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Wu L, Rajamani S, Li H, January CT, Shryock JC, Belardinelli L: Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na (+) current in the heart. Am J Physiol Heart Circ Physiol. 2009 Sep;297(3):H1048-57. Epub 2009 Jul 10.
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 BaCl (2) were used; to block endogenous late I (Na), tetrodotoxin (TTX) and ranolazine were used. E-4031 (1-60 nM) concentration-dependently prolonged MAP duration (MAPD (90)) 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 MAPD (90). 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 muM) and ranolazine (5-10 muM) shortened MAPD (90), decreased TDR, BVR, and T (peak)-T (end) (n = 9-20, P < 0.01), and abolished episodes of TdP. In hearts treated with BaCl (2) or 4-aminopyridine plus E-4031, TTX (0.6-3 muM) shortened MAPD (90) 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. |
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