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 Ca-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.

Impact of arrhythmogenic calmodulin variants on small conductance Ca 2+ ‐activated K + (SK3) channels

“…As SK channels appears to play a role in some pathological conditions in the ventricles (Gui ; Bonilla ; Hundahl ; Chen ; Hamilton ), it could be speculated that the SK channels also have a contributory role in the pathogenesis of CaM‐associated LQTS. Three out of the four LQTS‐associated CaM variants significantly down‐regulated the SK current, with CaM D130G being the variant most profoundly decreasing SK current with no effect on the trafficking of the channel.…”

First Clinical Study with AP30663 ‐ a KCa2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation

“…Under these conditions, some studies have shown that ventricular small-conductance Ca2+-activated K+ current can be upregulated and that blocking small-conductance Ca2+activated K+ current can exhibit both proarrhythmic 17,18 and antiarrhythmic. [19][20][21] In addition, preclinical experiments with AP30663 yielded conflicting results. In an in vitro experiment, no effect of AP30663 on the ventricular interval was observed at a concentration of 30 µM (estimated concentration: 12,000 ng/mL).…”

Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) Increases Small-Conductance Ca2+-Activated K+ Current in Patients with Chronic Atrial Fibrillation

“…In a pacing-induced rat AF model, intravenous application of NS8593, a highly selective SK channels blocker, reduced the duration of AF by 64.5% [ 9 ]. Pharmacological blockade of SK channels with the pore blocker ICA in acute myocardial infarction with development of ventricular fibrillation (VF) significantly decreased VT duration and returned monophasic action potential duration at 80% repolarization (MAPD80) to baseline [ 10 ]. Hsueh et al demonstrated that SK channel blockade promoted arrhythmias in the canine left atrium, which could be attributed to the increase in APD heterogeneity [ 11 ].…”