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Inhibition of the angiotensin II Type 1 receptor by TCV-116: quantitation by in vitro autoradiography
1Department of Pharmacology, Osaka Medical College, Takatsuki, 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.
Insights
TCV-116 effectively inhibits angiotensin II type 1 (AT1) receptors in various rat tissues, including the brain, after oral administration. This selective AT1 receptor blockade demonstrates TCV-116
Area of Science:
- Pharmacology
- Cardiovascular Research
- Neuroscience
Background:
- Angiotensin II (Ang II) plays a crucial role in regulating blood pressure and cardiovascular function through its type 1 (AT1) receptors.
- Selective AT1 receptor antagonists are vital therapeutic agents for cardiovascular diseases.
- Understanding the tissue distribution and receptor binding of novel antagonists is essential for evaluating their efficacy and safety.
Purpose of the Study:
- To investigate the inhibitory effects of TCV-116 on Angiotensin II type 1 (AT1) receptors in various peripheral and central tissues.
- To assess the selectivity of TCV-116 for AT1 receptors over AT2 receptors.
- To determine the duration of TCV-116's inhibitory action following oral administration.
Main Methods:
- Adult Sprague-Dawley rats were administered TCV-116 orally at a dose of 1 mg/kg.
- Quantitative in vitro autoradiography using 125I-[Sar1,Ile8]Ang II as a ligand was employed to measure Ang II-receptor binding.
- Receptor binding was assessed in various tissues, including the kidney, adrenal cortex, aorta, heart, testis, and brain regions, at 4 and 24 hours post-administration.
Main Results:
- Four hours after TCV-116 administration, significant inhibition of Ang II-receptor binding was observed in tissues rich in AT1 receptors, such as the kidney (80% inhibition), adrenal cortex (73% inhibition), aorta (43% inhibition), heart (45% inhibition), and testis (24% inhibition).
- In the brain, TCV-116 inhibited AT1 receptor binding in circumventricular organs (62% inhibition) and within the blood-brain barrier (BBB) in regions like the paraventricular hypothalamic nucleus (52% inhibition) and nucleus of the solitary tract (40% inhibition).
- Ang II-receptor binding showed partial recovery within 24 hours, with minimal effects observed in tissues predominantly expressing AT2 receptors, indicating high selectivity for AT1 receptors.
Conclusions:
- Oral administration of TCV-116 specifically targets and inhibits angiotensin II type 1 (AT1) receptors in both peripheral tissues and the central nervous system.
- TCV-116 demonstrates high selectivity for AT1 receptors, with minimal impact on AT2 receptors.
- These findings support the potential of TCV-116 as an effective therapeutic agent for conditions modulated by the renin-angiotensin system.
