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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...
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Published in: | The Journal of pharmacology and experimental therapeutics 2004-08, Vol.310 (2), p.599-605 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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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 (0.1â50 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 (1â20 nM)
markedly increased APD and caused EADs and VT. Ranolazine (5â30 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 . |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.104.066100 |