression of the plateau of the action potential, probably because of the effect of ranolazine to inhibit ICa and late ICa. The preferential prolongation of epicardial APD was more apparent at a [K+]o of 2 mmol/L than at 4 mmol/L (Figure 5, right). Early afterdepolarizations (EADs) were not observed at any concentration of ranolazine, not even under bradycardic and hypokalemic conditions known to potentiate the effect of IKr blocker to induce EADs.
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These concentration- and rate-dependent characteristics of ranolazine distinguish it from other agents that block IKr. Whereas selective IKr blockers invariably produce a concentration-dependent prolongation of APD that is greater in Purkinje fibers and M cells than in epicardial cells, the multiion channel block produced by ranolazine causes a concentration-dependent abbreviation of Purkinje and M cell APD but a slight prolongation of APD of epicardial cells.
Figure 6 illustrates another important distinction between typical IKr blockers and ranolazine. E-4031, a highly selective IKr blocker, caused a reverse rate-dependent prolongation of APD that is much greater in M cells than in epicardial cells, leading to a bradycardia-dependent accentuation of transmural dispersion of APD (TD-APD), typical of the actions of IKr blockers. In contrast, ranolazine produced a largely rate-independent prolongation of APD in epicardium and abbreviation in M cells, leading to a rate-independent reduction of transmural dispersion of APD. The reverse rate-dependent prolongation of APD and accentuation of TD-APD by E-4031 were still more dramatic at a [K+]o of 2 mmol/L (Figure 6, right). In contrast, ranolazine persisted in causing a rate-independent reduction of TD-APD at the lower [K+]o. These results are consistent with the clinical finding that prolongation of QTc by ranolazine, unlike that of pure IKr blockers, is not reverse rate dependent.7 Thus, although ranolazine modestly prolongs APD and QTc, it is fundamentally different from other IKr blockers, which are typically associated with proarrhythmic actions.
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Effect of Ranolazine in Canine Left Ventricular Wedge Preparation
Table 2 shows the effect of ranolazine in isolated canine left ventricular wedge preparations. In the presence of 4 mmol/L [K+]o and at a BCL of 2000 ms, ranolazine caused a small concentration-dependent prolongation of epicardial APD and a small biphasic effect in the M region, resulting in a 30-ms QT prolongation at the highest concentration tested (100 µmol/L). It is noteworthy that much of the QT-interval prolongation observed at the higher concentrations of ranolazine is a result of a slowing of conduction secondary to sodium channel inhibition. Transmural dispersion of repolarization (TDR) showed a tendency to diminish, although the decrease was not statistically significant. Under hypokalemic conditions ([K+]o=3 mmol/L), ranolazine produced a much greater prolongation of the QT interval, but TDR showed a similar tendency to decrease.
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Ranolazine did not induce either spontaneous or programmed electrical stimulationmediated torsade de pointes (TdP) during endocardial or epicardial pacing of the canine left ventricular wedge preparation at any concentration up to 100 µmol/L. TdP did not develop, nor could it be induced, even in the presence of extremely low [K+]o (2 or 3 mmol/L) and high concentrations of ranolazine. In contrast, both spontaneous and stimulation-induced TdP have been shown to develop in the perfused wedge preparation in response to a wide variety of IKr blockers.8
Neither early nor delayed afterdepolarizations were observed in either tissue or wedge preparations pretreated with any concentration of ranolazine. On the contrary, as illustrated in Figure 7, ranolazine proved to be effective in suppressing EADs in M cell and Purkinje fiber preparations pretreated with other IKr blockers, such as d-sotalol. d-Sotalol (100 µmol/L) produced a remarkable prolongation of repolarization and induced EADs in both M cell and Purkinje fiber preparations. Ranolazine caused a concentration-dependent abbreviation of the action potential and abolished the EADs. A similar effect of ranolazine (5 to 20 µmol/L) to suppress EAD activity and abbreviate APD was observed in 4 of 4 M cell and 3 of 3 Purkinje fiber preparations. Moreover, ranolazine was found to be effective in reducing TD-APD, the interval between the peak and end of the T wave (Tpeak-Tend) and TDR under long-QT conditions (d-sotalol, moxifloxacin, and sea anemone toxin [ATX]-II) (data not shown).
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| Discussion |
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Drugs with QT-prolonging properties have attracted considerable attention in recent years because of their proclivity to induce life-threatening cardiac arrhythmias, such as TdP.911 More than 50 commercially available or investigational noncardiovascular and 20 cardiovascular nonantiarrhythmic drugs have been shown or are suspected to have proarrhythmic effects.
