Contemporary reviewElectrophysiologic basis for the antiarrhythmic actions of ranolazine
Section snippets
Ion channel currents
Ranolazine is known to inhibit a number of ion currents (e.g., INa, IK, ICa,L) that are important for the genesis of the transmembrane cardiac action potential (AP).1, 2, 3, 4, 5 Table 1 summarizes the concentrations of ranolazine that cause 50% inhibition (IC50 values) of the various ion currents. In ventricular myocytes, the two ion currents most sensitive to ranolazine are the late/sustained/persistent sodium channel current (late INa) and the rapidly activating delayed rectifier potassium
Resting membrane potential
Ranolazine has no effect on the resting membrane potentials of canine and guinea pig ventricular myocytes, guinea pig papillary muscles, canine Purkinje fibers, or canine atrial preparations,1, 4, 14 which is consistent with the lack of effect of the drug on IK1.
AP amplitude, overshoot, and rate of rise of upstroke (Vmax)
In canine epicardial and M cells as well as in Purkinje fibers, ranolazine at concentrations ≤50 μM has minimal or no effect in AP amplitude and overshoot1 but does depress AP amplitude and Vmax at higher concentrations in ventricular
ERP, postrepolarization refractoriness, diastolic threshold of excitation, and conduction time
Ranolazine prolongs ERP, increases diastolic the threshold of excitation, and slows conduction velocity exclusively or predominantly in atria.4, 18 Ranolazine-induced prolongation of atrial ERP is due both to prolongation of APD and development of postrepolarization refractoriness. In the ventricles, ranolazine does not induce postrepolarization refractoriness. Atrial-selective prolongation of ERP and increased diastolic threshold of excitation as well as slowing of conduction velocity have
Ventricles
Arrhythmogenesis associated with reduced repolarization reserve caused by an increased late INa, reduced IKr, or a combination of both is effectively suppressed by ranolazine (Figure 2; see Section B.3). Besides prolonging APD and destabilizing repolarization, enhanced late INa increases Na+ influx and, and via NCX, increases intracellular Ca2+ (Cai2+), resulting in calcium overload. Abnormal Cai2+ handling and Cai2+ transients lead to spontaneous release of Ca2+ from sarcoplasmic reticulum,
Safety of ranolazine
In multiple clinical studies, ranolazine has demonstrated a relatively good clinical safety profile.11, 55, 56 Despite its effect to block IKr and prolong the QT interval, ranolazine does not induce TdP arrhythmias and, in fact, suppresses long QT–related ventricular arrhythmias in all long QT experimental models tested, including LQT1, LQT2, and LQT3.21, 30, 33, 35 The principal protective mechanism of ranolazine against TdP is its potent inhibition of late INa, which opposes the APD- and
Future directions
Despite growing experimental and clinical evidence that ranolazine possesses antiarrhythmic activity, no randomized placebo-controlled clinical trial has specifically tested this hypothesis. Randomized placebo-controlled clinical trials examining the efficacy of ranolazine against atrial and ventricular arrhythmias are warranted. One such clinical trial planned to start in the first half of 2011 is a study designed to determine the effect of ranolazine to reduce implantable
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Dr. Antzelevitch received a research grant and serves as a consultant to Gilead Sciences. Dr. Belardinelli is employed by Gilead Sciences.