Ranolazine Antagonizes the Effects of Increased Late Sodium Current on Intracellular Calcium Cycling in Rat Isolated Intact Heart

Abstract

Pathological conditions, including ischemia and heart failure, are associated with altered sodium channel function and increased late sodium current (I Na,L ), leading to prolonged action potential duration, increased intracellular sodium and calcium concentrations, and arrhythmias. We used anemone toxin (ATX)-II to study the effects of increasing I Na,L on intracellular calcium cycling in rat isolated hearts. Cardiac contraction was abolished using paralytic agents. Ranolazine (RAN) was used to inhibit late I Na . Hearts were loaded with fluo-4-acetoxymethyl ester, and myocyte intracellular calcium transients (CaTs) were measured using laser scanning confocal microscopy. ATX (1 nM) prolonged CaT duration at 50% recovery in hearts paced at a basal rate of 2 Hz and increased the sensitivity of the heart to the development of calcium alternans caused by fast pacing.ATX increased the time required for recovery of CaT amplitude following a previous beat, and ATX induced spontaneous calcium release waves during rapid pacing of the heart. ATX prolonged the duration of repolarization from the initiation of the activation to terminal repolarization in the pseudo-electrocardiogram. All actions of ATX were both reversed and prevented by subsequent or prior exposure, respectively, of hearts to RAN (10 M). Most importantly, the increased vulnerability of the heart to the development of calcium alternans during rapid pacing was reversed or prevented by 10 M RAN. These results suggest that enhancement of I Na,L alters calcium cycling. Reduction by RAN of I Na,L -induced dysregulation of calcium cycling could contribute to the antiarrhythmic actions of this agent in both reentrant and triggered arrhythmias.The pathology of calcium overload in the heart includes both mechanical and electrical dysfunction (Vassalle and Lin, 2004). At slow rates of pacing, the reopening of calcium channels late in the action potential plateau may facilitate the occurrence of early afterdepolarizations, whereas at fast rates, abnormalities of calcium handling and intracellular calcium transients become manifest, including spontaneous release of calcium from the sarcoplasmic reticulum (SR), transient inward current, delayed afterdepolarizations and aftercontractions, calcium alternans, and triggered arrhythmic activity. There is growing evidence that rate-dependent alternations in SR calcium release (i.e., calcium alternans) contribute to action potential duration alternans (Walker and Rosenbaum, 2003;Pruvot et al., 2004;Wasserstrom et al., 2008; Kapur et al., 2009a,b), which may be responsible for T-wave alternans, the development of repolarization gradients, and re-entrant arrhythmias.As a consequence of Na,Ca-exchange, an increase of sodium influx can lead to increases of calcium influx and intracellular calcium concentration and calcium overload in the heart (Verdonck et al., 1991;Verdonck et al., 1993). Cardiac sodium channels that fail to inactivate quickly after a brief This work was supported by a grant from Gilead Sciences, Inc. Ar...

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