Localization of a novel non-peptide angiotensin II type 1 receptor antagonist, E4177, in rat adrenal glomerulosa.
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 125I-labeled angiotensin II (125I-[Sal1, Ile8] Ang II) binding, and its IC50 value was 6.9 +/- 0.5 nM. This IC50 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 125I-[Sal1, Ile8] 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 [14C]E4177, indicated the localization of 14C, 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.
Drug Metabolism Research Section, Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
M
M
Kakiki
T
T
Horie
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001345:Autoradiography; D007093:Imidazoles / Q000032:analysis* / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D011725:Pyridines / Q000032:analysis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D015384:Zona Glomerulosa / Q000737:chemistry*
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C083778:3-((2'-carboxybiphenyl-4-yl)methyl)-2-cyclopropyl-7-methyl-3H-imidazo(4,5-b)pyridine