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 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.

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) (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.

Figures

Figure 1

Effect of ranolazine on the rapidly activating component of the delayed rectifier current (IKr, left) and the inward rectifier current (IK1, right) in canine left ventricular myocytes. Top panels illustrate the voltage protocol and representative current traces. Bottom panels are the concentration-response relationships. Data are presented as mean ± S.E.M. (n = 5–8).

Figure 2

Effect of ranolazine on the sodium calcium exchange current (INa-Ca, left), peak and late calcium channel current (ICa and late ICa, middle) and late sodium current (late INa, right). Top panels show the voltage protocols used and representative current traces. Bottom panels are the concentration-response relationships. Data are presented as mean ± S.E.M. (n = 3 – 14 as indicated over data points)

Figure 3

Summary of the concentration–response relationships for the effect of ranolazine to inhibit inward and outward ion channel currents in canine ventricular myocytes. Numbers inside the parentheses are IC50 values for the effect of ranolazine to inhibit the rapidly activating delayed rectifier potassium current (IKr), late sodium current (late INa), peak calcium current (ICa), late ICa, and the sodium-calcium exchange current (INa-Ca).

Figure 4

Concentration -dependent effects of ranolazine on the rate of rise of the upstroke of a Purkinje fiber action potential (Vmax). A: Shown are superimposed action potentials and corresponding differentiated upstrokes (dV/dt) recorded in the absence and presence of ranolazine (1–100 μM) (BCL=500 ms). B: Concentration-response relationship of ranolazine’s effect to reduce Vmax. Data are presented as mean ± S.E.M. (n=5). C: Concentration-dependent effect of ranolazine on action potential duration at 50 and 90% repolarization (APD50and APD90). BCL=2000 ms. Values are mean ± SEM. * − 0.05 vs. control

Figure 5

Left Panel: 4 mM [K+]o. Effects of ranolazine on epicardial and M cell action potentials. A: Superimposed transmembrane action potentials recorded under control conditions and following the addition of progressively higher concentrations of ranolazine (1–100 μM). B: Concentration-response curves for the effect of ranolazine on action potential duration (APD50 and APD90). Right Panels: 2 mM [K+]o. Effects of ranolazine on epicardial and M cell action potentials recorded at a pacing cycle length of 2000 ms and [K+]0 = 2 mM. C: Shown are superimposed transmembrane action potentials recorded in the absence and presence of ranolazine (1–100 μM). D: Concentration-dependent effect of ranolazine on action potential duration (APD50 and APD90). BCL=2000 ms. Data presented as mean ± SEM.

Figure 6

Rate-dependent effect of ranolazine (10 μM) and E-4031 (1 μM) on action potential duration (APD) in canine ventricular M cell and Epicardial tissue slices in the presence of 4 mM (A and B) and 2 mM (C and D) [K+]o. A and C: Rate-dependence of E-4031 and ranolazine-induced change in APD90 of M and epicardial cells, respectively. B and D: Rate-dependence of drug-induced change in transmural dispersion of action potential duration (TD-APD90). Values are mean ± SEM.

Figure 7

Effect of ranolazine to suppress d-sotalol-induced early afterdepolarizations (EAD) in M cell and Purkinje fiber preparations. A: Shown are superimposed transmembrane action potentials recorded from a Purkinje fiber preparation in the presence of IKr block (100 μM d-sotalol), and following addition of increasing concentrations of ranolazine (5 and 10 μM) in the continued presence of d-sotalol. [K+]o=3 mM. BCL=8000 ms and B: Superimposed transmembrane action potentials recorded from an M cell preparation under control conditions, in the presence of IKr block (100 μM d-sotalol), and following increasing concentrations of ranolazine (5, 10, and 20 μM) in the continued presence of d-sotalol. BCL=2000 ms.