title: Abilities of candesartan and other AT(1) receptor blockers to impair angiotensin II-induced AT(1) receptor activation after wash-out.
abstract: Angiotensin II (Ang II) binds to Ang II type 1 (AT(1)) receptor and evokes cell signaling, and subsequently stimulates vasoconstriction and cell proliferation, which eventually lead to cardiovascular disease. Since most AT(1) 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 AT(1) 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 Gln(257) in the AT(1) 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.
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Jonan-ku, Fukuoka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kiya
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Miura
authors.forename: Yoshino
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Sadashiva S
authors.initials: SS
authors.lastname: Karnik
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D019556:COS Cells; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007295:Inositol Phosphates; D050505:Mutant Proteins; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; C081643:candesartan