title: Candesartan (CV-11974) dissociates slowly from the angiotensin AT1 receptor.
abstract: The mechanisms of the insurmountable antagonism of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]1H-benzimid azole -7-carboxylic acid, candesartan (CV-11974), an angiotensin AT1 receptor antagonist, on angiotensin II-induced rabbit aortic contraction were examined in contraction and binding studies. Preincubation of the rabbit aorta with CV-11974 (0.1 nM) for 30 min reduced the maximal contractile response to angiostensin II by approximately 50%. This insurmountable antagonism of CV-11974 was reversed in the presence of losartan (1 microM), a surmountable angiotensin AT1 receptor antagonist. The inhibitory effect of CV-11974 on angiotensin II-induced contraction persisted longer after washing than did that of losartan but was irreversible. Scatchard analysis of [3H]CV-11974 binding in bovine adrenal cortical membranes indicated the existence of a single class of binding sites (Kd = 7.4 nM). Competition binding studies using angiotensin II receptor agonists and antagonists have demonstrated that [3H[CV-11974 binding sites may be identical to angiotensin AT1 receptors. The dissociation rate of [3H]CV-11974 binding (t1/2 = 66 min) was 5 times slower than that of [125I]angiotensin II binding (t1/2 = 12 min). These results suggest that the insurmountable antagonism by CV-11974 is due to its slow dissociation from angiotensin AT1 receptors.
authors.affiliation: Pharmaceutical Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ojima
authors.forename: Y
authors.initials: Y
authors.lastname: Inada
authors.forename: Y
authors.initials: Y
authors.lastname: Shibouta
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.forename: T
authors.initials: T
authors.lastname: Sanada
authors.forename: K
authors.initials: K
authors.lastname: Kubo
authors.forename: K
authors.initials: K
authors.lastname: Nishikawa
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism* / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002417:Cattle; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D011817:Rabbits; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013777:Tetrazoles / Q000378:metabolism* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan; C081643:candesartan