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


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.
Murphey
L J
LJ
Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
Gainer
J V
JV
Vaughan
D E
DE
Brown
N J
NJ
D000328:Adult; D000483:Alleles; D001916:Brachial Artery; D001920:Bradykinin / Q000008:administration & dosage / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D010446:Peptide Fragments / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics*; D011110:Polymorphism, Genetic; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000378:metabolism
D010446:Peptide Fragments; C079000:bradykinin (1-5); D007703:Peptidyl-Dipeptidase A; D010959:Tissue Plasminogen Activator; D001920:Bradykinin