Abstract 10642: Small Conductance Calcium Activated Potassium Channels as a New Atrial Fibrillation Target
Background: Recently, single nucleotide polymorphisms (SNPs) in Ca2+-dependent K+-channels (encoded by SK (KCa2.x) subunits) have been implicated in atrial fibrillation (AF) risk. Here, we assessed SK-channel expression, function and role in AF-maintenance in control (CTL) dogs and dogs with an AF substrate induced by 1-wk atrial tachypacing (AT-P). A highly-selective SK-current blocker (NS8593) was used as a probe to assess SK-channel function in vitro and to evaluate the importance of SK-channels in maintaining AF in vivo.
Methods: Perforated-patch and tight-seal patch-clamp methods were used respectively to record action potential duration (APD) and SK-current (ISK) in isolated canine left-atrial (LA) cells. SK mRNA and protein were quantified by qPCR and immunoblot respectively. Effective refractory period (ERP) and mean duration of burst pacing-induced AF (average of 10 inductions) were measured at open-chest study in dogs subjected to 7-day atrial tachypacing at 400 bpm as well as in control dogs, before and after i.v. NS8593.
Results: ISK was significantly increased by ATR (Figure A) as was corresponding SK1 (KCa2.1) protein (Figure B). NS8593 reduced LA ISK (by 71±4% at 10 µM; IC50= 5.3 µM) without altering other K+-currents (inward or delayed rectifiers, transient outward current), L-type Ca2+-currrent or Na+-current. NS8593 significantly increased APD in both CTL and AT-P cells (Figure C). Intravenous administration of NS8593 (5 mg/kg) significantly increased atrial ERP (Figure D) and reduced AF-duration (Figure E), without affecting left ventricular ERP or blood pressure.
Conclusions: ISK is expressed in canine LA and is upregulated by AT-P. A highly-selective ISK blocker increases LA APD and ERP, while showing clear anti-AF effects. These results bear light on the potential mechanisms underlying the association between SK SNPs and AF and suggest SK-blockers as potentially interesting anti-AF drugs.
- © 2012 by American Heart Association, Inc.