Copyright © 2006, European Society of Cardiology
RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents
aCardiome Pharma Corporation, 6th Floor, 6190 Agronomy Road, Vancouver BC, Canada V6T 1Z3
bDepartment of Cellular and Physiological Sciences, University of British Columbia, 2146 Health Sciences Mall, Vancouver BC, Canada V6T 1Z3
* Corresponding author. Tel.: +1 604 822 5806; fax: +1 604 822 6048. Email address: fedida{at}interchange.ubc.ca
Objective RSD1235 is a novel antiarrhythmic drug with atria-selective electrophysiological actions on Na+ and K+ currents. The mechanism for its protection of ventricular repolarization was assessed by its action on Purkinje fibers, and by block of late sodium current active during repolarization. Further, RSD1235's ability to reverse the pro-arrhythmic actions of the class III agents dofetilide and clofilium was assessed in isolated Purkinje fibers and an in vivo model of torsades de pointes (TdP).
Methods Action potential and early afterdepolarization (EAD) recordings were made from in situ and isolated rabbit Purkinje fibers at 37 °C using floating sharp microelectrodes; late INa was recorded using a whole-cell patch clamp technique of Nav1.5 expressed in HEK cells at 22 °C; In vivo, anesthetized methoxamine-sensitized rabbits were used to test the ability of RSD1235 to suppress clofilium-induced TdP.
Results RSD1235 (0.5–30 µM) had minor dose-dependent effects on action potential duration (APD) at 50% and 90% repolarization in Purkinje fibers, but pre-treatment significantly attenuated the APD-prolonging effects of dofetilide (300 nM). EADs induced by 300 nM dofetilide were terminated by 30 µM RSD1235 in all experiments (n=7). RSD1235 blocked a late component of Na current (INa), which can produce inward currents contributing to EAD formation. RSD1235 pre-treatment (1 µmol/kg/min) or acute infusions prevented/terminated TdP induced by clofilium in 8 of 9 rabbits, and reduced the duration of TdP episodes from 71±23 s in control to 17±7 and 14±14 s at infusion rates of 0.3 and 1.0 µmol/kg/min, respectively (n=9, p<0.001).
Conclusion RSD1235 itself has minor actions on repolarization in Purkinje fibers, but can reverse the AP-prolonging actions of class III agents and terminate arrhythmias in a model of TdP. We suggest that these protective actions of RSD1235 may result, at least in part, from its ability to inhibit late INa during action potential repolarization.
KEYWORDS Antiarrhythmic drug; Torsades de pointes; Atrial fibrillation; Potassium channel block; Sodium channel block
Time for primary review 22 days
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