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

ABSTRACT: 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.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.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 ?M, 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.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.

SUBMITTER: Ji Y

PROVIDER: S-EPMC5513871 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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

Ji Yuan Y Varkevisser Rosanne R Opacic Dragan D Bossu Alexandre A Kuiper Marion M Beekman Jet D M JDM Yang Sihyung S Khan Azinwi Phina AP Dobrev Dobromir D Voigt Niels N Wang Michael Zhuo MZ Verheule Sander S Vos Marc A MA van der Heyden Marcel A G MAG

British journal of pharmacology 20170628 15

<h4>Background and purpose</h4>The density of the inward rectifier current (I<sub>K1</sub> ) 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 I<sub>K1</sub> inhibitor. We tested PA-6 for anti-AF efficacy and potential proarrhythmia, using established models in large animals.<h4>Experimental approach</h4>PA-6 was applied i.v. in anaesthetized goats with r ...[more]

PMID: 28542844

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Dataset Information

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

Publications

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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