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.
Footnotes
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This work was supported by National Institutes of Health grant GM48090 (to G.K.W. and S.-Y.W.).
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ABBREVIATIONS: LA, local anesthetic; rNav1.4, the rat skeletal muscle Na+ channel; hNav1.5, the human cardiac Na+ channel; hNav1.7, the human neuronal type 1.7 Na+ channels; HEK, human embryonic kidney; rNav1.4-WCW, L435W/L437C/A438W mutant.
- Received September 10, 2007.
- Accepted December 12, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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