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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.

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 …