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

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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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Ji, Y., Varkevisser, R., Opacic, D., Bossu, A., Kuiper, M., Beekman, J. D. M., … van der Heyden, M. A. G. (2017). The inward rectifier current inhibitor PA-6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models. British Journal of Pharmacology, 174(15), 2576–2590. https://doi.org/10.1111/bph.13869

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