title: Ranolazine inhibits shear sensitivity of endogenous Na+ current and spontaneous action potentials in HL-1 cells.
abstract: Na(V)1.5 is a mechanosensitive voltage-gated Na(+) channel encoded by the gene SCN5A, expressed in cardiac myocytes and required for phase 0 of the cardiac action potential (AP). In the cardiomyocyte, ranolazine inhibits depolarizing Na(+) current and delayed rectifier (I(Kr)) currents. Recently, ranolazine was also shown to be an inhibitor of Na(V)1.5 mechanosensitivity. Stretch also accelerates the firing frequency of the SA node, and fluid shear stress increases the beating rate of cultured cardiomyocytes in vitro. However, no cultured cell platform exists currently for examination of spontaneous electrical activity in response to mechanical stimulation. In the present study, flow of solution over atrial myocyte-derived HL-1 cultured cells was used to study shear stress mechanosensitivity of Na(+) current and spontaneous, endogenous rhythmic action potentials. In voltage-clamped HL-1 cells, bath flow increased peak Na(+) current by 14 ± 5%. In current-clamped cells, bath flow increased the frequency and decay rate of AP by 27 ± 12% and 18 ± 4%, respectively. Ranolazine blocked both responses to shear stress. This study suggests that cultured HL-1 cells are a viable in vitro model for detailed study of the effects of mechanical stimulation on spontaneous cardiac action potentials. Inhibition of the frequency and decay rate of action potentials in HL-1 cells are potential mechanisms behind the antiarrhythmic effect of ranolazine.
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Strege
authors.forename: Arthur
authors.initials: A
authors.lastname: Beyder
authors.forename: Cheryl
authors.initials: C
authors.lastname: Bernard
authors.forename: Ruben
authors.initials: R
authors.lastname: Crespo-Diaz
authors.forename: Atta
authors.initials: A
authors.lastname: Behfar
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
authors.forename: Michael
authors.initials: M
authors.lastname: Ackerman
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002460:Cell Line; D057809:HEK293 Cells; D006325:Heart Atria / Q000166:cytology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D012212:Rheology / Q000187:drug effects; D033081:Shear Strength / Q000187:drug effects*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D000083:Acetanilides; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000069458:Ranolazine