title: State- and use-dependent block of muscle Nav1.4 and neuronal Nav1.7 voltage-gated Na+ channel isoforms by ranolazine.
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 (IC(50)) >/= 60 microM. Use-dependent block of Na(+) channel isoforms by ranolazine during repetitive pulses (+50 mV/10 ms at 5 Hz) was strong at 100 microM, 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 IC(50) values of 2.4, 6.2, and 1.7 microM, respectively. On- and off-rates of ranolazine were 8.2 microM(-1) s(-1) and 22 s(-1), respectively, for Nav1.4 open channels and 7.1 microM(-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 approximately 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.
authors: Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. wang@zeus.bwh.harvard.edu
authors: Ging Kuo
authors: GK
authors: Wang
authors: Joanna
authors: J
authors: Calderon
authors: Sho-Ya
authors: SY
authors: Wang
mesh_terms: D000083:Acetanilides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006801:Humans; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D015394:Molecular Structure; D009124:Muscle Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009132:Muscles / Q000187:drug effects / Q000502:physiology*; D009154:Mutation; D062553:NAV1.4 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000069458:Ranolazine; D011994:Recombinant Proteins / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
chemical_list: D000083:Acetanilides; D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010879:Piperazines; D020033:Protein Isoforms; D011994:Recombinant Proteins; C106251:SCN4A protein, human; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000069458:Ranolazine