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CARDIOVASCULAR
Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida (Y.S.); Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, California (J.C.S., L.B.); and Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany (S.W., L.S.M.)
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 INa). Guinea pig and rabbit isolated ventricular myocytes were exposed to 200 µM 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 µM tetrodotoxin (TTX). 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 µM), a novel inhibitor of late INa, attenuated H2O2-induced late INa by 51 ± 9%. TTX (2 µM) or 10 µM 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 INa during exposure of ventricular myocytes to H2O2 contributes to electrical and contractile dysfunction and suggest that inhibition of late INa may offer protection against ROS-induced Na+ and Ca2+ overload.
Address correspondence to: Dr. Yejia Song, Division of Cardiovascular Medicine, University of Florida, 1600 SW Archer Rd., M-411, Gainesville, FL 32610-0277. E-mail: songy{at}medicine.ufl.edu
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