Blocking late sodium current reduces hydrogen peroxide-induced arrhythmogenic activity and contractile dysfunction

Reactive oxygen species (ROS), including H2O2, cause intracellular calcium overload and ischemia-reperfusion damage. The objective of this study was to examine the hypothesis that H2O2-induced arrhythmic activity and contractile dysfunction are the results of an effect of H2O2 to increase the magnitude of the late sodium current (late I-Na). Guinea pig and rabbit isolated ventricular myocytes were exposed to 200 mu M H2O2. Transmembrane voltages and currents and twitch shortening were measured using the whole-cell patch-clamp technique and video edge detection, respectively. [Na+](i) and [Ca2+](i) were determined by fluorescence measurements. H2O2 caused a persistent late INa that was almost completely inhibited by 10 mu M tetrodotoxin (TTX). H2O2 prolonged the action potential duration (APD), slowed the relaxation rate of cell contraction, and induced early afterdepolarizations (EADs) and after contractions. H2O2 also caused increases of [Na+](i) and [Ca2+](i). Ranolazine (10 mu M), a novel inhibitor of late 1 Na, attenuated H2O2 induced late I-Na by 51 +/- 9%. TTX ( 2 mu M) or 10 mu M ranolazine attenuated H2O2-induced APD prolongation and suppressed EADs. Ranolazine accelerated the twitch relaxation rate in the presence of H2O2 and abolished H2O2-induced aftercontractions. Pretreatment of myocytes with ranolazine delayed and reduced the increases of APD, [Na+](i), and [Ca2+](i) caused by H2O2. In conclusion, the results confirm the hypothesis that an increase in late I-Na during exposure of ventricular myocytes to H2O2 contributes to electrical and contractile dysfunction and suggest that inhibition of late I-Na may offer protection against ROS-induced Na+ and Ca2+ overload.