Angiotensin-converting enzyme insertion/deletion polymorphism modulates the human in vivo metabolism of bradykinin

Background-Bradykinin is a cardioprotective peptide metabolized by the angi otensin-converting enzyme (ACE). An insertion/deletion (I/D) polymorphism i n the ACE gene determines plasma ACE levels. The D allele is associated wit h cardiovascular disease, which may relate to enhanced angiotensin II produ ction or to increased bradykinin degradation to the inactive metabolite bra dykinin 1-5 (BK1-5). Therefore, we determined the effect of the ACE I/D pol ymorphism on human bradykinin metabolism in vivo. Methods and Results-Bradykinin (400 ng/min) was infused into the brachial a rtery of volunteers with ACE I/I, I/D, or D/D genotypes (n=9 each). The bra dykinin and BK1-5 levels in forearm venous return were quantified by liquid chromatography-mass spectroscopy. Plasma ACE activity was highest in those with the D/D genotype (36.8+/-6.2 U/mL), intermediate in those with the I/ D genotype (25.3+/-3.3 U/mL), and lowest in those with the VI genotype (20. 3+/-2.3 U/mL; P=0.017 for effect of number of D alleles), Bradykinin concen trations were 726 +/- 242, 469 +/- 50, and 545 +/- 104 fmol/ml in I/I, I/D, and D/D subjects, respectively (P>0.10). Significant correlations existed between the number of D alleles and BK1-5 concentrations (1113+/-290, 1520/-318, and 1887+/-388 fmol/mL in the I/I, I/D, and D/D groups, respectively ; P=0.027) and the ratio of BK1-5 to bradykinin (1.87+/-0.35, 3.09+/-0.40, and 4.31+/-0.97 in the I/I, I/D, and D/D volunteers, respectively; P=0.010) . The venous blood BK1-5:bradykinin ratio correlated with plasma ACE activi ty (r(2)=0.16, P=0.039), and total kinin concentration correlated with net tissue plasminogen activator release across the forearm (r(2)=0.20, P=0.027 ). Conclusions-The ACE D allele has a significant effect on the in vivo degrad ation of bradykinin in humans. The ratio of BK1-5:bradykinin may serve as a marker for tissue ACE activity.