title: Genetic variation and gender determine bradykinin type 1 receptor responses in human tissue: implications for the ACE-inhibitor-induced effects in patients with coronary artery disease.
abstract: The efficacy of the ACE (angiotensin-converting enzyme) inhibitor perindopril in coronary artery disease [EUROPA (European trial on reduction of cardiac events with perindopril in stable coronary artery disease) study] is associated with the rs12050217 A/G single nucleotide polymorphism in the B1 receptor (bradykinin type 1 receptor) gene. To investigate the underlying mechanism, we examined the effect of this polymorphism on B1-receptor-mediated coronary artery dilation and peripheral blood mononuclear cell activation. Vasorelaxant responses of human coronary microarteries from subjects without coronary disease to des-Arg(9)-bradykinin and to bradykinin were studied in organ bath experiments. Des-Arg9-bradykinin responses were endothelium-dependent and exclusively mediated by B1 receptors, whereas responses to bradykinin were induced through B2 receptors (bradykinin type 2 receptors). The presence of the G allele reduced the response to 3 × 10(-8) mol/l des-Arg(9)-bradykinin by 29% [AA (n=13) compared with AG/GG (n=8); P<0.03], and tended to lower concentration-related responses (P=0.065) to this agonist, whereas the responses to bradykinin were unaffected by the rs12050217 genotype. In freshly obtained human mononuclear cells 1 μmol/l des-Arg(9)-bradykinin increased expression of the pro-inflammatory factors CXCL5 (CXC chemokine ligand 5) and IL6 (interleukin-6). These responses were not affected by genotype and exclusively occurred in blood cells from women, correlating (in the case of CXCL5) with their plasma 17β-oestradiol levels (r(2)=0.32, P=0.02; n=17). IL-1β (interleukin-1β) increased CXCL5 and IL6 expression in both genders, and this response was not associated with 17β-oestradiol levels. The gender difference in responses to B1 receptor stimulation in blood mononuclear cells implies possible gender differences in the response to ACE inhibitor therapy, which needs to be studied more comprehensively. The observed decrease in coronary vasodilator response might contribute to the impaired treatment response to perindopril of G allele carriers found in the EUROPA study.
authors.affiliation: *Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wu
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: Roks
authors.forename: Frank P J
authors.initials: FP
authors.lastname: Leijten
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: Usha M
authors.initials: UM
authors.lastname: Musterd-Bhaggoe
authors.forename: Antoon J
authors.initials: AJ
authors.lastname: van den Bogaerdt
authors.forename: Moniek P M
authors.initials: MP
authors.lastname: de Maat
authors.forename: Maarten L
authors.initials: ML
authors.lastname: Simoons
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.forename: Hisko
authors.initials: H
authors.lastname: Oeseburg
mesh_terms: D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D054365:Chemokine CXCL5 / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000097:blood; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D020641:Polymorphism, Single Nucleotide; D043783:Receptor, Bradykinin B1 / Q000235:genetics*; D012727:Sex Characteristics; D012737:Sex Factors; D014664:Vasodilation / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C486263:CXCL5 protein, human; D054365:Chemokine CXCL5; D018836:Inflammation Mediators; D043783:Receptor, Bradykinin B1; D014665:Vasodilator Agents; C024626:bradykinin, des-Arg(9)-; D004958:Estradiol; D001920:Bradykinin