The mechanisms underlying TdP have long been a matter of debate. Recent studies have identified dispersion of repolarization secondary to accentuation of electrical heterogeneities intrinsic to ventricular myocardium as the substrate and EADs as the trigger for the development of TdP.8,10,1215
Ventricular myocardium is composed of at least 3 electrophysiologically distinct cell types: epicardial, M, and endocardial. M cells are distinguished by having action potentials that prolong disproportionately relative to the action potentials of other ventricular myocardial cell types in response to a slowing of rate and/or in response to many QT-prolonging drugs.1618 The ionic bases for these features include the presence of a smaller slowly activating delayed rectifier current (IKs),19 a larger late INa,20 and INa-Ca.21 IKr and IK1 are similar in the 3 transmural cell types. M cells, like Purkinje fibers, develop EADs in response to agents and pathophysiological conditions that reduce the repolarization reserve of the ventricular myocardium. Epicardial and endocardial cells generally do not.
Most drugs that prolong the QT interval accentuate the normal transmural heterogeneity of final ventricular repolarization by causing a preferential prolongation of the action potential of M cells. IKr blockers, including d-sotalol, almokalant, E-4031, moxifloxacin, and erythromycin augment transmural dispersion of repolarization as a consequence. These agents cause relatively little prolongation of the APD of epicardial and endocardial cells, because these cell types possess a much more prominent IKs than the M cell. A similar preferential prolongation of the M cell APD is seen with agents that increase calcium current (ICa), such as Bay K 8644, as well as with agents that increase late INa, such as ATX-II, anthopleurin-A, and DPI 201-106. An exception to this rule applies to agents that block IKs, which cause a similar percentage of APD prolongation in the 3 transmural cell types.
A more complex electrophysiological effect is observed with drugs affecting 2 or more ion channels, such as amiodarone, sodium pentobarbital, quinidine, cisapride, and azimilide. Amiodarone is a potent antiarrhythmic agent used in the management of both atrial and ventricular arrhythmias. In addition to its ß-blocking properties, amiodarone is known to block late INa, ICa, IKr, and IKs. The efficacy of the amiodarone and its low incidence of proarrhythmia relative to other agents with class III actions are attributable to this complex multichannel inhibition.22 When administered chronically, amiodarone increases QT without augmenting spatial dispersion of repolarization, unlike other IKr blockers.2325 In some cases, transmural dispersion of repolarization is reduced.23 Chronic amiodarone therapy can also suppress the effect of other IKr blockers, like d-sotalol, to increase TDR or induce EADs.23 Thus, chronic amiodarone alters the cellular electrophysiology of ventricular myocardium so as to reduce TDR and suppress EADs, especially under conditions in which they are accentuated. The drugs potent inhibition of late INa is thought to play a key role.
The multichannel inhibition, particularly the ability to potently block late INa, has been suggested to underlie the effect of IKr blockers to prolong QT without creating the substrate or trigger for the development of TdP. Indeed, this feature could contribute to the suppression of EADs and reduction of spatial dispersion of repolarization, the substrate and trigger for TdP. This is the case for amiodarone and sodium pentobarbital, as well as for high concentrations of quinidine and cisapride.24,2628 Our data suggest that ranolazine fits this pharmacological profile as well. Like amiodarone and sodium pentobarbital, ranolazine produces a preferential prolongation of epicardial APD90, leading to a reduction in transmural dispersion of repolarization. The opposite effects of ranolazine on M cells and Purkinje fibers to that of epicardial APD is most likely because of the more prominent late INa in the M cell and Purkinje fiber than in epicardial cells.20 Ranolazine is among the most potent late INa blockers reported. It causes a decrease in net inward current in the M cells and Purkinje fiber but a decrease in net outward current in epicardium. The effect of ranolazine to block late INa and late ICa most likely underlies its effect to suppress EAD activity. Thus, unlike other IKr blockers, ranolazine does not lead to the development of TdP, either spontaneous or stimulation induced. Of note, ranolazine has recently been evaluated in an anesthetized dog model with acute complete atrioventricular block, a model susceptible to drug-induced polymorphic ventricular tachycardia. At doses that prolonged the QT interval by approximately 5% to 11% above control, ranolazine did not cause spontaneous TdP or TdP facilitated by an intravenous bolus of phenylephrine (which increases susceptibility to TdP) in 5 dogs, whereas sotalol induced TdP in all 5 dogs under these conditions.29 Recent studies involving isolated guinea pig and rabbit hearts have also reported failure of ranolazine to induce TdP but its effectiveness to suppress TdP induced by selective IKr blockers (E-4031) and agents that augment late INa (ATX-II).29
In summary, the available data suggest that ranolazine, in addition to its antianginal actions, may possess important antiarrhythmic activity.
| Acknowledgments |
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| Footnotes |
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| References |
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