title: Pharmacological blockade of small conductance Ca2+-activated K+channels by ICA reduces arrhythmic load in rats with acute myocardial infarction.
abstract: Acute myocardial infarction (AMI) with development of ventricular fibrillation (VF) is a common cause of sudden cardiac death (SCD). At present, no pharmacological treatment has successfully been able to prevent VF in the acute stage of AMI. This study investigates the antiarrhythmic effect of inhibiting small conductance Ca2+-activated K+(SK) channels using the pore blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) in AMI rats. Acute coronary ligation was performed in 26 anesthetized rats, and ECG, monophasic action potentials (MAPs), and ventricular effective refractory period (vERP) were recorded. Rats were randomized into four groups: (i) 3 mg/kg i.v. ICA with AMI (AMI-ICA-group, n = 9), (ii) vehicle with AMI (AMI-vehicle-group, n = 9), (iii) vehicle with sham operation (sham-vehicle-group, n = 8), and (iv) 3 mg/kg i.v. ICA with sham operation (sham-ICA-group, n = 6). At the end of experiments, hearts were stained for the non-perfused area at risk (AAR). AMI resulted in the development of ventricular tachycardia (VT) in all AMI-vehicle and AMI-ICA rats; however, ICA significantly decreased VT duration. VF occurred in 44% of AMI-vehicle rats but not in AMI-ICA rats. Monophasic action potential duration at 80% repolarization (MAPD80) in the ischemic area decreased rapidly in both AMI-vehicle and AMI-ICA rats. However, 5 min after occlusion, MAPD80 returned to baseline in AMI-ICA rats but not in AMI-vehicle rats. The vERP was prolonged in the AMI-ICA group compared to AMI-vehicle after ligation. AAR was similar between the AMI-vehicle group and the AMI-ICA group. In rats with AMI, ICA reduces the burden of arrhythmia.
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. cpv592@alumni.ku.dk.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Hundahl
authors.affiliation: Department of Cardiology, Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Sattler
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lasse
authors.initials: L
authors.lastname: Skibsbye
authors.affiliation: Acesion Pharma, Copenhagen, Denmark.
authors.forename: Jonas G
authors.initials: JG
authors.lastname: Diness
authors.affiliation: Department of Cardiology, Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Tfelt-Hansen
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C000591601:N-(pyridin-2-yl)thiazol-2-amine; D026902:Potassium Channel Blockers; D011725:Pyridines; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013844:Thiazoles
keywords: Acute myocardial infarction; Calcium-activated potassium channels; N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine; Ventricular arrhythmia