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1 Birmingham Veteran Affairs Medical Center and Division of Cardiovascular Disease, Department of Medicine, Vascular Biology and Hypertension Program, University of Alabama, Birmingham, Alabama 35294; and 2 Department of Anesthesia, University of Pennsylvania Health System, Philadelphia, Pennsylvania 19104
We utilized mice with homozygous
disruption of angiotensin-converting enzyme (ACE) (
/
), mice with
heterozygous deletion of ACE (+/
), and wild-type mice (+/+) to test
the hypothesis that genetic variation in ACE modulates tissue and
plasma angiotensin (ANG) II concentrations. With the use of ANG I as
substrate, kidney, heart, and lung ACE activity was reduced 80% in
/
mice compared with +/+ mice. However, ANG II concentrations and
ANG II-to-ANG I ratios in the kidney, heart, and lung did not differ
among genotypes. In contrast, plasma ANG II concentrations in
/
mice were <2 fmol/ml, whereas plasma ANG I concentrations were
extremely high (765 fmol/ml). Chymase activity was increased 14-fold in
the kidney (P < 0.05) and 1.5-fold in the heart
(P < 0.05) of
/
versus +/+ mice but did not differ
among genotypes in the lung. ANG II formation from enzymes other than
ACE and chymase contributed <2% of total ANG II formation in all
genotypes. These data suggest that ACE is essential to ANG II formation
in the vascular space, whereas chymase may provide an important
mechanism in maintaining steady-state ANG II levels in tissue.
angiotensin I; chymase; angiotensin-converting enzyme
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