Effect of selective I K,ACh inhibition by XAF‐1407 in an equine model of tachypacing‐induced persistent atrial fibrillation

Merle Friederike Fenner, Helena Carstensen, Sarah Dalgas Nissen, Eva Melis Hesselkilde, Christine Scott Lunddahl, Maja Adler Hess Jensen, Ameli Victoria Loft-Andersen, Stefan Michael Sather, Pyotr Platonov, Said El-Haou, Claire Jackson, Raymond Tang, Robert Kirby, John Ford, Ulrich Schotten, James Milnes, Ulrik Svane Sorensen, Thomas Jespersen, Rikke Buhl*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Web of Science)

Abstract

Background and Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, I-K,I-ACh may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specificI(K,ACh)inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in horses with persistent AF.

Experimental Approach: The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug-induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction.

Key Results: XAF-1407 potently and selectively inhibited K(ir)3.1/3.4 and K(ir)3.4/3.4, underlying theI(K,ACh)current. XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (similar to 20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened atrioventricular-nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min of drug infusion was observed, however, without any evidence of ventricular arrhythmia.

Conclusion and Implications: XAF-1407 efficiently cardioverted sustained tachypacing-induced AF of short duration in horses without notable side effects. This supportsI(K,ACh)inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.

Original languageEnglish
Pages (from-to)3778-3794
Number of pages17
JournalBritish Journal of Pharmacology
Volume177
Issue number16
DOIs
Publication statusPublished - Aug 2020

Keywords

  • POTASSIUM CHANNELS
  • IKACH BLOCKER
  • CONCISE GUIDE
  • IN-VIVO
  • PROTEIN
  • CONTRACTILE
  • MANAGEMENT
  • TERTIAPIN
  • THERAPY
  • TARGETS

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