Slow Dissociation of Long-Acting Ca^<2+> Antagonist Amlodipine from ^3H-PN200-110 Binding Sites in Membranes of Rat Hearts and Brains
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概要
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The dissociation rate of amlodipine ((±)-3-ethyl 5-methyl 2-[(2-aminoethoxy) methyl]-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate) from rat heart and brain membranes preincubated with drugs and washed out with buffer was assessed by radioligand binding assay using ^3H-PN200-110 as a radioligand. The remaining KCl-induced contraction in rat aortic strips washed out after treatment with this drug and the pK_i (inhibition constant) values of the drug were compared with those of nisoldipine, nifedipine, manidipine and benidipine. The inhibition of ^3H-PN200-110 binding induced by nifedipine was reversed by washing, whereas that induced by amlodipine, manidipine, and benidipine was not readily reversed under these conditions. When rat aortic strips were pretreated with Ca^<2+> antagonists, the rank order of the inhibition of contractions induced by 50mM KCl was manidipine=benidipine>amlodipine>nisoldipine>nifedipine, even though Ca^<2+> antagonists were not present in the extracellular medium. The pK_i values of amlodipine in the heart and brain were 6.86 and 7.41,respectively, and these values were lower than those of the other Ca^<2+> antagonists. There was a good correlation between the potency of the inhibition of ^3H-PN200-110 binding by drugs after the washout of membranes and the inhibition exerted by the drugs in contractions induced by 50mM KCl after the washout of tissues, although this residual inhibition was not correlated with pK_i values. Thus, these results suggest that amlodipine has a very slow rate of dissociation from ^3H-PN200-110 binding sites, as do manidipine and benidipine, and this property may explain its long-lasting antihypertensive effect.
- 公益社団法人日本薬学会の論文
- 1996-02-15
著者
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NAGATOMO Takafumi
Department of Pharmacology, Niigata University of Pharmacy and Applied Life Sciences
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Hattori K
Niigata Coll. Pharmacy Niigata Jpn
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Hattori Kaoru
Department Of Cardiology Miki City Hospital
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Hattori Kaoru
新潟薬科大学 薬理
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WATANABE KENICHI
Division of Cardiology, Tsubame Rosai Hospital
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Nagatomo T
Dep. Of Pharmacology Fac. Of Pharmaceutical Sciences Niigata Univ. Of Pharmacy And Applied Life Scie
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Watanabe K
New Drug Research Department High Quality-life Research Laboratories Bio-medical Division
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Hattori K
Tohoku Univ. Sendai Jpn
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Maruyama Keiko
Department Of Pharmacology Niigata College Of Pharmacy
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Nagatomo Takafumi
Department Of Pharmacology Faculty Of Pharmaceutical Sciences Niigata University Of Pharmacy And App
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Komukai Shintaro
Niigata Univ. Graduate School Of Medical And Dental Sci. Niigata Jpn
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Watanabe K
Cardiovascular Division Tsubame Rosai Hospital
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Watanabe Kenichi
Division Of Cardiology Tsubame Rosai Hospital
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Watanabe Kenichi
Division Of Cardiology Niigata University Graduate School Of Medical And Dental Sciences
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Namikawa Tomoko
Biological Res. Dep. Sawai Pharmaceutical Co. Ltd.
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Hattori Kaoru
Department of Pharmacology, Niigata College of Pharmacy
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