Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism Modulates the Human In Vivo Metabolism of Bradykinin

Abstract

Background —Bradykinin is a cardioprotective peptide metabolized by the angiotensin-converting enzyme (ACE). An insertion/deletion (I/D) polymorphism in the ACE gene determines plasma ACE levels. The D allele is associated with cardiovascular disease, which may relate to enhanced angiotensin II production or to increased bradykinin degradation to the inactive metabolite bradykinin 1–5 (BK1–5). Therefore, we determined the effect of the ACE I/D polymorphism on human bradykinin metabolism in vivo. Methods and Results —Bradykinin (400 ng/min) was infused into the brachial artery of volunteers with ACE I/I, I/D, or D/D genotypes (n=9 each). The bradykinin 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 I/I genotype (20.3±2.3 U/mL; P =0.017 for effect of number of D alleles). Bradykinin concentrations 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 activity ( 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 degradation of bradykinin in humans. The ratio of BK1–5:bradykinin may serve as a marker for tissue ACE activity.