Ranolazine Attenuates The Enhanced Reverse Na⁺-Ca²⁺ Exchange Current Via Inhibiting Hypoxia-increased Late Sodium Current In Ventricular Myocytes

Ranolazine（RAN）, a novel clinical antianginal agent, inhibits late sodium current（INa.L） under many pathological conditions, while it is unclear whetherhypoxia-increased INa.Lcan be inhibited by RAN. In this study, whole-cell patch-clamptechnique was used to explore the effects of RAN on hypoxia-increased INa.Land reverseNa+/Ca2+exchange current（INCX）in therapeutic concentrations. The data show that INa.Land reverse INCXcould be significantly reduced by2μM tetrodotoxin（TTX）or9μMRAN under normoxia, while the inward INCXchanged very little. In addition, INa.Landreverse INCXwere decreased obviously by2μM TTX, but no longer changed when9μM RAN was added into afterwards in normoxia. RAN（3,6, and9μM）attenuated theincrease of INa.Land reverse INCXin a concentration-dependent manner during hypoxia,while inward INCXremained unaffected throughout the study. In the other two separateexperiments, the hypoxia-increased INa.Land reverse INCXwere associated with differentsequences of drug administration. One is that INa.Land reverse INCXwere inhibited by2μM TTX, whereas no changes appeared with adding9μM RAN afterwards. In anothergroup, INa.Land reverse INCXwere decreased by9μM RAN, but no further change wasdetected after adding2μM TTX. In monophasic action potentia（lMAP）recording, earlyafterdepolarizations（EADs）were suppressed by RAN（9μM）during hypoxia.Conclusion: RAN decreased reverse INCXby inhibiting INa.Lin normoxia,concentration-dependently attenuated the increase of INa.Lwhich thereby decreased thereverse INCX, and obviously relieved EADs during hypoxia.