Maria Mathilde Haugaard1, Eva Zander Hesselkilde2, Steen Pehrson3, Helena Carstensen2, Mette Flethøj2, Kirstine Færgemand Præstegaard2, Ulrik Svane Sørensen4, Jonas Goldin Diness4, Morten Grunnet4, Rikke Buhl2, Thomas Jespersen5. 1. Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: mmha@sund.ku.dk. 2. Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 3. Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Taastrup, Denmark. 4. Acesion Pharma, Copenhagen, Denmark. 5. Danish National Foundation Research Centre in Arrhythmias (DARC) and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Abstract
BACKGROUND: Small-conductance calcium-activated potassium (SK) channels have been found to play an important role in atrial repolarization and atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to investigate the existence and functional role of SK channels in the equine heart. METHODS: Cardiac biopsies were analyzed to investigate the expression level of the most prominent cardiac ion channels, with special focus on SK channels, in the equine heart. Subcellular distribution of SK isoform 2 (SK2) was assessed by immunohistochemistry and confocal microscopy. The electrophysiologic and anti-AF effects of the relative selective SK channel inhibitor NS8593 (5 mg/kg IV) were evaluated in anesthetized horses, focusing on the potential of NS8593 to terminate acute pacing-induced AF, drug-induced changes in atrial effective refractory period, AF duration and vulnerability, and ventricular depolarization and repolarization times. RESULTS: Analysis revealed equivalent mRNA transcript levels of the 3 SK channel isoforms in atria compared to ventricles. Immunohistochemistry and confocal microscopy displayed a widespread distribution of SK2 in both atrial and ventricular cardiomyocytes. NS8593 terminated all induced AF episodes (duration ≥15 minutes), caused pronounced prolongation of atrial effective refractory period, and reduced AF duration and vulnerability. QRS duration and QTc interval were not affected by treatment. CONCLUSION: SK channels are widely distributed in atrial and ventricular cardiomyocytes and contribute to atrial repolarization. Inhibition by NS8593 terminates pacing-induced AF of short duration and decreases AF duration and vulnerability without affecting ventricular conduction and repolarization. Thus, inhibition by NS8593 demonstrates clear atrial antiarrhythmic properties in healthy horses.
BACKGROUND: Small-conductance calcium-activated potassium (SK) channels have been found to play an important role in atrial repolarization and atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to investigate the existence and functional role of SK channels in the equine heart. METHODS: Cardiac biopsies were analyzed to investigate the expression level of the most prominent cardiac ion channels, with special focus on SK channels, in the equine heart. Subcellular distribution of SK isoform 2 (SK2) was assessed by immunohistochemistry and confocal microscopy. The electrophysiologic and anti-AF effects of the relative selective SK channel inhibitor NS8593 (5 mg/kg IV) were evaluated in anesthetized horses, focusing on the potential of NS8593 to terminate acute pacing-induced AF, drug-induced changes in atrial effective refractory period, AF duration and vulnerability, and ventricular depolarization and repolarization times. RESULTS: Analysis revealed equivalent mRNA transcript levels of the 3 SK channel isoforms in atria compared to ventricles. Immunohistochemistry and confocal microscopy displayed a widespread distribution of SK2 in both atrial and ventricular cardiomyocytes. NS8593 terminated all induced AF episodes (duration ≥15 minutes), caused pronounced prolongation of atrial effective refractory period, and reduced AF duration and vulnerability. QRS duration and QTc interval were not affected by treatment. CONCLUSION: SK channels are widely distributed in atrial and ventricular cardiomyocytes and contribute to atrial repolarization. Inhibition by NS8593 terminates pacing-induced AF of short duration and decreases AF duration and vulnerability without affecting ventricular conduction and repolarization. Thus, inhibition by NS8593 demonstrates clear atrial antiarrhythmic properties in healthy horses.
Authors: Laura A Hundahl; Stefan M Sattler; Lasse Skibsbye; Jonas G Diness; Jacob Tfelt-Hansen; Thomas Jespersen Journal: Pflugers Arch Date: 2017-03-11 Impact factor: 3.657
Authors: Merle Friederike Fenner; Helena Carstensen; Sarah Dalgas Nissen; Eva Melis Hesselkilde; Christine Scott Lunddahl; Maja Adler Hess Jensen; Ameli Victoria Loft-Andersen; Stefan Michael Sattler; Pyotr Platonov; Said El-Haou; Claire Jackson; Raymond Tang; Robert Kirby; John Ford; Ulrich Schotten; James Milnes; Ulrik Svane Sørensen; Thomas Jespersen; Rikke Buhl Journal: Br J Pharmacol Date: 2020-06-24 Impact factor: 8.739