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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/H1048    most recent 00467.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wu, L. Articles by Belardinelli, L. PubMed PubMed Citation Articles by Wu, L. Articles by Belardinelli, L.

Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na⁺ current in the heart

¹Pharmacological Sciences, Gilead Sciences, Palo Alto, California; and ²Department of Medicine (Cardiovascular Medicine), University of Wisconsin, Madison, Wisconsin

Submitted 20 May 2009 ; accepted in final form 8 July 2009

Reduction of repolarization reserve increases the risk of arrhythmia. We hypothesized that inhibition of K⁺ current (I_K) to decrease repolarization reserve would unmask the proarrhythmic role of endogenous, physiological late Na⁺ current (late I_Na). Monophasic action potentials (MAP) and 12-lead electrocardiogram were recorded from female rabbit isolated hearts. To block I_K and reduce repolarization reserve, E-4031, 4-aminopyridine, and BaCl₂ were used; to block endogenous late I_Na, tetrodotoxin (TTX) and ranolazine were used. E-4031 (1–60 nM) concentration-dependently prolonged MAP duration (MAPD₉₀) and increased duration of the T wave from T_peak to T_end (T_peak-T_end), transmural dispersion of repolarization (TDR), and beat-to-beat variability (BVR) of MAPD₉₀. E-4031 caused spontaneous and pause-triggered polymorphic ventricular tachycardia [torsade de pointes (TdP)]. In the presence of 60 nM E-4031, TTX (0.6–3 µM) and ranolazine (5–10 µM) shortened MAPD₉₀, decreased TDR, BVR, and T_peak-T_end (n = 9–20, P < 0.01), and abolished episodes of TdP. In hearts treated with BaCl₂ or 4-aminopyridine plus E-4031, TTX (0.6–3 µM) shortened MAPD₉₀ and decreased T_peak-T_end. Ranolazine could not reverse the effect of E-4031 to inhibit human ether-a-go-go-related gene (HERG) K⁺ current; thus, the reversal by ranolazine of effects of E-4031 was likely due to inhibition of late I_Na and not to antagonism of the HERG-blocking action of E-4031. We conclude that endogenous, physiological late I_Na contributes to arrhythmogenesis in hearts with reduced repolarization reserve. Inhibition of this current partially reverses MAPD prolongation and abolishes arrhythmic activity caused by I_K inhibitors.

late sodium current; repolarization reserve; ventricular tachycardia; monophasic action potential; ion currents