title: Increased Late Sodium Current Contributes to the Electrophysiological Effects of Chronic, but Not Acute, Dofetilide Administration.
abstract: BACKGROUND
  Drugs are screened for delayed rectifier potassium current (IKr) blockade to predict long QT syndrome prolongation and arrhythmogenesis. However, single-cell studies have shown that chronic (hours) exposure to some IKr blockers (eg, dofetilide) prolongs repolarization additionally by increasing late sodium current (INa-L) via inhibition of phosphoinositide 3-kinase. We hypothesized that chronic dofetilide administration to intact dogs prolongs repolarization by blocking IKr and increasing INa-L.
  
  
  RESULTS
  We continuously infused dofetilide (6-9 μg/kg bolus+6-9 μg/kg per hour IV infusion) into anesthetized dogs for 7 hours, maintaining plasma levels within the therapeutic range. In separate experiments, myocardial biopsies were taken before and during 6-hour intravenous dofetide infusion, and the level of phospho-Akt was determined. Acute and chronic dofetilide effects on action potential duration (APD) were studied in canine left ventricular subendocardial slabs using microelectrode techniques. Dofetilide monotonically increased QTc and APD throughout 6.5-hour exposure. Dofetilide infusion during ≥210 minutes inhibited Akt phosphorylation. INa-L block with lidocaine shortened QTc and APD more at 6.5 hours than at 50 minutes (QTc) or 30 minutes (APD) dofetilide administration. In comparison, moxifloxacin, an IKr blocker with no effects on phosphoinositide 3-kinase and INa-L prolonged APD acutely but no additional prolongation occurred on chronic superfusion. Lidocaine shortened APD equally during acute and chronic moxifloxacin superfusion.
  
  
  CONCLUSIONS
  Increased INa-L contributes to chronic dofetilide effects in vivo. These data emphasize the need to include time and INa-L in evaluating the phosphoinositide 3-kinase inhibition-derived proarrhythmic potential of drugs and provide a mechanism for benefit from lidocaine administration in clinical acquired long QT syndrome.
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Xiaoliang S
authors.initials: XS
authors.lastname: Qiu
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Samuel
authors.initials: S
authors.lastname: Chauveau
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Evgeny P
authors.initials: EP
authors.lastname: Anyukhovsky
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Tania
authors.initials: T
authors.lastname: Rahim
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Jiang
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Erin
authors.initials: E
authors.lastname: Harleton
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Feinmark
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Lin
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Ruben
authors.initials: R
authors.lastname: Coronel
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Michiel J
authors.initials: MJ
authors.lastname: Janse
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Tobias
authors.initials: T
authors.lastname: Opthof
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Tove S
authors.initials: TS
authors.lastname: Rosen
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.). Ira.Cohen@stonybrook.edu.
authors.forename: Ira S
authors.initials: IS
authors.lastname: Cohen
authors.affiliation: From the Department of Physiology and Biophysics, Stony Brook University, NY (X.S.Q., S.C., E.P.A., T.R., Y.-P.J., R.Z.L., I.S.C.); Departments of Pharmacology (E.H., S.J.F., M.R.R.) and Pediatrics (T.S.R., M.R.R.), College of Physician and Surgeons of Columbia University, New York, NY; Medical Service, Northport VA Medical Center, NY (R.Z.L.); Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (R.C., M.J.J., T.O.); L'Institut de RYthmologie et de modélisation Cardiaque (LIRYC), Université Bordeaux Segalen, Bordeaux, France (R.C.); and Department of Medical Physiology, University Medical Center Utrecht, The Netherlands (T.O.).
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rosen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics; D012964:Sodium / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D012964:Sodium; C063533:dofetilide
keywords: PI3-kinase; dofetilide; dogs; lidocaine; long QT syndrome