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(Hypertension. 2005;46:1368.)
© 2005 American Heart Association, Inc.

Original Articles

Hydrolysis of Angiotensin Peptides by Human Angiotensin I–Converting Enzyme and the Resensitization of B₂ Kinin Receptors

From the Departments of Pharmacology (Z.C., F.T., E.G.E., P.A.D.), Anesthesiology (F.T., E.G.E.), and Anatomy and Cell Biology (P.A.D.), University of Illinois College of Medicine, Chicago.

Correspondence to Ervin G. Erdös, MD, Professor, Department of Pharmacology, 835 S Wolcott (MC 868), Chicago, IL 60612. E-mail EGErdos{at}uic.edu

We measured the cleavage of angiotensin I (Ang I) metabolites by angiotensin I–converting enzyme (ACE) in cultured cells and examined how they augment actions of bradykinin B₂ receptor agonists. Monolayers of Chinese hamster ovary cells transfected to stably express human ACE and bradykinin B₂ receptors coupled to green fluorescent protein (B₂GFP) or to express only coupled B₂GFP receptors. We used 2 ACE-resistant bradykinin analogues to activate the B₂ receptors. We used high-performance liquid chromatography to analyze the peptides cleaved by ACE on cell monolayers and found that Ang 1-9 was hydrolyzed 18x slower than Ang I and &30% slower than Ang 1-7. Ang 1-7 was cleaved to Ang 1-5. Although µmol/L concentrations of slowly cleaved substrates Ang 1-7 and Ang 1-9 inhibit ACE, they resensitize the desensitized B₂GFP receptors in nmol/L concentration, independent of ACE inhibition. This is reflected by release of arachidonic acid through a mechanism involving cross-talk between ACE and B₂ receptors. When ACE was not expressed, the Ang 1-9, Ang 1-7 peptides were inactive. Inhibitors of protein kinase C-, phosphatases and Tyr-kinase blocked this resensitization activity, but not basal B₂ activation by bradykinin. Ang 1-9 and Ang 1-7 enhance bradykinin activity, probably by acting as endogenous allosteric modifiers of the ACE and B₂ receptor complex. Consequently, when ACE inhibitors block conversion of Ang I, other enzymes can still release Ang I metabolites to enhance the efficacy of ACE inhibitors.

Key Words: angiotensin • angiotensin-converting enzyme • bradykinin • enalapril • protein kinases

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