title: Ranolazine decreases mechanosensitivity of the voltage-gated sodium ion channel Na(v)1.5: a novel mechanism of drug action.
abstract: BACKGROUND
  Na(V)1.5 is a mechanosensitive voltage-gated sodium-selective ion channel responsible for the depolarizing current and maintenance of the action potential plateau in the heart. Ranolazine is a Na(V)1.5 antagonist with antianginal and antiarrhythmic properties.
  
  
  RESULTS
  Mechanosensitivity of Na(V)1.5 was tested in voltage-clamped whole cells and cell-attached patches by bath flow and patch pressure, respectively. In whole cells, bath flow increased peak inward current in both murine ventricular cardiac myocytes (24±8%) and human embryonic kidney 293 cells heterologously expressing Na(V)1.5 (18±3%). The flow-induced increases in peak current were blocked by ranolazine. In cell-attached patches from cardiac myocytes and Na(V)1.5-expressing human embryonic kidney 293 cells, negative pressure increased Na(V) peak currents by 27±18% and 18±4% and hyperpolarized voltage dependence of activation by -11 mV and -10 mV, respectively. In human embryonic kidney 293 cells, negative pressure also increased the window current (250%) and increased late open channel events (250%). Ranolazine decreased pressure-induced shift in the voltage dependence (IC(50) 54 μmol/L) and eliminated the pressure-induced increases in window current and late current event numbers. Block of Na(V)1.5 mechanosensitivity by ranolazine was not due to the known binding site on DIVS6 (F1760). The effect of ranolazine on mechanosensitivity of Na(V)1.5 was approximated by lidocaine. However, ionized ranolazine and charged lidocaine analog (QX-314) failed to block mechanosensitivity.
  
  
  CONCLUSIONS
  Ranolazine effectively inhibits mechanosensitivity of Na(V)1.5. The block of Na(V)1.5 mechanosensitivity by ranolazine does not utilize the established binding site and may require bilayer partitioning. Ranolazine block of Na(V)1.5 mechanosensitivity may be relevant in disorders of mechanoelectric dysfunction.
authors.affiliation: Division of Gastroenterology & Hepatology, Enteric Neuroscience Program, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Beyder
authors.forename: Peter R
authors.initials: PR
authors.lastname: Strege
authors.forename: Santiago
authors.initials: S
authors.lastname: Reyes
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Bernard
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
authors.forename: Jonathan
authors.initials: J
authors.lastname: Makielski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D001696:Biomechanical Phenomena; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D014162:Transfection
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010879:Piperazines; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; C012647:QX-314; D008012:Lidocaine; D000069458:Ranolazine