title: Pseudo-noncompetitive antagonism by BQ123 of intracellular calcium transients mediated by human ETA endothelin receptor.
abstract: The family of endothelins, endothelin-1 (ET-1), ET-2 and ET-3, act on two subtypes of receptors called ETA and ETB receptors. BQ123 is an ETA-selective competitive antagonist. In this study, however, BQ123 inhibited ET-1-induced transients of cytosolic Ca2+ concentrations ([Ca2+]i) in an apparently noncompetitive manner in mouse L cell stably expressing cloned human ETA receptor. BQ123 (3-30 nM) did not change the EC50 of ET-1 (6.6 nM), but reduced the maximum responses down to 15.0%. In an non-equilibrium binding assay which mimicks the conditions of [Ca2+]i transient assay (cells were incubated with [125I]ET-1 only for 30 s), BQ123 (30 nM) constantly decreased the specific [125I]ET-1 binding to approximately 13% of that without the antagonist. Thus, the apparent noncompetitive antagonism by BQ123 of ETA receptor-mediated [Ca2+]i transient is due to the assay condition where the interactions of the agonist, antagonist and receptor remained non-equilibrium state.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kyoto University, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Sakamoto
authors.forename: M
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: G
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: K
authors.initials: K
authors.lastname: Nakao
authors.forename: T
authors.initials: T
authors.lastname: Toyo-oka
authors.forename: T
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007739:L Cells; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology*; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium