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 (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 IC50were 90±10µmol/l vs 60±10µmol/l for dofetilide and 42±4µmol/l vs 80±20µmol/l for propafenone (hKCa2.3 vs hKCa2.2). Whether this inhibition has clinical importance for their antiarrhythmic effect is unlikely, as the calculated IC50values 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.
Biomedical Institute, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark; Acesion Pharma, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Rafel
R
Simó-Vicens
Biomedical Institute, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark; Acesion Pharma, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Daniel R P
DRP
Sauter
Acesion Pharma, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Morten
M
Grunnet
Acesion Pharma, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Jonas G
JG
Diness
Biomedical Institute, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark; Acesion Pharma, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark. Electronic address: bobe@sund.ku.dk.
Bo H
BH
Bentzen
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*
D000889:Anti-Arrhythmia Agents; D051640:Small-Conductance Calcium-Activated Potassium Channels
Amiodarone hydrochloride (PubChem CID: 441325); Antiarrhythmic drug; Atrial fibrillation; Automated patch clamp; Calcium-activated potassium channel; Disopyramide (PubChem CID: 3114); Dofetilide (PubChem CID: 71329); Dronedarone (PubChem CID: 208898); Flecainide (PubChem CID: 3356); Ibutilide (PubChem CID: 60753); K(Ca)2 channel; Propafenone (PubChem CID: 4932); Quinidine (PubChem CID: 441074); Sotalol (PubChem CID: 5253); Vernakalant hydrochloride (PubChem CID: 9930048)