Late INa Inhibition as an Antiarrhythmic Strategy

Late sodium channel current (late I-Na) is considered to be an antiarrhythmic target. The prime antiarrhythmic mechanisms of late INa inhibition have been suggested to be (1) suppression of intracellular calcium [Cai]-mediated rhythmic activity (through reduction in Cai secondary to the decrease in intracellular sodium [Nai]) and (2) normalization of repolarization. Endogenous late I-Na is a small current and acceleration of the heart rate decreases late I-Na density. Late I-Na influx may significantly contribute to Nai loading, but it seems to largely occur under the combined conditions of augmented late I-Na density, bradycardia, and prolonged repolarization. At the same time, the relative contribution of late I-Na (including endogenous) in any type of prolonged cardiac repolarization is critical. Sodium channel blockers inhibit both late I-Na and peak INa, and a specific block of late I-Na might be achieved at slow and normal but seems not at rapid activation rates, at which peak I-Na, a much greater current, is also likely to be inhibited. The antiarrhythmic potential of a specific inhibition of late I-Na seems to best fit for, or may be limited to, the prevention of arrhythmias associated with prolonged repolarization, but it seems to be applicable to all types of arrhythmic abnormalities with elongated cardiac repolarization.