Keifu Song (1), Hironori Kanehara (1), Shinji Takai (1), Naotaka Shiota
(1), Takeo Wada (2), Yoshiyuki Inada (2) and Mizuo Miyazaki (1)
(1) Department of Pharmacology, Osaka Medical College, 2-7, Daigakumachi, Takatsuki, Osaka 569-8686, Japan
(2) Pharmaceutical Research Division, Takeda Chemical Industry Co., Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-0024, Japan
Abstract: Inhibition of angiotensin (Ang) II type 1 (AT1) receptors in various target tissues of adult Sprague-Dawley rats was studied after single oral administration of TCV-116. The effects of TCV-116 on Ang II-receptor binding were assessed by quantitative in vitro autoradiography using 125I-[Sar1,Ile8]Ang II as a ligand. Four hours after the administration of TCV-116 (1 mg/kg), Ang II-receptor binding was markedly inhibited in the kidney (20% of control), adrenal cortex (27%), thoracic aorta (57%), heart (55%) and testis (76%) where AT1 receptors predominate. In the brain, orally administered TCV-116 produced a significant inhibition of binding both to the circumventricular organs (38%), which are devoid of the blood-brain barrier (BBB), and to the discrete regions within the BBB such as the paraventricular hypothalamic nucleus (48%), nucleus of the solitary tract (60%). Twenty-four hours after the administration, Ang II-receptor binding had partly recovered to approximately 50 - 85% of control levels. In contrast, throughout the experimental period, Ang II-receptor binding was little affected in sites where Ang II type 2 (AT2) receptors predominate such as the adrenal medulla and the nucleus of the inferior olive. These data indicate that orally administered TCV-116 specifically binds to AT1 receptors both in peripheral tissues and the central nervous system.
Keywords: Angiotensin II receptor, TCV-116, CV-11974, Blood-brain barrier