Benzodiazepines Inhibit the Acetylcholine Receptor-Operated Potassium Current (IK.ACh) by Different Mechanisms in Guinea-pig Atrial Myocytes
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概要
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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 (IK.ACh) in guinea-pig atrial myocytes. All of these benzodiazepines (0.3–300 μM) inhibited carbachol (1 μM)-induced IK.ACh in a concentration-dependent manner. The ascending order of IC50 values for carbachol-induced IK.ACh was as follows; medazepam, diazepam, camazepam, triazolam, bromazepam, lorazepam and chlordiazepoxide (>300 μM). The compounds, except for bromazepam, also inhibited IK.ACh activated by an intracellular loading of 100 μM guanosine 5’-[γ-thio]triphosphate (GTPγS) in a concentration-dependent manner. The ascending order of IC50 values for GTPγS-activated IK.ACh was as follows; medazepam, diazepam, camazepam, lorazepam, triazolam chlordiazepoxide (>300 μM) and bromazepam (>300 μM). To clarify the molecular mechanism of the inhibition, IC50 ratio, the ratio of IC50 for GTPγS-activated IK.ACh to carbachol-induced IK.ACh, was calculated. The IC50 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 IC50 ratio for bromazepam is presumably much higher than unity judging from the IC50 values (104.0 ± 30.0 μM for carbachol-induced IK.ACh and >300 μM for GTPγS-activated IK.ACh), it would act on the muscarinic receptor. In summary, benzodiazepines had the anticholinergic effects on atrial myocytes through inhibiting IK.ACh by different molecular mechanisms.
- 日本獣医学会の論文
著者
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Yamawaki Hideyuki
Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
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Okada Muneyoshi
Department Of Veterinary Pharmacology School Of Veterinary Medicine And Animal Sciences Kitasato Uni
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Okada Muneyoshi
Laboratory Of Veterinary Pharmacology School Of Veterinary Medicine Kitasato University
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Hara Yukio
Laboratory Of Veterinary Pharmacology School Of Veterinary Medicine Kitasato University
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MIZUNO Wataru
Laboratory of Veterinary Pharmacology, Kitasato University, Towada, Aomori 034–8628, Japan
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NAKARAI Ryu
Laboratory of Veterinary Pharmacology, Kitasato University, Towada, Aomori 034–8628, Japan
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MATADA Takashi
Laboratory of Veterinary Pharmacology, Kitasato University, Towada, Aomori 034–8628, Japan
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YAMAWAKI Hideyuki
Laboratory of Veterinary Pharmacology, Kitasato University, Towada, Aomori 034–8628, Japan
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HARA Yukio
Laboratory of Veterinary Pharmacology, Kitasato University, Towada, Aomori 034–8628, Japan
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MATADA Takashi
Laboratory of Veterinary Pharmacology, Kitasato University, Towada, Aomori 034–8628, Japan
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MIZUNO Wataru
Laboratory of Veterinary Pharmacology, Kitasato University, Towada, Aomori 034–8628, Japan
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NAKARAI Ryu
Laboratory of Veterinary Pharmacology, Kitasato University, Towada, Aomori 034–8628, Japan
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OKADA Muneyoshi
Laboratory of Veterinary Pharmacology, Kitasato University, Towada, Aomori 034–8628, Japan
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