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The effect of ranolazine to convert AF to SR is likely a result of preferential blockade of the open state of the sodium channel, yielding a use-dependent effect on sodium current at faster activation rates, as occurs during AF.35 One advantage of ranolazine over other sodium channel blockers is its atrial selectivity for inhibition of INa.14 Sodium channel blockade by ranolazine is dependent on membrane potential and activation rate, and is much more potent in atria than ventricle.14 Atrial and ventricular sodium channels have distinct biophysical inactivation properties, with a much more negative half-inactivation voltage (V0.5) in atria than ventricles, differing by about 15 mV.14 The presence of ranolazine negatively shifts the V0.5 for sodium channel inactivation, but the shift is twice as large in atria than ventricles. These differences in inactivation biophysical properties, combined with a more depolarized diastolic membrane potential and slower phase 3 repolarization in atria, imparts greater INa inhibition from ranolazine in atria than in ventricles. Despite its selectivity for INa, ranolazine may also exert its antiarrhythmic effects in part by blockade of other currents in a concentration dependent manner, notably, the rapid delayed rectifier K+ current, IKr. Taken together, these ionic effects might help explain the conversion of PxAF to SR by ranolazine in our studies. The lack of effect of ranolazine in PsAF compared with success of chloroquine or PA-6 can also be partly attributed to the differences in key ionic targets of the respective drugs; ranolazine selectively tends to inhibit INa, whereas chloroquine/PA-6 target inward rectifier K+ channels which have been shown to be key in maintaining rotors that drive fibrillation.17 This is particularly relevant for PsAF, where the density of IK1 is increased, both in the sheep model7 and in humans.36
