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

1 We investigated the effects of JTV-519 (4-[3-(4-benzylpiperidin-1-yl)prop ionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine monohydrochloride), a novel cardioprotective drug, on the repolarizing K+ currents in guinea-p ig atrial cells by use of patch-clamp techniques. We also evaluated the eff ects 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 an d 1 muM slightly prolonged the action potential duration (APD). The drug al so reversed the action potential shortening induced by the muscarinic agoni st 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 t he 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) Electroph ysiological 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 a ction potential (MAP) and effective refractory period (ERP), and lowered at rial fibrillation threshold (AFT). Addition of JTV-519 (1 muM) inhibited th e induction of AF by prolonging MAP and ERP. 6 We conclude that JTV-519 can exert antiarrhythmic effects against AF by i nhibiting repolarizing K+ currents. The drug may be useful for the treatmen t of AF in patients with ischaemic heart disease.