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Comparative Study
, 142 (8), 1300-8

Ranolazine: Ion-Channel-Blocking Actions and in Vivo Electrophysiological Effects

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Comparative Study

Ranolazine: Ion-Channel-Blocking Actions and in Vivo Electrophysiological Effects

Gernot Schram et al. Br J Pharmacol.

Abstract

Ranolazine is a novel anti-ischemic drug that prolongs the QT interval. To evaluate the potential mechanisms and consequences, we studied: (i) Ranolazine's effects on HERG and IsK currents in Xenopus oocytes with two-electrode voltage clamp; (ii) effects of ranolazine, compared to d-sotalol, on effective refractory period (ERP), QT interval and ventricular rhythm in a dog model of acquired long QT syndrome; and (iii) effects on selected native currents in canine atrial myocytes with whole-cell patch-clamp technique. Ranolazine inhibited HERG and IsK currents with different potencies. HERG was inhibited with an IC(50) of 106 micromol l(-1), whereas the IC(50) for IsK was 1.7 mmol l(-1). d-Sotalol caused reverse use-dependent ERP and QT interval prolongation, whereas ranolazine produced modest, nonsignificant increases that plateaued at submaximal doses. Neither drug affected QRS duration. d-Sotalol had clear proarrhythmic effects, with all d-sotalol-treated dogs developing torsades de pointes (TdP) ventricular tachyarrhythmias, of which they ultimately died. In contrast, ranolazine did not generate TdP. Effects on I(Kr) and I(Ks) were similar to those on HERG and IsK. Ranolazine blocked I(Ca) with an IC(50) of approximately 300 micromol l(-1). I(Na) was unaffected. We conclude that ranolazine inhibits I(Kr) by blocking HERG currents, inhibits I(Ca) at slightly larger concentrations, and has modest and self-limited effects on the QT interval. Unlike d-sotalol, ranolazine does not cause TdP in a dog model. The greater safety of ranolazine may be due to its ability to inhibit I(Ca) at concentrations only slightly larger than those that inhibit I(Kr), thus producing offsetting effects on repolarization.

Figures

Figure 1
Figure 1
Inhibition of IHERG current by ranolazine. (a, b) Currents from a representative cell before (a) and after application of 100 μmol l−1 ranolazine (b). Currents were elicited by the protocol shown in the inset. (c) Mean current–voltage relationships of IHERG tail currents under control conditions (filled circles) and in the presence of 100 μmol l−1 ranolazine (open circles). (d) Mean concentration–response curve at a test potential of 0 mV. Results are mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001 vs control, n=5. (e) 50% inhibition of IHERG by ranolazine (IC50; y-axis) as a function of test potential (x-axis).
Figure 2
Figure 2
Inhibition of IsK by ranolazine. (a, b) Currents from a representative cell under control conditions (a) and in the presence of 1 mmol l−1 ranolazine (b). Currents were elicited by the protocol shown in the inset. (c) Mean current–voltage relationships of IsK under control conditions (filled circles) and in the presence of 1 mmol l−1 ranolazine (open circles). (d) Mean concentration–response curve at a test potential of 0 mV. Results are mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001 vs control, n=6. (e) 50% inhibition of IsK by ranolazine (IC50; y-axis) as a function of test potential (x-axis).
Figure 3
Figure 3
Effects of D-sotalol and ranolazine on right ventricular ERP and QT interval as a function of BCL. (a, b) Effect of D-sotalol on ERP (a) and QT duration (b). Filled diamonds: Control, n=5. Open diamonds: D-Sotalol bolus of 8 mg kg−1, followed by a maintenance dose of 4 mg kg−1 h−1, n=5. (c, d) Effects of ranolazine on ERP (c) and QT duration (d). Filled diamonds: Control, open squares: ranolazine 3 mg kg−1 h−1, open diamonds: ranolazine 15 mg kg−1 h−1. *P<0.05, **P<0.01, n=5.
Figure 4
Figure 4
Arrhythmogenic effects of D-sotalol and ranolazine. TdP was induced by challenge with phenylephrine, which was administered as an intravenous bolus of 10–50 μg kg−1. (a) D-Sotalol 8 mg kg−1 bolus followed by continuous infusion of 4 mg kg−1 h−1 and phenylephrine 10 μg kg−1 bolus. (b) D-Sotalol 8 mg kg−1 bolus followed by continuous infusion of 4 mg kg−1 h−1 and phenylephrine 40 μg kg−1 bolus. (c) Ranolazine 3 mg kg−1 and phenylephrine 20 μg kg−1 bolus. (d) Ranolazine 15 mg kg−1 and phenylephrine 50 μg kg−1 bolus. The bar graphs on the right-hand panel of each ECG illustrate the number of animals (in %; n=6 in each group) developing TdP in each series of experiments.
Figure 5
Figure 5
IKr and IKs inhibition by ranolazine. (a, b) IKr from a representative cell before (a) and after application of 100 μmol l−1 ranolazine (b). Currents were elicited by the protocol shown in the inset. (c) Concentration–response curve of mean data at a test potential of 0 mV. *P<0.05, **P<0.01 vs control, n=10. (d, e) Representative IKs recordings before (d) and after 1 mmol l−1 ranolazine (e). (f) Concentration–response curve of mean data at a test potential of +40 mV. *P<0.05, **P<0.01 vs control, n=6.
Figure 6
Figure 6
ICa inhibition by ranolazine. (a, b) ICa current recordings before (a) and after application of 300 μmol l−1 ranolazine (b). Currents were elicited from a holding potential of −50 mV to test potentials between −40 mV (arrow) and +60 mV as shown by the protocol in the inset. (c) Mean current–voltage relationships under control conditions (filled circles) and in the presence of 300 μmol l−1 ranolazine (open circles). (d) Mean concentration–response curve at a test potential of 10 mV. Results are mean±s.e.m. *P<0.05 and **P<0.01 vs control, n=8.
Figure 7
Figure 7
Effect of ranolazine on INa. (a, b) Currents from a representative cell before (a) and after 1 mmol l−1 ranolazine (b). Currents were elicited by the protocol shown in the inset. (c) Mean current–voltage relationship under control conditions (filled circles) and in the presence of 1 mmol l−1 ranolazine (open circles), n=6. Results are mean±s.e.m.

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