Nonpeptide Angiotensin II Receptor Antagonists: In Vivo Inhibition of [¹²⁵I-SAR¹, ILE⁸]Angiotensin II Binding by Losartan, EXP597 and L-159,282 in Rats

Abstract

Effects of losartan, L-159,282 and EXP597 on the in vivo binding of [¹²⁵I-Sar¹, Ile⁸]angiotensin II to kidney cortex and adrenal were examined in rats. Losartan, an AT₁ receptor antagonist, completely blocked [¹²⁵I-Sar¹, Ile⁸]angiotensin II binding to the kidney cortex which contains only AT₁ binding sites with an ID₅₀ of 0.06 mg/kg. Losartan partially inhibited [¹²⁵I-Sar¹, Ile⁸]angiotensin II binding to the adrenal which contains equal amounts of AT₁ and AT₂ binding sites. Blockade by the AT₁ receptor antagonist L-159,282 sufficiently increased the plasma levels of angiotensin II to block the AT₂ receptor. EXP597 inhibited [¹²⁵I-Sar¹, Ile⁸]angiotensin II binding to the kidney cortex and adrenal almost totally with ID₅₀S of 0.05 and 0.06 mg/kg, respectively. This result suggests that EXP597 exhibits almost equal binding affinity for AT₁ and AT₂ binding sites in vivo in rats.

Key Words:

• angiotensin II receptor
• antihypertensive agents
• losartan
• renin-angiotensin system