Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts

1 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. 2 In atrial cells stimulated at 0.2 Hz, JTV-519 in concentrations of 0.3 and 1 muM 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. 3 3 The muscarinic acetylcholine receptor-operated K+ current (I-K,I-ACh) was activated by the extracellular application of carbachol (1 muM), adenosine (10 muM) or by the intracellular loading of GTP gammaS (100 muM). JTV-519 inhibited the carbachol-, adenosine- and GTP gammaS-induced I-K,I-ACh With the IC50 values of 0.12, 2.29 and 2.42 muM, respectively, suggesting that the drug may inhibit I-K,I-ACh mainly by blocking the muscarinic receptors. 4 JTV-519 (1 muM) inhibited the delayed rectifier K+ current (IK) Electrophysiological analyses indicated that the drug preferentially inhibits I-Kr (rapidly activating component) but not I-Ks (slowly activating component). 5 In isolated hearts, perfusion of carbachol (1 muM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold (AFT). Addition of JTV-519 (1 muM) inhibited the induction of AF by prolonging MAP and ERP. 6 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.