The inward rectifier current inhibitor PA-6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models

  • Br J Pharmacol. 2017 Aug;174(15):2576-2590. doi: 10.1111/bph.13869.
Yuan Ji  1 ,  Rosanne Varkevisser  1 ,  Dragan Opacic  2 ,  Alexandre Bossu  1 ,  Marion Kuiper  2 ,  Jet D M Beekman  1 ,  Sihyung Yang  3 ,  Azinwi Phina Khan  4 ,  Dobromir Dobrev  4 ,  Niels Voigt  4  5  6 ,  Michael Zhuo Wang  3 ,  Sander Verheule  2 ,  Marc A Vos  1 ,  Marcel A G van der Heyden  1
Affiliations
  • 1. Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 2. Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
  • 3. Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, KS, USA.
  • 4. Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
  • 5. Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Göttingen, Germany.
  • 6. DZHK (German Centre for Cardiovascular Research), Göttingen, Germany.
PMID: 28542844 DOI: 10.1111/bph.13869
Abstract

Background and purpose: The density of the inward rectifier current (IK1 ) increases in atrial fibrillation (AF), shortening effective refractory period and thus promoting atrial re-entry. The synthetic compound pentamidine analogue 6 (PA-6) is a selective and potent IK1 inhibitor. We tested PA-6 for anti-AF efficacy and potential proarrhythmia, using established models in large Animals.

Experimental approach: PA-6 was applied i.v. in anaesthetized goats with rapid pacing-induced AF and anaesthetized dogs with chronic atrio-ventricular (AV) block. Electrophysiological and pharmacological parameters were determined.

Key results: PA-6 (2.5 mg·kg-1 ·10 min-1 ) induced cardioversion to sinus rhythm (SR) in 5/6 goats and prolonged AF cycle length. AF complexity decreased significantly before cardioversion. PA-6 accumulated in cardiac tissue with ratios between skeletal muscle : atrial muscle : ventricular muscle of approximately 1:8:21. In SR dogs, PA-6 peak plasma levels 10 min post infusion were 5.5 ± 0.9 μM, PA-6 did not induce significant prolongation of QTc and did not affect heart rate, PQ or QRS duration. In dogs with chronic AV block, PA-6 did not affect QRS but lengthened QTc during the experiment, but not chronically. PA-6 did not induce TdP arrhythmias in nine Animals (0/9) in contrast to dofetilide (5/9). PA-6 (200 nM) inhibited IK1 , but not IK,ACh , in human isolated atrial cardiomyocytes.

Conclusion and implications: PA-6 restored SR in goats with persistent AF and, in dogs with chronic AV block, prolonged QT intervals, without inducing TdP arrhythmias. Our results demonstrate cardiac safety and good anti-AF properties for PA-6.

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