Xiaoliang S Qiu1, Samuel Chauveau1, Evgeny P Anyukhovsky1, Tania Rahim1, Ya-Ping Jiang1, Erin Harleton1, Steven J Feinmark1, Richard Z Lin1, Ruben Coronel1, Michiel J Janse1, Tobias Opthof1, Tove S Rosen1, Ira S Cohen2, Michael R Rosen1. 1. 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.). 2. 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.
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. METHODS AND 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.
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. METHODS AND 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: Ruth L Martin; Jeff S McDermott; Heinz J Salmen; Jason Palmatier; Bryan F Cox; Gary A Gintant Journal: J Cardiovasc Pharmacol Date: 2004-03 Impact factor: 3.105
Authors: Robert R Fenichel; Marek Malik; Charles Antzelevitch; Michael Sanguinetti; Dan M Roden; Silvia G Priori; Jeremy N Ruskin; Raymond J Lipicky; Louis R Cantilena Journal: J Cardiovasc Electrophysiol Date: 2004-04
Authors: Gerald A Faich; Joel Morganroth; Alan B Whitehouse; Jugroop S Brar; Peter Arcuri; Steven F Kowalsky; Daniel C Haverstock; Roger A Celesk; Deborah A Church Journal: Ann Pharmacother Date: 2004-03-16 Impact factor: 3.154