TY - JOUR

T1 - Effect of antiarrhythmic drugs on small conductance calcium –activated potassium channels

AU - Simo Vicens, Rafel

AU - Sauter, Daniel Rafael Peter

AU - Grunnet, Morten

AU - Diness, Jonas Goldin

AU - Bentzen, Bo Hjorth

PY - 2017/5/15

Y1 - 2017/5/15

N2 - 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 (KCa2.X, SK channels). In the heart, KCa2.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 KCa2.X channels is unknown. To this end, we tested a large number of AADs on the human KCa2.2 and KCa2.3 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 hKCa2.X channels, with no subtype selectivity. The calculated IC50 were 90 ± 10 µmol/l vs 60 ± 10 µmol/l for dofetilide and 42 ± 4 µmol/ l vs 80 ± 20 µmol/l for propafenone (hKCa2.3 vs hKCa2.2). 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.

AB - 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 (KCa2.X, SK channels). In the heart, KCa2.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 KCa2.X channels is unknown. To this end, we tested a large number of AADs on the human KCa2.2 and KCa2.3 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 hKCa2.X channels, with no subtype selectivity. The calculated IC50 were 90 ± 10 µmol/l vs 60 ± 10 µmol/l for dofetilide and 42 ± 4 µmol/ l vs 80 ± 20 µmol/l for propafenone (hKCa2.3 vs hKCa2.2). 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.

KW - Faculty of Health and Medical Sciences

KW - Atrial Fibrillation

KW - kca2 channel

KW - calcium-activated potassium channel

KW - antiarrhythmic drug

KW - automated patch clamp

U2 - 10.1016/j.ejphar.2017.03.039

DO - 10.1016/j.ejphar.2017.03.039

M3 - Journal article

C2 - 28322838

VL - 803

SP - 118

EP - 123

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

ER -