Jpn. J. Pharmacol. 79 (2), 131-139 (1999)

Inhibition of the Angiotensin II Type 1 Receptor by TCV-116: Quantitation by In Vitro Autoradiography

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

Copyrightę The Japanese Pharmacological Society 1999

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