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

Autor: Ji, Yuan, Varkevisser, Rosanne, Opacic, Dragan, Bossu, Alexandre, Kuiper, Marion, Beekman, Jet D.M., Yang, Sihyung, Khan, Azinwi Phina, Dobrev, Dobromir, Voigt, Niels, Wang, Michael Zhuo, Verheule, Sander, Vos, Marc A., van der Heyden, Marcel A.G.
Přispěvatelé: Fysiologie, RS: CARIM - R2.11 - Experimental atrial fibrillation, Cardiologie
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: British Journal of Pharmacology, 174(15), 2576-2590. Wiley
British Journal of Pharmacology, 174(15), 2576. Wiley-Blackwell
ISSN: 0007-1188
Popis: BACKGROUND AND PURPOSE The density of the inward rectifier current (I-K1) 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-K1 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 mu 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 I-K1, but not I-K,I-ACh,I- 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.
Databáze: OpenAIRE
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