Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome.
Prolongation of the QT interval of the ECG is associated with increased risk of torsades de pointes ventricular tachycardia. Ranolazine, a novel antianginal agent, is reported to decrease the delayed rectifier potassium current, I(Kr), and to increase action potential duration (APD) and the QT interval. However, ranolazine is also reported to reduce late sodium current (late I(Na)), a depolarizing current that contributes to prolongation of the plateau of the ventricular action potential. We hypothesized that ranolazine would decrease APD and the occurrence of arrhythmias when late I(Na) is increased. Therefore, we measured the effects of ranolazine alone and in the presence of anemone toxin (ATX)-II, whose action mimics the sodium channelopathy associated with long-QT3 syndrome, on epicardial monophasic action potentials and ECGs recorded from guinea pig isolated hearts. Ranolazine (0.1-50 microM) prolonged monophasic APD at 90% repolarization (MAPD(90)) by up to 22% but did not cause either early afterdepolarizations (EADs) or ventricular tachycardia (VT). ATX-II (1-20 nM) markedly increased APD and caused EADs and VT. Ranolazine (5-30 microM) significantly attenuated increases in MAPD(90) and reduced episodes of EADs and VT produced by ATX-II. Ranolazine also attenuated the synergistic effect of MAPD(90) increase caused by combinations of ATX-II and blockers of I(K) [E-4031; 1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)piperidine]. Thus, although ranolazine alone prolonged APD, it reduced APD and ventricular arrhythmias caused by agents that increased late I(Na) and decreased I(K).
Wu
Lin
L
CV Therapeutics, Inc., Palo Alto, California. lin.wu@cvt.com
Shryock
John C
JC
Song
Yejia
Y
Li
Yuan
Y
Antzelevitch
Charles
C
Belardinelli
Luiz
L
D000083:Acetanilides; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D000069458:Ranolazine
D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D000069458:Ranolazine