Effect of antiarrhythmic drugs on small conductance calcium - activated potassium channels

Atrial fibrillation (AF) is the most common type of arrhythmia. Current pharmacological treatment for AF is moderately effective and/or increases the risk of serious ventricular adverse effects. To avoid ventricular adverse effects, a new target has been considered, the small conductance calcium-activated K⁺ channels (K_Ca2.X, SK channels). In the heart, K_Ca2.X channels are functionally more important in atria compared to ventricles, and pharmacological inhibition of the channel confers atrial selective prolongation of the cardiac action potential and converts AF to sinus rhythm in animal models of AF. Whether antiarrhythmic drugs (AADs) recommended for treating AF target K_Ca2.X channels is unknown. To this end, we tested a large number of AADs on the human K_Ca2.2 and K_Ca2.3 channels to assess their effect on this new target using automated whole-cell patch clamp. Of the AADs recommended for treatment of AF only dofetilide and propafenone inhibited hK_Ca2.X channels, with no subtype selectivity. The calculated IC₅₀ were 90±10µmol/l vs 60±10µmol/l for dofetilide and 42±4µmol/l vs 80±20µmol/l for propafenone (hK_Ca2.3 vs hK_Ca2.2). Whether this inhibition has clinical importance for their antiarrhythmic effect is unlikely, as the calculated IC₅₀ values are very high compared to the effective free therapeutic plasma concentration of the drugs when used for AF treatment, 40,000-fold for dofetilide and 140-fold higher for propafenone.