title: Vernakalant activates human cardiac K(2P)17.1 background K(+) channels.
abstract: Atrial fibrillation (AF) contributes significantly to cardiovascular morbidity and mortality. The growing epidemic is associated with cardiac repolarization abnormalities and requires the development of more effective antiarrhythmic strategies. Two-pore-domain K(+) channels stabilize the resting membrane potential and repolarize action potentials. Recently discovered K2P17.1 channels are expressed in human atrium and represent potential targets for AF therapy. However, cardiac electropharmacology of K2P17.1 channels remains to be investigated. This study was designed to elucidate human K2P17.1 regulation by antiarrhythmic drugs. Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record K2P currents from Xenopus oocytes and Chinese hamster ovary (CHO) cells. The class III antiarrhythmic compound vernakalant activated K2P17.1 currents in oocytes an in mammalian cells (EC50,CHO=40 μM) in frequency-dependent manner. K2P17.1 channel activation by vernakalant was specific among K2P channel family members. By contrast, vernakalant reduced K2P4.1 and K2P10.1 currents, in line with K2P2.1 blockade reported earlier. K2P17.1 open rectification characteristics and current-voltage relationships were not affected by vernakalant. The class I drug flecainide did not significantly modulate K2P currents. In conclusion, vernakalant activates K2P17.1 background potassium channels. Pharmacologic K2P channel activation by cardiovascular drugs has not been reported previously and may be employed for personalized rhythm control in patients with AF-associated reduction of K(+) channel function.
authors.affiliation: Department of Cardiology, Medical University Hospital, Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Seyler
authors.affiliation: Department of Cardiology, Medical University Hospital, Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Schweizer
authors.affiliation: Department of Cardiology, Medical University Hospital, Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
authors.affiliation: Department of Cardiology, Medical University Hospital, Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, Medical University Hospital, Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. Electronic address: dierk.thomas@med.uni-heidelberg.de.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005424:Flecainide / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D024683:Potassium Channels, Tandem Pore Domain / Q000187:drug effects* / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D024683:Potassium Channels, Tandem Pore Domain; D011759:Pyrrolidines; C524581:vernakalant; D005424:Flecainide
keywords: Antiarrhythmic drug; Atrial fibrillation; Flecainide; K(2P) channel; Personalized medicine; Vernakalant