Inhibition of reverse‐mode sodium‐calcium exchange by the anti‐anginal agent ranolazine.

Abstract

Myocardial calcium overload observed during ischemia‐reperfusion is largely mediated via reverse mode cardiac sodium‐calcium exchange (NCX1.1), resulting from intracellular sodium overload that occurs via sodium‐hydrogen exchange and induction of late sodium current (late INa). The anti‐anginal agent Ranolazine (Ranexa™) is thought to act by selective inhibition of late INa thus reducing the NCX1.1‐mediated intracellular calcium overload occurs. In preliminary studies, we observed that ranolazine reduces ouabain‐induced calcium overload in rat hearts perfused in working‐mode, that is likely independent of late INa. Therefore, we hypothesized that ranolazine may also directly inhibit reverse‐mode sodium‐calcium exchange. To test this notion, we investigated the effect of ranolazine on recombinant NCX1.1 currents using the inside‐out excised patch‐clamp technique. Interestingly, we observed that ranolazine is a selective and potent inhibitor of the inactivating reverse‐mode NCX1.1 currents (IC50 = 40.8 ± 3.9 nM), with no effect on the non‐inactivating forward‐mode NCX1.1 currents. To further probe the inactivation dependence of ranolazine, we examined the effects of ranolazine on reverse‐mode currents from the NCX1.1 mutants F258E and K264Q that display either no inactivation or accelerated inactivation. Furthermore, ranolazine inhibits reverse‐mode evoked NCX1.1 activity in intact neonatal rat cardiac myoyctes. These results strongly suggest that, at therapeutic concentrations in the micromolar range, ranolazine may exert some of its cardioprotective efficacy via direct inhibition of reverse‐mode NCX1.1 in addition to inhibition of late INa. Source of Research Support: Canadian Institutes for Health Research.