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

Abstract

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

2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart

“…11 , 27 Other reports have shown that it can affect several sarcolemmal ion channels, e.g., L-type Ca 2+ channel. 25 , 28 , 29 In these studies, we found that JTV519(K201) had a potent effect on abnormal Ca 2+ release events in Purkinje cells. The drug reduced RMS F by 20% (Fig.…”

Mechanisms of Ca2+-Triggered Arrhythmias

“…As shown in Table 1, K201 has been reported to have various actions at multiple sites in the cardiomyocyte, including non-specific multi-ion channel blocking effect (Kimura et al, 1999;Nakaya et al, 2000) and inhibition of SERCA (Loughrey et al, 2007). Most important is the finding that K201 stabilizes RyR2 and suppresses SR Ca 2+ leak by increasing the binding affinity for the FKBP12.6 to RyR2 (Wehrens et al, 2004).…”

“…Inhibition of the muscarinic acetylcholine-receptor operated K current, delayed rectifier K + current, prolonged action potential duration (Nakaya et al, 2000) 1 and 3 M (2-3 min) …”

A Novel Cardioprotective Agent, JTV-519, Is Abolished by Nitric Oxide Synthase Inhibitor on Myocardial Metabolism in Ischemia-Reperfused Rabbit Hearts

“…Kiriyama et al demonstrated that JTV-519 inhibited the delayed rectifier K current in guinea-pig ventricular myocytes (24). Nakaya et al showed that JTV-519 exerted antiarrhythmic effects against atrial fibrillation by inhibiting repolarizing K currents in isolated guinea-pig hearts (25).…”