Excessive reverse-mode (RM) sodium/calcium exchanger 1.1 (NCX1.1) activity, 
resulting from intracellular sodium accumulation caused by reduced Na+/K+-ATPase 
activity, increased Na-H exchanger 1 activity. The induction of the 
voltage-gated sodium channel late current component (late INa), is a major 
pathway for intracellular calcium (Ca2+i) loading in cardiac 
ischemia-reperfusion (IR) injury and cardiac glycoside toxicity. Inhibition of 
late INa with the antianginal agent ranolazine is protective in models of IR 
injury and cardiac glycoside toxicity. However, whether inhibition of late INa 
alone is sufficient to provide maximal protection or additional inhibition of RM 
NCX1.1 provides further benefit remains to be determined conclusively. 
Therefore, the effects of ranolazine were compared with the INa inhibitor 
lidocaine in models of IR injury and ouabain toxicity, RM NCX1.1-mediated Ca2+ 
overload, and patch-clamp assays of RM NCX1.1 currents. Ranolazine and lidocaine 
(10 μM) similarly reduced Ca2+i overload and improved left ventricle work 
recovery in whole-heart models of IR injury or exposure to ouabain (80 μM). 
Ranolazine (10 μM), but not lidocaine (10 μM), reduced RM NCX1.1-mediated Ca2+i 
overload in ventricular myocytes. Furthermore, ranolazine inhibited RM NCX1.1 
currents (IC50 1.7 μM), without affecting forward mode currents, revealing that 
ranolazine has novel RM NCX1.1 inhibitory actions. However, because lidocaine 
provides similar protection to ranolazine in whole-heart models but does not 
inhibit RM NCX1.1, we conclude that induction of late INa is upstream of RM 
NCX1.1 activity and selective inhibition of late INa alone is sufficient to 
reduce Ca2+i overload and contractile dysfunction in IR injury and cardiac 
glycoside toxicity.