Ability of the new AT 1 receptor blocker azilsartan to block angiotensin II-induced AT 1 receptor activation after wash-out

Abstract

Introduction:

The recently approved angiotensin II (Ang II) type 1 (AT₁) receptor blocker (ARB) azilsartan strongly reduces blood pressure (BP) in patients with hypertension. We previously reported that azilsartan showed unique binding behavior to the AT₁ receptor because of its 5-oxo-1,2,4-oxadiazole moiety. However, the ability of azilsartan to block Ang II-dependent AT₁ receptor activation is not yet clear.

Materials and methods:

Azilsartan and a derivative of azilsartan (azilsartan-7H) that lacks a carboxyl group at the benzimidazole ring were used. Ang II-induced inositol phosphate (IP) production and extracellular signal-regulated kinase (ERK) activation were analyzed in a cell-based wash-out assay.

Results:

Azilsartan, but not azilsartan-7H, completely blocked Ang II-induced IP production and ERK activation. Our previous report demonstrated that azilsartan mainly interacts with Tyr¹¹³, Lys¹⁹⁹, and Gln²⁵⁷ in the AT₁ receptor. The interactions between azilsartan and Tyr¹¹³ and Gln²⁵⁷, but not Lys¹⁹⁹, were critical for blocking Ang II-induced IP production and ERK activation after wash-out.

Conclusions:

Although our findings regarding the molecule-specific effects of azilsartan are based on basic research, they may lead to an exciting insight into the mechanism of azilsartan.