Anticholinergic Effects of Class III Antiarrhythmic Drugs in Guinea Pig Atrial Cells

Mori, Katsumi; Hara, Yukio; Saito, Toshihiro; Masuda, Yoshiaki; Nakaya, Haruaki

doi:10.1161/01.cir.91.11.2834

Cited by 71 publications

(50 citation statements)

References 37 publications

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“…Many antiarrhythmic drugs were reported to inhibit I K.ACh in isolated guineapig atrial cells (Nakajima et al, 1989;Inomata et al, 1993;Wu et al, 1994;Mori et al, 1995;Watanabe et al, 1996;Ohmoto-Sekine et al, 1999). Two mechanisms by which antiarrhythmic drugs inhibit I K.ACh have been proposed; some drugs block the muscarinic receptors and others inhibit the muscarinic K + channel itself and/or GTP-binding proteins.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Interaction of acetylcholine receptor-operated potassium channel and Gβγ subunit of GTP binding proteins is important for activation of I K.ACh in cardiac myocytes [20,21]. Many drugs, including antiarrhythmic drugs, anticancer chemotherapeutic drugs and antimalarial drugs, that produce anticholinergic actions in the heart have been reported to inhibit I K.ACh [10,11,14,24,26]. Molecular mechanisms by which several drugs inhibit I K.ACh have been proposed; some drugs block the muscarinic receptors and others inhibit the muscarinic potassium channel itself and/or GTP-binding proteins [10,11,18,19,24].…”

Section: Discussionmentioning

confidence: 99%

“…Many drugs, including antiarrhythmic drugs, anticancer chemotherapeutic drugs and antimalarial drugs, that produce anticholinergic actions in the heart have been reported to inhibit I K.ACh [10,11,14,24,26]. Molecular mechanisms by which several drugs inhibit I K.ACh have been proposed; some drugs block the muscarinic receptors and others inhibit the muscarinic potassium channel itself and/or GTP-binding proteins [10,11,18,19,24]. These molecular mechanisms can be elucidated using data from the patch clamp method in atrial myocytes [3,11,24].…”

Section: Discussionmentioning

confidence: 99%

“…Molecular mechanisms by which several drugs inhibit I K.ACh have been proposed; some drugs block the muscarinic receptors and others inhibit the muscarinic potassium channel itself and/or GTP-binding proteins [10,11,18,19,24]. These molecular mechanisms can be elucidated using data from the patch clamp method in atrial myocytes [3,11,24]. The I K.ACh is activated by an application of carbachol through binding to the muscarinic M 2 receptor in GTP-loaded cells.…”

Section: Discussionmentioning

confidence: 99%

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Benzodiazepines Inhibit the Acetylcholine Receptor-Operated Potassium Current (I<sub>K.ACh</sub>) by Different Mechanisms in Guinea-pig Atrial Myocytes

Okada

Mizuno

Nakarai

et al. 2012

The Journal of Veterinary Medical Science

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ABSTRACT. The anticholinergic effects of 7 benzodiazepines, bromazepam, camazepam, chlordiazepoxide, diazepam, lorazepam, medazepam and triazolam, were compared by examining their inhibitory effects on the acetylcholine receptor-operated potassium current (I K.ACh ) in guinea-pig atrial myocytes. All of these benzodiazepines (0.3-300 µM) inhibited carbachol (1 µM)-induced I K.ACh in a concentration-dependent manner. The ascending order of IC 50 values for carbachol-induced I K.ACh was as follows; medazepam, diazepam, camazepam, triazolam, bromazepam, lorazepam and chlordiazepoxide (>300 µM). The compounds, except for bromazepam, also inhibited I K.ACh activated by an intracellular loading of 100 µM guanosine 5'-[γ-thio]triphosphate (GTPγS) in a concentration-dependent manner. The ascending order of IC 50 values for GTPγS-activated I K.ACh was as follows; medazepam, diazepam, camazepam, lorazepam, triazolam chlordiazepoxide (>300 µM) and bromazepam (>300 µM). To clarify the molecular mechanism of the inhibition, IC 50 ratio, the ratio of IC 50 for GTPγS-activated I K.ACh to carbachol-induced I K.ACh , was calculated. The IC 50 ratio for camazepam, diazepam, lorazepam, medazepam and triazolam was close to unity, while it for chlordiazepoxide could not be calculated. These compounds would act on the GTP binding protein and/or potassium channel to achieve the anticholinergic effects in atrial myocytes. In contrast, since the IC 50 ratio for bromazepam is presumably much higher than unity judging from the IC 50 values (104.0 ± 30.0 µM for carbachol-induced I K.ACh and >300 µM for GTPγS-activated I K.ACh ), it would act on the muscarinic receptor. In summary, benzodiazepines had the anticholinergic effects on atrial myocytes through inhibiting I K.ACh by different molecular mechanisms. KEY WORDS: acetylcholine receptor-operated potassium current, atrial myocyte, benzodiazepines, bromazepam, patch clamp method.

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“…Several class III antiarrhythmic drugs have been shown to block I KACh in atrial cell (Guillemare et al, 2000;Mori et al, 1995). The blocking effects on I KACh might work additively for their antiarrhythmic efficacy.…”

Section: In Vitro and In Vivo Profiles Of Selective I Kach Blockersmentioning

confidence: 99%

Acetylcholine-Activated Potassium Channel as a Novel Target for AF Treatment

Hashimoto¹

2012

Atrial Fibrillation - Basic Research and Clinical Applications

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Anticholinergic Effects of Class III Antiarrhythmic Drugs in Guinea Pig Atrial Cells

Cited by 71 publications

References 37 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

Benzodiazepines Inhibit the Acetylcholine Receptor-Operated Potassium Current (I<sub>K.ACh</sub>) by Different Mechanisms in Guinea-pig Atrial Myocytes

Acetylcholine-Activated Potassium Channel as a Novel Target for AF Treatment

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