Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent.
Ranolazine is a novel antianginal agent capable of producing anti-ischemic effects at plasma concentrations of 2 to 6 microM without a significant reduction of heart rate or blood pressure. This review summarizes the electrophysiologic properties of ranolazine. Ranolazine significantly blocks I(Kr) (IC(50) = 12 microM), late I(Na), late I(Ca), peak I(Ca), I(Na-Ca) (IC(50) = 5.9, 50, 296, and 91 microM, respectively) and I(Ks) (17% at 30 microM), but causes little or no inhibition of I(to) or I(K1). In left ventricular tissue and wedge preparations, ranolazine produces a concentration-dependent prolongation of action potential duration (APD) in epicardium, but abbreviation of APD of M cells, leading to either no change or a reduction in transmural dispersion of repolarization (TDR). The result is a modest prolongation of the QT interval. Prolongation of APD and QT by ranolazine is fundamentally different from that of other drugs that block I(Kr) and induce torsade de pointes in that APD prolongation is rate-independent (ie, does not display reverse rate-dependent prolongation of APD) and is not associated with early after depolarizations, triggered activity, increased spatial dispersion of repolarization, or polymorphic ventricular tachycardia. Torsade de pointes arrhythmias were not observed spontaneously nor could they be induced with programmed electrical stimulation in the presence of ranolazine at concentrations as high as 100 microM. Indeed, ranolazine was found to possess significant antiarrhythmic activity, acting to suppress the arrhythmogenic effects of other QT-prolonging drugs. Ranolazine produces ion channel effects similar to those observed after chronic exposure to amiodarone (reduced late I(Na), I(Kr), I(Ks), and I(Ca)). Ranolazine's actions to reduce TDR and suppress early after depolarization suggest that in addition to its anti-anginal actions, the drug possesses antiarrhythmic activity.
Antzelevitch
Charles
C
Masonic Medical Research Laboratory, Utica, NY 13501, USA. ca@mmrl.edu
Belardinelli
Luiz
L
Wu
Lin
L
Fraser
Heather
H
Zygmunt
Andrew C
AC
Burashnikov
Alexander
A
Di Diego
José M
JM
Fish
Jeffrey M
JM
Cordeiro
Jonathan M
JM
Goodrow
Robert J
RJ
Scornik
Fabiana
F
Perez
Guillermo
G
D000083:Acetanilides; D000200:Action Potentials / Q000187:drug effects; D000787:Angina Pectoris / Q000145:classification / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D022062:Electrophysiologic Techniques, Cardiac / Q000379:methods; D006801:Humans; D007473:Ion Channels / Q000145:classification / Q000187:drug effects / Q000502:physiology; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000069458:Ranolazine; D013237:Stereoisomerism; D016171:Torsades de Pointes / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
D000083:Acetanilides; D007473:Ion Channels; D010879:Piperazines; D000069458:Ranolazine