title: Effects of TCV-116 and CV-11974 on angiotensin II-induced responses in vascular smooth muscle cells.
abstract: (+/-)-1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116, Candesartan) and its active metabolite 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974) are specific nonpeptide angiotensin AT1 receptor antagonists. In the present study, the inhibitory potency of these two antagonists on the angiotensin II-induced responses in aortic vascular smooth muscle cells from Wystar Kyoto rats was investigated. The specific binding of 125I-angiotensin II to cells was inhibited by CV-11974 and TCV-116 with a half-maximal inhibitory concentration (IC50) of 3 x 10(-11) M and 1 x 10(-9) M, respectively. CV-11974 and TCV-116 inhibited the angiotensin II-induced increase in [3H]thymidine incorporation with an IC50 of 3 x 10(-10) and 5 x 10(-9) M, respectively. Both CV-11974 and TCV-116 (10(-7) M) completely blocked the angiotensin II-induced increase in c-fos mRNA. The inhibitory potency of the metabolite CV-11974 was about 30-100-fold higher than that of the prodrug TCV-116.
authors.affiliation: Medizinische Universitäts-Poliklinik, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Flesch
authors.forename: Y
authors.initials: Y
authors.lastname: Ko
authors.forename: C
authors.initials: C
authors.lastname: Seul
authors.forename: R
authors.initials: R
authors.lastname: Düsing
authors.forename: H
authors.initials: H
authors.lastname: Feltkamp
authors.forename: H
authors.initials: H
authors.lastname: Vetter
authors.forename: A
authors.initials: A
authors.lastname: Sachinidis
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016760:Proto-Oncogene Proteins c-fos; D013777:Tetrazoles; D000804:Angiotensin II; C077793:candesartan cilexetil; C081643:candesartan