Figure 1
The carboxyl group and the hydroxyl group are critical structural characteristics of olmesartan that lead to its insurmountable inhibition of angiotensin II (AT1) receptors. (a) The chemical structures of olmesartan and its derivative compounds, R-239470 and R-90929, are shown. Olmesartan contains a carboxyl group and a hydroxyl group on its benzimidazole ring. R-239470 has a non-acidic carbamoyl group (circled CONH2) instead of the carboxyl group, and R-90929 has no hydroxyl group (circled). (b) Response curves of AngII-mediated extracellular signal-regulated protein kinase (ERK) activation (upper panels). HEK293-AT1 cells were pretreated with 10−7 M olmesartan, R-239470 or R-90929, and stimulated by AngII at indicated concentrations (lower panels). The activation of ERKs was determined using a polyclonal antibody against phosphorylated ERKs (p-ERKs). (c) The inhibitory effects of olmesartan and its derivative compounds, R-239470 and R-90929, on AngII-induced c-fos gene expression in HEK293 cells expressing the AT1 receptor were examined by northern blot analysis of c-fos mRNA. (d) The inhibitory effects of olmesartan and its derivative compounds, R-239470 and R-90929, on AngII-induced c-fos gene expression in HEK293 cells expressing the AT1 receptor were examined using a luciferase assay examining c-fos promoter activation. *P<0.01 vs. that with no stimulation, #P<0.01 vs. that with AngII stimulation with no treatment, §P<0.05 vs. that with AngII stimulation with olmesartan (10−7 M) treatment.
