We investigated the effects of JTV‐519 (4‐[3‐(4‐benzylpiperidin‐1‐yl)propionyl]‐7‐methoxy‐2,3,4,5‐tetrahydro‐1,4‐benzothiazepine monohydrochloride), a novel cardioprotective drug, on the repolarizing K+ currents in guinea‐pig atrial cells by use of patch‐clamp techniques. We also evaluated the effects of JTV‐519 on experimental atrial fibrillation (AF) in isolated guinea‐pig hearts. In atrial cells stimulated at 0.2 Hz, JTV‐519 in concentrations of 0.3 and 1 μM slightly prolonged the action potential duration (APD). The drug also reversed the action potential shortening induced by the muscarinic agonist carbachol in a concentration‐dependent manner. The muscarinic acetylcholine receptor‐operated K+ current (IK.ACh) was activated by the extracellular application of carbachol (1 μM), adenosine (10 μM) or by the intracellular loading of GTPγS (100 μM). JTV‐519 inhibited the carbachol‐, adenosine‐ and GTPγS‐induced IK.ACh with the IC50 values of 0.12, 2.29 and 2.42 μM, respectively, suggesting that the drug may inhibit IK.ACh mainly by blocking the muscarinic receptors. JTV‐519 (1 μM) inhibited the delayed rectifier K+ current (IK). Electrophysiological analyses indicated that the drug preferentially inhibits IKr (rapidly activating component) but not IKs (slowly activating component). In isolated hearts, perfusion of carbachol (1 μM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold (AFT). Addition of JTV‐519 (1 μM) inhibited the induction of AF by prolonging MAP and ERP. We conclude that JTV‐519 can exert antiarrhythmic effects against AF by inhibiting repolarizing K+ currents. The drug may be useful for the treatment of AF in patients with ischaemic heart disease. British Journal of Pharmacology (2000) 131, 1363–1372; doi:10.1038/sj.bjp.0703713

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