Journal
HYPERTENSION
Volume 46, Issue 6, Pages 1368-1373Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.HYP.0000188905.20884.63
Keywords
angiotensin; angiotensin; converting enzyme; bradykinin; enalapril; protein kinases
Categories
Funding
- NHLBI NIH HHS [R01 HL036473-19, R01 HL036473-20, R01 HL036473, R01 HL036473-17, HL68580, R01 HL068580-03, R01 HL068580-01, R01 HL036473-18, R01 HL068580, HL36473, R01 HL068580-02, R01 HL068580-04] Funding Source: Medline
Ask authors/readers for more resources
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 B-2 receptor agonists. Monolayers of Chinese hamster ovary cells transfected to stably express human ACE and bradykinin B-2 receptors coupled to green fluorescent protein (B(2)GFP) or to express only coupled B(2)GFP receptors. We used 2 ACE-resistant bradykinin analogues to activate the B-2 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 approximate to 30% slower than Ang 1-7. Ang 1-7 was cleaved to Ang 1-5. Although mu mol/L concentrations of slowly cleaved substrates Ang 1-7 and Ang 1- 9 inhibit ACE, they resensitize the desensitized B(2)GFP 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 B-2 receptors. When ACE was not expressed, the Ang 1-9, Ang 1-7 peptides were inactive. Inhibitors of protein kinase C-alpha, phosphatases and Tyr-kinase blocked this resensitization activity, but not basal B-2 activation by bradykinin. Ang 1- 9 and Ang 1-7 enhance bradykinin activity, probably by acting as endogenous allosteric modifiers of the ACE and B-2 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available