Abstract

Ranolazine is an antianginal agent that targets a number of ion channels in the heart, including cardiac voltage-gated Na⁺ channels. However, ranolazine block of muscle and neuronal Na⁺ channel isoforms has not been examined. We compared the state- and use-dependent ranolazine block of Na⁺ currents carried by muscle Nav1.4, cardiac Nav1.5, and neuronal Nav1.7 isoforms expressed in human embryonic kidney 293T cells. Resting and inactivated block of Na⁺ channels by ranolazine were generally weak, with a 50% inhibitory concentration (IC₅₀) ≥ 60 μM. Use-dependent block of Na⁺ channel isoforms by ranolazine during repetitive pulses (+50 mV/10 ms at 5 Hz) was strong at 100 μM, up to 77% peak current reduction for Nav1.4, 67% for Nav1.5, and 83% for Nav1.7. In addition, we found conspicuous time-dependent block of inactivation-deficient Nav1.4, Nav1.5, and Nav1.7 Na⁺ currents by ranolazine with estimated IC₅₀ values of 2.4, 6.2, and 1.7 μM, respectively. On- and off-rates of ranolazine were 8.2 μM^-1 s^-1 and 22 s^-1, respectively, for Nav1.4 open channels and 7.1 μM^-1 s^-1 and 14 s^-1, respectively, for Nav1.7 counterparts. A F1579K mutation at the local anesthetic receptor of inactivation-deficient Nav1.4 Na⁺ channels reduced the potency of ranolazine ∼17-fold. We conclude that: 1) both muscle and neuronal Na⁺ channels are as sensitive to ranolazine block as their cardiac counterparts; 2) at its therapeutic plasma concentrations, ranolazine interacts predominantly with the open but not resting or inactivated Na⁺ channels; and 3) ranolazine block of open Na⁺ channels is via the conserved local anesthetic receptor albeit with a relatively slow on-rate.