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Ranolazine attenuates hydrogen peroxide‐induced increases in late sodium‐channel open probability and open time

Hydrogen peroxide (H2O2) increases late sodium current (INa) and is implicated in ischemia/reperfusion injury to myocardium. Inhibition of late INa is a mechanism underlying the cardioprotective effect of ranolazine (Ran). The objective of this study was to examine the hypothesis that Ran attenuates H2O2‐stimulated late INa by reducing the open probability and open time of Na+‐channel late openings. Single‐channel INa of guinea pig ventricular myocytes was measured using the cell‐attached patch‐clamp technique. H2O2 (300 μmol/L) significantly increased the mean open probability and open time of late Na+‐channel openings from 0.013±0.001 to 0.107±0.004 and from 0.689±0.015 to 1.486±0.016 ms, respectively. When tetrodotoxin (2 μmol/L) was included in the pipette solution, H2O2‐induced late channel openings were completely inhibited. The stimulatory effect of H2O2 on both open probability and open time was attenuated by Ran in a concentration‐dependent manner. Ran at 3 and 6 μmol/L significantly reduced H2O2‐induced increase of mean open probability by 60±3% and 95±1%, respectively, and H2O2‐induced increase of mean open time by 31±8% and 82±2%, respectively. The attenuations of H2O2‐induced late Na+‐channel openings by Ran at 3 and 6 μmol/L were comparable to those of lidocaine at 30 and 60 μmol/L. In conclusion, at concentrations within its therapeutic range, Ran attenuates H2O2‐induced late INa by reducing the open probability and open time of late Na+‐channel openings.