title: A two-state receptor model for the interaction between angiotensin II type 1 receptors and non-peptide antagonists.
abstract: The interaction between non-peptide antagonists and the human angiotensin II type 1 (AT1) receptor in CHO-K1 cells was investigated by incubating the cells with antagonist, followed by a brief exposure to angiotensin II and measurement of the resulting inositol phosphate accumulation. The experimental data, expressed either as angiotensin II concentration-response curves or as antagonist concentration-inhibition curves, were in good agreement with computer-generated data according to a single-state model for the surmountable antagonist losartan and according to a two-step, two-state receptor model for the insurmountable antagonists candesartan, EXP3174, and irbesartan. Experimental and computer-generated data concerning the simultaneous exposure of the receptors to EXP3174 and losartan indicated that losartan produced a concentration-dependent restoration of the maximal response (angiotensin II concentration-response curves) as well as a rightward shift of the insurmountable portion of the EXP3174 inhibition curves, thus counteracting the higher-affinity EXP3174 binding. In conclusion, these findings provide further support for the concept that insurmountable and surmountable AT1 antagonists are mutually competitive and that insurmountable antagonist-receptor complexes may adopt different states.
authors.affiliation: Department of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), Sint-Genesius Rode, Belgium. gvauquel@vub.ac.be
authors.forename: G
authors.initials: G
authors.lastname: Vauquelin
authors.forename: P
authors.initials: P
authors.lastname: Morsing
authors.forename: F L
authors.initials: FL
authors.lastname: Fierens
authors.forename: J P
authors.initials: JP
authors.lastname: De Backer
authors.forename: P M
authors.initials: PM
authors.lastname: Vanderheyden
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D016466:CHO Cells; D003198:Computer Simulation; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D007295:Inositol Phosphates / Q000378:metabolism; D000077405:Irbesartan; D007700:Kinetics; D019808:Losartan / Q000494:pharmacology; D008954:Models, Biological; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007295:Inositol Phosphates; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D000077405:Irbesartan; D019808:Losartan; C081643:candesartan