From the University of Illinois College of Medicine (Chicago).
Correspondence to Ervin G. Erdös, MD, University of Illinois College of Medicine at Chicago, Department of Pharmacology (M/C 868), 835 S Wolcott Ave, Chicago, IL 60612-7344. E-mail EGErdos{at}uic.edu
Abstract—We used the isolated N- and
C-domains of the angiotensin I–converting enzyme (N-ACE
and C-ACE; ACE; kininase II) to investigate the hydrolysis of the
active 1–7 derivative of angiotensin (Ang) II
and inhibition by
5-S-5-benzamido-4-oxo-6-phenylhexanoyl-L-proline
(keto-ACE). Ang-(1–7) is both a substrate and an
inhibitor; it is cleaved by N-ACE at approximately one half
the rate of bradykinin but negligibly by C-ACE. It inhibits C-ACE,
however, at an order of magnitude lower concentration than N-ACE; the
IC50 of C-ACE with 100 µmol/L Ang I substrate was
1.2 µmol/L and the Ki was 0.13. While
searching for a specific inhibitor of a single active site
of ACE, we found that keto-ACE inhibited bradykinin and Ang I
hydrolysis by C-ACE in approximately a 38- to 47-times lower
concentration than by N-ACE; IC50 values with C-ACE were
0.5 and 0.04 µmol/L. Furthermore, we investigated how Ang-(1–7)
acts via bradykinin and the involvement of its B2 receptor.
Ang-(1–7) was ineffective directly on the human bradykinin
B2 receptor transfected and expressed in Chinese hamster
ovary cells. However, Ang-(1–7) potentiated
arachidonic acid release by an ACE-resistant
bradykinin analogue (1 µmol/L), acting on the B2
receptor when the cells were cotransfected with cDNAs of both
B2 receptor and ACE and the proteins were expressed on the
plasma membrane of Chinese hamster ovary cells. Thus like other ACE
inhibitors, Ang-(1–7) can potentiate the actions of a
ligand of the B2 receptor indirectly by binding to the
active site of ACE and independent of blocking ligand hydrolysis. This
potentiation of kinins at the receptor level can explain some of the
well-documented kininlike actions of Ang-(1–7).
© 1998 American Heart Association, Inc.
Scientific Contributions
N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme
Angiotensin-(1–7) and Keto-ACE
Key Words: bradykinin • receptors • signal transduction • arachidonic acid • enzymes
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