Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.
BACKGROUND
Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 micromol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations.


RESULTS
Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited I(Kr) (IC50=11.5 micromol/L), late I(Na), late I(Ca), peak I(Ca), and I(Na-Ca) (IC50=5.9, 50, 296, and 91 micromol/L, respectively) and I(Ks) (17% at 30 micromol/L), but caused little or no inhibition of I(to) or I(K1). In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K+]o=4 mmol/L, 10 micromol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+]o. Ranolazine (5 to 20 micromol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective I(Kr) blocker d-sotalol.


CONCLUSIONS
Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced I(Kr), I(Ks), late I(Na), and I(Ca)). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.
Antzelevitch
Charles
C
Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501, USA. ca@mmrl.edu
Belardinelli
Luiz
L
Zygmunt
Andrew C
AC
Burashnikov
Alexander
A
Di Diego
José M
JM
Fish
Jeffrey M
JM
Cordeiro
Jonathan M
JM
Thomas
George
G
D000083:Acetanilides; D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects; D051668:Delayed Rectifier Potassium Channels; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D006352:Heart Ventricles; D007473:Ion Channels / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D000069458:Ranolazine; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors
D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D007473:Ion Channels; D010879:Piperazines; D010880:Piperidines; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D019831:Sodium-Calcium Exchanger; C063968:E 4031; D012964:Sodium; D000069458:Ranolazine; D011188:Potassium; D002118:Calcium