title: Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na(+) current in the heart.
abstract: 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.
authors: Pharmacological Sciences, Gilead Sciences, Palo Alto, California 94304, USA.
authors: Lin
authors: L
authors: Wu
authors: Sridharan
authors: S
authors: Rajamani
authors: Hong
authors: H
authors: Li
authors: Craig T
authors: CT
authors: January
authors: John C
authors: JC
authors: Shryock
authors: Luiz
authors: L
authors: Belardinelli
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000083:Acetanilides / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D017609:Barium Compounds / Q000494:pharmacology; D002460:Cell Line; D002712:Chlorides / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D005260:Female; D006329:Heart Conduction System / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D000069458:Ranolazine; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology*; D017180:Tachycardia, Ventricular / Q000503:physiopathology*; D013779:Tetrodotoxin / Q000494:pharmacology; D016171:Torsades de Pointes / Q000503:physiopathology*
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D017609:Barium Compounds; D002712:Chlorides; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010879:Piperazines; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C024986:barium chloride; C063968:E 4031; D013779:Tetrodotoxin; D012964:Sodium; D000069458:Ranolazine; D015761:4-Aminopyridine