Effects of E-4031 on atrial fibrillation threhold: A comparative study with class I antiarrhythmic drugs.

Inoue, Miho; Inoue, Daisuke; Ishibashi, Keiichiro; Sakai, Ryuta; Omori, Itsuki; Yamahara, Yasuhiro; Miyazaki, Hiroshi; Asayama, Jun; Nakagawa, Masao

doi:10.5105/jse.14.116

Cited by 5 publications

(7 citation statements)

References 19 publications

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“…The wavelength is designated as the product of refractory period and conduction velocity. Although AF could not be induced under a normal condition, it was easily induced by a high frequency atrial stimulation during CCh perfusion in isolated guinea-pig hearts, which is consistent with previous reports from our and other laboratories (Watanabe et al, 1996;OhmotoSekine et al, 1999;Inoue et al, 1994). Since perfusion of CCh did not a ect CT, the shortening of ERP resulting from the activation of I K.ACh seemed to underlie the shortening of the atrial wavelength and the induction of AF in this study.…”

Section: Discussionsupporting

confidence: 92%

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

Nakaya

Furusawa

Ogura

et al. 2000

British J Pharmacology

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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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Section: Discussionsupporting

confidence: 92%

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

Nakaya

Furusawa

Ogura

et al. 2000

British J Pharmacology

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“…Under a normal condition AF could not be induced, but during cholinergic stimulation it was easily induced by a high frequency atrial stimulation in isolated guinea‐pig heart, which is consistent with previous reports from our and other laboratories ( Inoue et al ., 1994 ; Watanabe et al ., 1996 ). The multiple wavelet hypothesis was proposed to explain the perpetuation of AF by Moe (1962) .…”

Section: Discussionsupporting

confidence: 92%

“…Atrial fibrillation threshold (AFT) was measured by rapid atrial electrical stimulation according to the method of Inoue et al . (1994) .…”

Section: Methodsmentioning

confidence: 99%

Inhibitory effects of aprindine on the delayed rectifier K⁺ current and the muscarinic acetylcholine receptor‐operated K⁺ current in guinea‐pig atrial cells

Ohmoto-Sekine

Uemura

Tamagawa

et al. 1999

British J Pharmacology

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1 In order to clarify the mechanisms by which the class Ib antiarrhythmic drug aprindine shows ecacy against atrial ®brillation (AF), we examined the eects of the drug on the repolarizing K + currents in guinea-pig atrial cells by use of patch-clamp techniques. We also evaluated the eects of aprindine on experimental AF in isolated guinea-pig hearts. 2 Aprindine (3 mM) inhibited the delayed recti®er K + current (I K ) with little in¯uence on the inward recti®er K + current (I K1 ) or the Ca 2+ current. Electrophysiological analyses including the envelope of tails test revealed that aprindine preferentially inhibits I Kr (rapidly activating component) but not I Ks (slowly activating component). 3 The muscarinic acetylcholine receptor-operated K + current (I K.ACh ) was activated by the extracellular application of carbachol (1 mM) or by the intracellular loading of GTPgS. Aprindine inhibited the carbachol-and GTPgS-induced I K.ACh with the IC 50 values of 0.4 and 2.5 mM, respectively. 4 In atrial cells stimulated at 0.2 Hz, aprindine (3 mM) per se prolonged the action potential duration (APD) by 50+4%. The drug also reversed the carbachol-induced action potential shortening in a concentration-dependent manner. 5 In isolated hearts, perfusion of carbachol (1 mM) shortened monophasic action potential (MAP) and eective refractory period (ERP), and lowered atrial ®brillation threshold. Addition of aprindine (3 mM) inhibited the induction of AF by prolonging MAP and ERP. 6 We conclude the ecacy of aprindine against AF may be at least in part explained by its inhibitory eects on I Kr and I K.ACh .

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“…The stimulation protocol for EFS-induced atrial tachyarrhythmia used in the present work was based on a method previously proposed by Godoy et al (1999). The results obtained with this method are qualitatively similar to those obtained by other authors who have studied atrial flutter/fibrillation in vivo and in vitro (Alessie et al 1984;Euler and Scanlon 1987;Schuessler et al 1992;Inoue et al 1994;Watanabe et al 1996). However, those authors used direct stimulation whereas we have used EFS to minimise the SS applied to the cardiac tissue (Godoy et al 2002).…”

Section: Discussionsupporting

confidence: 84%

Influence of age on inducibility and cholinergic modulation of arrhythmia in isolated rat right atria

Faria

Viviane

Galvão

et al. 2008

AGE

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The effects of carbachol and atropine on the number of trains (NT) and on the train stimulus strength (SS) necessary to induce arrhythmia were studied in isolated right atria of infant, young, adult and mature rats submitted to electric field stimulation (66.7 Hz, 5 ms pulse-duration, 250 pulses). Carbachol (1 μM) decreased NT from four (control) to two in all ages tested. Atropine (1 μM) prevented tachyarrhythmia induction in tissue of all ages, even with NT equal to 12, except for mature rats (typically four trains). The SS decreases from infant to adult age [5-to 2-fold atrial threshold (AT)] and increases in mature animals (5-fold AT). Carbachol changes this result only for mature rats (5-to 2-fold AT). The SS was decreased by carbachol (1 μM) from 5-to 3-fold AT in mature rats, but atropine did not modify SS in this age. These results indicate that inducibility and cholinergic modulation of atrial tachyarrhythmia is influenced by age.

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Effects of E-4031 on atrial fibrillation threhold: A comparative study with class I antiarrhythmic drugs.

Cited by 5 publications

References 19 publications

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

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

Inhibitory effects of aprindine on the delayed rectifier K⁺ current and the muscarinic acetylcholine receptor‐operated K⁺ current in guinea‐pig atrial cells

Influence of age on inducibility and cholinergic modulation of arrhythmia in isolated rat right atria

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Effects of E-4031 on atrial fibrillation threhold: A comparative study with class I antiarrhythmic drugs.

Cited by 5 publications

References 19 publications

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

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

Inhibitory effects of aprindine on the delayed rectifier K+ current and the muscarinic acetylcholine receptor‐operated K+ current in guinea‐pig atrial cells

Influence of age on inducibility and cholinergic modulation of arrhythmia in isolated rat right atria

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Inhibitory effects of aprindine on the delayed rectifier K⁺ current and the muscarinic acetylcholine receptor‐operated K⁺ current in guinea‐pig atrial cells