Received for publication January 25, 2006.
Revised March 22, 2006.
Accepted for publication March 23, 2006.

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

Abstract

Reactive oxygen species (ROS), including hydrogen peroxide (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 result 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 H₂O₂ (200 µmol/L). Transmembrane voltages and currents, and twitch shortening were measured using the whole-cell patch-clamp technique and video edge detection, respectively. Intracellular concentrations of sodium ([Na⁺]_i) and calcium ([Ca²⁺]_i) were determined by fluorescence measurements. H₂O₂ caused a persistent late I_Na that was almost completely inhibited by tetrodotoxin (TTX, 10 µmol/L). H₂O₂ prolonged the action potential duration (APD), slowed the relaxation rate of cell contraction, and induced early afterdepolarizations (EADs) and aftercontractions. H₂O₂ also caused increases of [Na⁺]_i and [Ca²⁺]_i. Ranolazine (10 µmol/L), a novel inhibitor of late I_Na, attenuated H₂O₂-induced late I_Na by 51±9%. TTX (2 µmol/L) or ranolazine (10 µmol/L) 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.

Key words: Hydrogen peroxide, Reactive oxygen species, Sodium current, action potential, contractile function, intracellular calcium

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