Role of Small Conductance Calcium-Activated Potassium Channels in Atrial Electrophysiology and Fibrillation in the Dog
Background—Recent evidence points to functional Ca2+-dependent K+ (SK)-channels in the heart that may govern atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. This study addressed the role of SK-channels in atrial repolarization and AF-persistence in a canine AF-model.
Methods and Results—Electrophysiological variables were assessed in dogs subjected to atrial remodeling by 7-day atrial tachypacing (AT-P), as well as controls. Ionic currents and single channel properties were measured in isolated canine atrial cardiomyocytes by patch-clamp. NS8593, a putative highly-selective SK-blocker, suppressed SK-current with an IC50 of ~5 μmol/L, without affecting Na+-, Ca2+, or other K+-currents. Whole-cell SK-current sensitive to NS8593 was significantly larger in pulmonary-vein (PV) versus left atrial (LA) cells, without a difference in SK single-channel open-probability (Po), whereas AT-P enhanced both whole-cell SK currents and single-channel Po. SK-current block significantly increased APD in both PV and LA cells. SK2-expression was more abundant at both mRNA and protein levels for PV versus LA in control dogs, in both control and AT-P; AT-P upregulated only SK1 at the protein level. Intravenous administration of NS8593 (5 mg/kg) significantly prolonged atrial refractoriness and reduced AF-duration without affecting the Wenckebach cycle length (WCL), left ventricular refractoriness or blood pressure.
Conclusions—SK-currents play a role in canine atrial repolarization, are larger in PVs than LA, are enhanced by atrial-tachycardia remodeling, and appear to participate in promoting AF-maintenance. These results are relevant to the potential mechanisms underlying the association between SK single nucleotide polymorphisms and AF, and suggest SK-blockers as potentially interesting anti-AF drugs.
- Received April 4, 2013.
- Revision received October 16, 2013.
- Accepted October 17, 2013.