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Abstract

Angiotensin II (Ang II) binds to Ang II type 1 (AT₁) receptor and evokes cell signaling, and subsequently stimulates vasoconstriction and cell proliferation, which eventually lead to cardiovascular disease. Since most AT₁ receptor blockers (ARBs) have molecular (differential) effects, we evaluated the specific features of candesartan and compared the abilities of candesartan and other ARBs (olmesartan, telmisartan, valsartan, irbesartan and losartan) to bind to and activate AT₁ receptors using a cell-based wash-out assay. Each ARB blocked Ang II-induced extracellular signal-regulated kinase (ERK) activation and inositol phosphate production to different degrees after wash-out. In addition, a small difference in the molecular structure, i.e. a carboxyl group, between candesartan and candesartan-7H was associated with a difference in the degree of this blocking effect. In addition, interaction between Gln²⁵⁷ in the AT₁ receptor and the carboxyl group of candesartan may be partially associated with the effect of candesartan after wash-out. Although our findings regarding the molecular effects of ARB are based on basic research, these findings may lead to an exciting new area in the clinical application of ARBs.

Keywords

Angiotensin II type 1 receptor blocker carboxyl group cell-based wash-out assay extracellular signal-regulated kinase activation inositol phosphate production effects

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Abilities of candesartan and other AT 1 receptor blockers to impair angiotensin II-induced AT 1 receptor activation after wash-out

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