The effects of ranolazine on cardiac ion currents at concentrations within the therapeutic range (i.e., 2–6 μM) include inhibition of IKr, late INa and late ICa,L. Ranolazine inhibition of IKr prolongs APD and its effect to inhibit late INa and late ICa,L, abbreviates APD. The net effect and clinical consequence of inhibition of these ion channel currents is a modest increase in the mean QTc interval over the therapeutic range. The drug differs significantly from other agents that block IKr and induce TdP. Ranolazine-induced prolongation of the APD is rate independent (i.e., does not display reverse rate dependent prolongation of APD), and is not associated with EADs, triggered activity, an increase in spatial dispersion of repolarization or polymorphic VT. Indeed, rather than displaying arrhythmogenic activity, ranolazine, via its actions to suppress EADs and reduce TDR, possesses significant antiarrhythmic activity, acting to suppress the arrhythmogenic effects induced by a variety of other QT-prolonging drugs.
Drugs with QT prolonging properties have attracted considerable attention in recent years due to their proclivity to induce life-threatening cardiac arrhythmias, such as Torsade de Pointes9–11
. More than 50 commercially available or investigational non-cardiovascular and 20 cardiovascular non-antiarrhythmic 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, 12–15
Ventricular myocardium is comprised of at least three 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.16–18
The ionic basis for these features include the presence of a smaller slowly activating delayed rectifier current (IKs
, a larger late INa 20
, and INa-Ca 21.
are similar in the three transmural cell types. M cells, like Purkinje fibers, develop EADs in response to agents and pathophysiologic 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 as compared to 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 three transmural cell types.
A more complex electrophysiological effect is observed with drugs affecting two 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 β-blocking properties, amiodarone is known to block late INa
. The efficacy of the amiodarone and its low incidence of proarrhythmia relative to other agents with Class III actions are attributable to this complex multi-channel inhibition.22
When administered chronically, amiodarone increases QT without augmenting spatial dispersion of repolarization, unlike other IKr
In some cases transmural dispersion of repolarization is reduced.23
Chronic amiodarone therapy can also suppress the effect of other IKr
blocker, like d-sotalol, to increase TDR or induce EADs. 23
Thus, chronic amiodarone alters 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 multi-channel 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, 26–28
Our data suggest that ranolazine fits this pharmacologic 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 and Purkinje fiber to that of epicardial APD is likely due to 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
likely underlie 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 VT. At doses that prolonged the QT interval by approximately 5% to 11% above control, ranolazine did not cause spontaneous TdP or TdP facilitated by iv bolus of phenylephrine (which increases susceptibility to TdP) in five dogs, whereas sotalol induced TdP in all five dogs under these conditions.29
Recent studies involving isolated guinea pig and rabbit hearts have also reported failure of ranolazine to induce TdP, but it effectiveness to suppress TdP induced by selective IKr
blockers (E-4031) and agents that augment late INa
In summary, the available data suggest that ranolazine, in addition to its anti-anginal actions, may possess important antiarrhythmic activity.