RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents.
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 after-depolarization (EAD) recordings were made from in situ and isolated rabbit Purkinje fibers at 37 degrees C using floating sharp microelectrodes; late I(Na) was recorded using a whole-cell patch clamp technique of Nav1.5 expressed in HEK cells at 22 degrees 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 microM) 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 microM RSD1235 in all experiments (n=7). RSD1235 blocked a late component of Na current (I(Na)), which can produce inward currents contributing to EAD formation. RSD1235 pre-treatment (1 micromol/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 micromol/kg/min, respectively (n = 9, p < 0.001).


CONCLUSIONS
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 I(Na) during action potential repolarization.
Cardiome Pharma Corporation, 6th Floor, Vancouver BC, Canada.
Peter M R
PM
Orth
J Christian
JC
Hesketh
Carmen K H
CK
Mak
Yi
Y
Yang
Shunping
S
Lin
Gregory N
GN
Beatch
Alan M
AM
Ezrin
David
D
Fedida
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D005117:Cardiac Complexes, Premature / Q000188:drug therapy / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D023421:Models, Animal; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D016171:Torsades de Pointes / Q000188:drug therapy* / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D049990:Membrane Transport Modulators; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D000644:Quaternary Ammonium Compounds; D026941:Sodium Channel Blockers; D013449:Sulfonamides; C022799:clofilium; C063533:dofetilide