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.