title: A single-nucleotide polymorphism of alanine to threonine at position 163 of the human angiotensin II type 1 receptor impairs Losartan affinity.
abstract: OBJECTIVE
  AT1 is the principal receptor for angiotensin II (AngII), which regulates blood pressure and osmotic homeostasis. Earlier studies have shown that position 163 interacts with the antihypertensive nonpeptide antagonist, Losartan. A recently discovered polymorphism found in humans (rs12721226) coding for residue 163 led us to determine whether this polymorphism would affect Losartan antihypertensive therapies. The pharmacological properties of the A163T hAT1 variant are described.
  
  
  RESULTS
  The A163T hAT1 mutation was evaluated by testing its affinity by dose displacement of AngII analogs in COS-7 cells expressing either wild-type hAT1 or the A163T hAT1. The expressions of the receptors were evaluated by saturation binding and the efficacies were assessed by measuring the 3H-inositol phosphate production. The results showed that the A163T hAT1 receptor is comparable with the affinity, expression, and efficacy of native hAT1 towards peptide ligands. The affinities were also tested with nonpeptide antagonists Losartan, L-158 809, valsartan, telmisartan, irbesartan, candesartan, and EXP3174. Losartan and EXP3174 displayed a 7-fold loss in affinity towards A163T hAT1. The ability of Losartan to inhibit AngII-induced inositol triphosphate production also confirmed a loss in efficacy. Molecular modeling showed a higher steric and hydrophilic hindrance of the A163T hAT1-Losartan complex.
  
  
  CONCLUSIONS
  The polymorphism that codes for the A163T hAT1 variant results in a receptor with normal physiological properties toward the endogenous hormone. However, the significant reduction in affinity to Losartan and its active metabolite, EXP3174, could significantly impair the clinical effectiveness of an antihypertensive therapy using Losartan with patients bearing the A163T polymorphism.
authors.affiliation: Département de Pharmacologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Arsenault
authors.forename: Julie
authors.initials: J
authors.lastname: Lehoux
authors.forename: Luc
authors.initials: L
authors.lastname: Lanthier
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cabana
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Guillemette
authors.forename: Pierre
authors.initials: P
authors.lastname: Lavigne
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.forename: Emanuel
authors.initials: E
authors.lastname: Escher
mesh_terms: D000409:Alanine / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007093:Imidazoles; D007295:Inositol Phosphates / Q000378:metabolism / Q000494:pharmacology; D000077405:Irbesartan; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1; D000077333:Telmisartan; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology; D013912:Threonine / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives; D000068756:Valsartan
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D007093:Imidazoles; D007295:Inositol Phosphates; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D013912:Threonine; D000068756:Valsartan; C066026:losartan carboxylic acid; D014633:Valine; D000077405:Irbesartan; D019808:Losartan; D000409:Alanine; C081643:candesartan; D000077333:Telmisartan