title: Ability of the new AT1 receptor blocker azilsartan to block angiotensin II-induced AT1 receptor activation after wash-out.
abstract: BACKGROUND
  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.
  
  
  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 Tyr(113), Lys(199), and Gln(257) in the AT1 receptor. The interactions between azilsartan and Tyr(113) and Gln(257), but not Lys(199), 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.
authors.affiliation: 1Department of Cardiology, Fukuoka University Hospital, Japan.
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Miura
authors.forename: Yoshino
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Asuka
authors.initials: A
authors.lastname: Nakayama
authors.forename: Sayo
authors.initials: S
authors.lastname: Tomita
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Suematsu
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D010069:Oxadiazoles; D044140:Receptor, Angiotensin, Type 1; D048049:Extracellular Signal-Regulated MAP Kinases; C521273:azilsartan
keywords: Azilsartan; cell-based wash-out assay; extracellular signal-regulated kinase activation; inositol phosphate production; molecule-specific effects