Inhibition of the angiotensin II type 1 receptor by TCV-116: Quantitation by in vitro autoradiography

Inhibition of angiotensin (Ang) II type 1 (AT(1)) receptors in various targ et tissues of adult Sprague-Dawley rats was studied after single oral admin istration of TCV-116. The effects of TCV-116 on Ang II-receptor binding wer e assessed by quantitative in vitro autoradiography using I-125-[Sar(1),Ile (8)]Ang II as a ligand. Four hours after the administration of TCV-116 (1 m g/kg), Ang II-receptor binding was markedly inhibited in the kidney (20% of control), adrenal cortex (27%), thoracic aorta (57%), heart (55%) and test is (76%) where ATI receptors predominate. In the brain, orally administered TCV-116 produced a significant inhibition of binding both to the circumven tricular organs (38%), which are devoid of the blood-brain barrier (BBB), a nd to the discrete regions within the BBB such as the paraventricular hypot halamic nucleus (48%), nucleus of the solitary tract (60%). Twenty-four hou rs after the administration, AngII-receptor binding had partly recovered to approximately 50- 85% of control levels. In contrast, throughout the exper imental period, Ang II-receptor binding was little affected in sites where Ang II type 2 (AT(2)) receptors predominate such as the adrenal medulla and the nucleus of the inferior olive. These data indicate that orally adminis tered TCV-116 specifically binds to ATI receptors both in peripheral tissue s and the central nervous system.