Published Online
on October 24, 2005

A more recent version of this article appeared on December 1, 2005

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Submitted on August 5, 2005
Revised on August 26, 2005

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

Zhenlong Chen; Fulong Tan; Ervin G. Erdös^*; and Peter A. Deddish

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.

^* To whom correspondence should be addressed. E-mail: EGErdos{at}uic.edu.

Abstract--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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