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

• Published in: Japanese journal of pharmacology 1999, Vol.79(2), pp.131-139
• Main Authors: Keifu, Song, Hironori, Kanehara, Shinji, Takai, Naotaka, Shiota, Takeo, Wada, Yoshiyuki, Inada, Mizuo, Miyazaki
• Format: Article
• Language: English
• Subjects: Administration, Oral; Angiotensin II receptor; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents - metabolism; Antihypertensive Agents - pharmacology; Autoradiography; Benzimidazoles - metabolism; Benzimidazoles - pharmacology; Biphenyl Compounds - metabolism; Biphenyl Compounds - pharmacology; Blood-brain barrier; Blood-Brain Barrier - physiology; CV-11974; Male; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin - classification; Receptors, Angiotensin - metabolism; TCV-116; Tetrazoles - metabolism; Tetrazoles - pharmacology; Tissue Distribution
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1254/jjp.79.131

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.