Late I_Na Inhibition as an Antiarrhythmic Strategy

Abstract

Late sodium channel current (late I_Na) is considered to be an antiarrhythmic target. The prime antiarrhythmic mechanisms of late I_Na inhibition have been suggested to be (1) suppression of intracellular calcium [Ca_i]-mediated rhythmic activity (through reduction in Ca_i secondary to the decrease in intracellular sodium [Na_i]) 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 Na_i 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 I_Na, 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.