State- and use-dependent block of muscle Nav1.4 and neuronal Nav1.7 voltage-gated Na+ channel isoforms by ranolazine

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 mu M. Use-dependent block of Na+ channel isoforms by ranolazine during repetitive pulses (+50 mV/10 ms at 5 Hz) was strong at 100 mu M, 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 mu M, respectively. On- and off-rates of ranolazine were 8.2 mu M-1 s(-1) and 22 s(-1), respectively, for Nav1.4 open channels and 7.1 mu M-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 similar to 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.