Jeppe Egedal Kirchhoff1, Jonas Goldin Diness2, Majid Sheykhzade3, Morten Grunnet4, Thomas Jespersen5. 1. The Danish National Research Foundation, Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. 2. The Danish National Research Foundation, Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark; Acesion Pharma, Copenhagen, Denmark. 3. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. 4. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Acesion Pharma, Copenhagen, Denmark; Lundbeck A/S, Copenhagen, Denmark. 5. The Danish National Research Foundation, Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark. Electronic address: thojes@sund.ku.dk.
Abstract
BACKGROUND: Application of antiarrhythmic compounds is limited by both proarrhythmic and extracardiac toxicities, as well as incomplete antiarrhythmic efficacy. An improved antiarrhythmic potential may be obtained by combining antiarrhythmic drugs with different modes of action, and a reduction of the adverse effect profile could be an additional advantage if compound concentrations could be reduced. OBJECTIVE: The purpose of this study was to test the hypothesis that combined inhibition of Ca(2+)-activated K(+) channels (SK channels) and voltage-gated Na(+) channels, in concentrations that would be subefficacious as monotherapy, may prevent atrial fibrillation (AF) and have reduced proarrhythmic potential in the ventricles. METHODS: Subefficacious concentrations of ranolazine, flecainide, and lidocaine were tested alone or in combination with the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) in a Langendorff-perfused guinea pig heart model in which AF was induced after acetylcholine application and burst pacing. RESULTS: AF duration was reduced when both flecainide and ranolazine were combined with ICA in doses that did not reduce AF as monotherapy. At higher concentrations, both flecainide and ranolazine revealed proarrhythmic properties. CONCLUSION: A synergistic effect in AF treatment was obtained by combining low concentrations of SK and Na(+) channel blockers.
BACKGROUND: Application of antiarrhythmic compounds is limited by both proarrhythmic and extracardiac toxicities, as well as incomplete antiarrhythmic efficacy. An improved antiarrhythmic potential may be obtained by combining antiarrhythmic drugs with different modes of action, and a reduction of the adverse effect profile could be an additional advantage if compound concentrations could be reduced. OBJECTIVE: The purpose of this study was to test the hypothesis that combined inhibition of Ca(2+)-activated K(+) channels (SK channels) and voltage-gated Na(+) channels, in concentrations that would be subefficacious as monotherapy, may prevent atrial fibrillation (AF) and have reduced proarrhythmic potential in the ventricles. METHODS: Subefficacious concentrations of ranolazine, flecainide, and lidocaine were tested alone or in combination with the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) in a Langendorff-perfused guinea pig heart model in which AF was induced after acetylcholine application and burst pacing. RESULTS:AF duration was reduced when both flecainide and ranolazine were combined with ICA in doses that did not reduce AF as monotherapy. At higher concentrations, both flecainide and ranolazine revealed proarrhythmic properties. CONCLUSION: A synergistic effect in AF treatment was obtained by combining low concentrations of SK and Na(+) channel blockers.
Authors: Haibo Ni; Alex Fogli Iseppe; Wayne R Giles; Sanjiv M Narayan; Henggui Zhang; Andrew G Edwards; Stefano Morotti; Eleonora Grandi Journal: Br J Pharmacol Date: 2020-08-09 Impact factor: 8.739
Authors: Mark A Skarsfeldt; Thomas A Jepps; Sofia H Bomholtz; Lea Abildgaard; Ulrik S Sørensen; Emilie Gregers; Jesper H Svendsen; Jonas G Diness; Morten Grunnet; Nicole Schmitt; Søren-Peter Olesen; Bo H Bentzen Journal: Pflugers Arch Date: 2016-01-05 Impact factor: 3.657
Authors: Haibo Ni; Dominic G Whittaker; Wei Wang; Wayne R Giles; Sanjiv M Narayan; Henggui Zhang Journal: Front Physiol Date: 2017-11-23 Impact factor: 4.566