title: Differential inhibition of cardiac and neuronal Na(+) channels by the selective serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine.
abstract: Duloxetine and venlafaxine are selective serotonin-norepinephrine-reuptake-inhibitors used as antidepressants and co-analgesics. While venlafaxine rather than duloxetine induce cardiovascular side-effects, neither of the substances are regarded cardiotoxic. Inhibition of cardiac Na(+)-channels can be associated with cardiotoxicity, and duloxetine was demonstrated to block neuronal Na(+)-channels. The aim of this study was to investigate if the non-life threatening cardiotoxicities of duloxetine and venlafaxine correlate with a weak inhibition of cardiac Na(+)-channels. Effects of duloxetine, venlafaxine and amitriptyline were examined on endogenous Na(+)-channels in neuroblastoma ND7/23 cells and on the α-subunits Nav1.5, Nav1.7 and Nav1.8 with whole-cell patch clamp recordings. Tonic block of the cardiac Na(+)-channel Nav1.5 and rat-cardiomyocytes (CM) revealed a higher potency for duloxetine (Nav 1.5 IC50 14±1µM, CM IC50 27±3µM) as compared to venlafaxine (Nav 1.5 IC50 671±26µM, CM IC50 452±34µM). Duloxetine was as potent as the cardiotoxic antidepressant amitriptyline (IC50 13±1µM). While venlafaxine almost failed to induce use-dependent block on Nav1.5 and cardiomyocytes, low concentrations of duloxetine (1, 10µM) induced prominent use-dependent block similar to amitriptyline. Duloxetine, but not venlafaxine stabilized fast and slow inactivation and delayed recovery from inactivation. Duloxetine induced an unselective inhibition of neuronal Na(+)-channels (IC50 ND7/23 23±1µM, Nav1.7 19±2µM, Nav1.8 29±2). Duloxetine, but not venlafaxine inhibits cardiac Na(+)-channels with a potency similar to amitriptyline. These data indicate that an inhibition of Na(+)-channels does not predict a clinically relevant cardiotoxicity.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. Electronic address: stoetzer.carsten@mh-hannover.de.
authors.forename: Carsten
authors.initials: C
authors.lastname: Stoetzer
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Papenberg
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany; Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany; Department of Craniomaxillofacial Surgery, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany; Department of Neurology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Thorben
authors.initials: T
authors.lastname: Doll
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Völker
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heineke
authors.affiliation: Department of Craniomaxillofacial Surgery, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Stoetzer
authors.affiliation: Department of Neurology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegner
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Leffler
mesh_terms: D000818:Animals; D000068736:Duloxetine Hydrochloride / Q000009:adverse effects*; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000009:adverse effects*; D026941:Sodium Channel Blockers / Q000009:adverse effects*; D000069470:Venlafaxine Hydrochloride / Q000009:adverse effects*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D026941:Sodium Channel Blockers; D000069470:Venlafaxine Hydrochloride; D000068736:Duloxetine Hydrochloride
keywords: Antidepressant; Cardiotoxicity; Na(+) channel; Patch-clamp; SNRI