Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties

Abstract

Background-Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 mol/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. Methods and 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 (IC 50 ϭ11.5 mol/L), late I Na , late I Ca , peak I Ca , and I Na-Ca (IC 50 ϭ5.9, 50, 296, and 91 mol/L, respectively) and I Ks (17% at 30 mol/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).

Ranolazine in Cardiac Arrhythmia

“…16 This effect of ranolazine was also seen in patients with LQT1 and LQT2. 17 Ranolazine and L-Type Calcium Channel: The inhibitory effect of ranolazine on I Ca-L is minimal at concentrations ≤10 μM and mainly affects late rather than peak I Ca-L , thus ranolazine is a weak direct vasodilator and has minimal direct effect on atrioventricular nodal conduction. 2,17 Thus, with current FDA-approved doses of ranolazine, the late I Na and I Kr currents will be predominantly inhibited in the ventricular myocytes, with minimal effect on late I Ca-L , whereas in the atrial myocytes, ranolazine will inhibit peak I Na as well as I Kr , with less effect on late I Na .…”

“…17 Ranolazine and L-Type Calcium Channel: The inhibitory effect of ranolazine on I Ca-L is minimal at concentrations ≤10 μM and mainly affects late rather than peak I Ca-L , thus ranolazine is a weak direct vasodilator and has minimal direct effect on atrioventricular nodal conduction. 2,17 Thus, with current FDA-approved doses of ranolazine, the late I Na and I Kr currents will be predominantly inhibited in the ventricular myocytes, with minimal effect on late I Ca-L , whereas in the atrial myocytes, ranolazine will inhibit peak I Na as well as I Kr , with less effect on late I Na . 17 Ranolazine and Cardiac Action Potential: Ranolazine exerts minimal effect on the resting membrane potential of both atrial and ventricular myocytes due to the lack of effect on inwardly rectifying K + current (I K1 ).…”

“…2,17 Thus, with current FDA-approved doses of ranolazine, the late I Na and I Kr currents will be predominantly inhibited in the ventricular myocytes, with minimal effect on late I Ca-L , whereas in the atrial myocytes, ranolazine will inhibit peak I Na as well as I Kr , with less effect on late I Na . 17 Ranolazine and Cardiac Action Potential: Ranolazine exerts minimal effect on the resting membrane potential of both atrial and ventricular myocytes due to the lack of effect on inwardly rectifying K + current (I K1 ). 9,17 In atrial myocytes, ranolazine causes significant depression of the action potential amplitude as well as the action potential upstroke (V max ), whereas it requires higher concentrations to exert the same effect in ventricular myocytes.…”

“…17 Ranolazine and Cardiac Action Potential: Ranolazine exerts minimal effect on the resting membrane potential of both atrial and ventricular myocytes due to the lack of effect on inwardly rectifying K + current (I K1 ). 9,17 In atrial myocytes, ranolazine causes significant depression of the action potential amplitude as well as the action potential upstroke (V max ), whereas it requires higher concentrations to exert the same effect in ventricular myocytes. 9 Late I Na and I Kr have opposite effects on action potential duration (APD) in ventricular myocytes, where late I Na causes its prolongation, whereas I Kr shortens it.…”

Comparison of Two Highly Automated ECG Algorithms for Detection of Drug‐Induced Cardiac Ion Channel Block

“…4 The last two drugs, ranolazine and verapamil, are associated with a low risk of torsade. 6,7 Although both are potent hERG blockers, ranolazine additionally inhibits the late sodium current while verapamil inhibits the L-type calcium current. 4 Using only supine resting ECGs, it was shown that, unlike QTc, early and late measures of repolarization (heart rate–corrected global J-T peak (c) and global T peak -T end , respectively) could differentiate pure hERG block associated with a high incidence of torsade risk, from multichannel block of hERG and either calcium or late sodium currents, which is associated with lower risk.…”