Localization of a Novel Non-peptide Angiotensin II Type 1 Receptor Antagonist, E4177,in Rat Adrenal Glomerulosa

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We investigated the distribution of a novel angiotensin II type 1 (AT1) receptor antagonist, E4177 (4'-[2-cyclopropyl-7-methyl-3H-imidazo[5,4-b]pyridine-3-yl]methyl-2-biphenylcarboxylic acid), in rat adrenal glomerulosa. In a binding assay of adrenal capsular tissue (mainly glomerulosa), E4177 exhibited a maximum displacement of approximately 80% of total ^<125>I-labeled angiotensin II (^<125>I-[Sal^1,Ile^8] Ang II) binding, and its IC_<50> value was 6.9±0.5 nM. This IC_<50> value indicated a slightly higher in vitro potency than that of losartan (21.0±0.6 nM). Also, in a receptor autoradiographic study, E4177 (10000 nM) displaced approximately 80% of radiolabeled ^<125>I-[Sal^1,Ile^8] Ang II in rat adrenal glomerulosa and caused only slight displacement in rat adrenal medulla. Further, light and electron microscopic autoradiography of adrenal glomerulosa for 15 min after the intravenous administration of 1 mg/kg [^<14>C]E4177,indicated the localization of ^<14>C, possibly in the adrenal zona glomerulosa cell plasma membrane. It was strongly suggested that E4177 is a potent and selective antagonist of the AT1 receptor, and that it specifically binds to AT1 receptors in the adrenal zona glomerulosa.
公益社団法人日本薬学会の論文
1996-10-15