Loading…

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 inter...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2004-08, Vol.310 (2), p.599-605
Main Authors: Wu, Lin, Shryock, John C, Song, Yejia, Li, Yuan, Antzelevitch, Charles, Belardinelli, Luiz
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 μM) 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 μM) 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 .
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.104.066100