title: Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans.
abstract: OBJECTIVE
  We aimed at examining the acetylcholine-dependent inward-rectifier current (IKAch) as a target for the management of atrial fibrillation (AF).
  
  
  RESULTS
  The investigative agents AZD2927 and A7071 concentration-dependently blocked IKACh in vitro with minimal off-target activity. In anaesthetized dogs (n = 17) subjected to 8 weeks of rapid atrial pacing (RAP), the left atrial effective refractory period (LAERP) was maximally increased by 50 ± 7.4 and 50 ± 4.8 ms following infusion of AZD2927 and A7071. Ventricular refractoriness and the QT interval were unaltered. During sustained AF, both drugs significantly reduced AF frequency and effectively restored sinus rhythm. AZD2927 successfully restored sinus rhythm at 10/10 conversion attempts and A7071 at 14/14 attempts, whereas saline converted 4/17 episodes only (P<0.001 vs. AZD2927 and A7071). In atrial flutter patients (n = 18) undergoing an invasive investigation, AZD2927 did not change LAERP, the paced QT interval, or ventricular refractoriness when compared with placebo. To address the discrepancy on LAERP by IKACh blockade in man and dog and the hypothesis that atrial electrical remodelling is a prerequisite for IKACh blockade being efficient, six dogs were studied after 8 weeks of RAP followed by sinus rhythm for 4 weeks to reverse electrical remodelling. In these dogs, both AZD2927 and A7071 were as effective in increasing LAERP as in the dogs studied immediately after the 8-week RAP period.
  
  
  CONCLUSIONS
  Based on the present series of experiments, an important role of IKACh in human atrial electrophysiology, as well as its potential as a viable target for effective management of AF, may be questioned.
authors.affiliation: Department of Cardiology, University Hospital, Linköping, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Walfridsson
authors.affiliation: Department of Cardiology, Rikshospitalet, Oslo, Norway.
authors.forename: Ole-Gunnar
authors.initials: OG
authors.lastname: Anfinsen
authors.affiliation: AstraZeneca R&D, CVMD Innovative Medicine, Pepparedsleden 1, Mölndal S-43183, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Berggren
authors.affiliation: AstraZeneca R&D, CVMD Innovative Medicine, Pepparedsleden 1, Mölndal S-43183, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Frison
authors.affiliation: Department of Cardiology, University Hospital, Umeå, Sweden.
authors.forename: Steen
authors.initials: S
authors.lastname: Jensen
authors.affiliation: AstraZeneca R&D, CVMD Innovative Medicine, Pepparedsleden 1, Mölndal S-43183, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Linhardt
authors.affiliation: AstraZeneca R&D, CVMD Innovative Medicine, Pepparedsleden 1, Mölndal S-43183, Sweden.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Nordkam
authors.affiliation: AstraZeneca R&D, CVMD Innovative Medicine, Pepparedsleden 1, Mölndal S-43183, Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Sundqvist
authors.affiliation: AstraZeneca R&D, CVMD Innovative Medicine, Pepparedsleden 1, Mölndal S-43183, Sweden leif.g.carlsson@astrazeneca.com.
authors.forename: Leif
authors.initials: L
authors.lastname: Carlsson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001282:Atrial Flutter / Q000188:drug therapy* / Q000601:surgery; D001384:Azetidines / Q000494:pharmacology* / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use*; D016466:CHO Cells; D017115:Catheter Ablation; D003412:Cricetulus; D004285:Dogs; D004311:Double-Blind Method; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000037:antagonists & inhibitors*; D006321:Heart / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D055815:Young Adult
chemical_list: C000603100:4-cyano-N-(2-(3-hydroxyazetidin-1-yl)-1-phenylethyl)-N-methylbenzamide; C000603099:AZD2927; D001384:Azetidines; D001549:Benzamides; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D026902:Potassium Channel Blockers
keywords: Antiarrhythmic agents; Arrhythmia; Electrophysiology; Ion channels; Remodelling