Ranolazine vs phenytoin: greater effect of ranolazine on the transient Na+ current than on the persistent Na+ current in central neurons

Voltage-gated Na+ channels (Na-V) are involved in pathologies and are important targets of drugs (Na-V-blockers), e.g. some anti-epileptic drugs (AEDs). Besides the fast inactivating transient Na+ current (I-NaT), they generate a slowly inactivating "persistent" current (I-NaP). Ranolazine, a Na-V-blocker approved for treatment of angina pectoris, is considered a preferential inhibitor of I-Nap and has been proposed as a novel AED. Although it is thought that classic Na-V-blockers used as AEDs target mainly I-NaT, they can also reduce I-NaP. It is important to disclose specific features of novel Na-V-blockers, which could be necessary for their effect as AEDs in drug resistant patients. We have compared the action of ranolazine and of the classic AED phenytoin in transfected cells expressing the neuronal Na(V)1.1 Na+ channel and in neurons of neocortical slices. Our results show that the relative block of I-NaT versus I-NaP of ranolazine and phenytoin is variable and depends on Na+ current activation conditions. Strikingly, ranolazine blocks with less efficacy I-NaP and more efficacy I-NaT than phenytoin in conditions mimicking pathological states (i.e. high frequency firing and long lasting depolarizations). The effects are consistent with binding of ranolazine to both open/pre-open and inactivated states; larger I-NaT block at high stimulation frequencies is caused by the induction of a slow inactivated state. Thus, contrary than expected, ranolazine is not a better I-NaP blocker than phenytoin in central neurons, and phenytoin is not a better I-NaT blocker than ranolazine. Nevertheless, they show a complementary action and could differentially target specific pathological dysfunctions. (C) 2016 Elsevier Ltd. All rights reserved.