Products of angiotensin I hydrolysis by human cardiac enzymes potentiate bradykinin.
Some beneficial effects of ACE inhibitors are attributed to potentiation of bradykinin's actions exerted through its B2 receptor. We investigated them on cultured cells transfected or constitutively expressing both ACE and B2 receptor. The potentiation of bradykinin was indirect and attributed to a crosstalk induced between enzyme and receptor via ACE, a heterodimer formation. While looking for endogenous activators, we investigated the split products of angiotensin I (Ang) Ang 1-9 and 1-7, peptides released by enzymes of human atria and ventricle. Ang 1-9 was liberated by a cathepsin A-type enzyme, Ang 1-7 by a different metallopeptidase-protease. Cathepsin A's presence in heart tissue was shown by deamidating enkephalinamide substrate, by immunoprecipitation and by immunohistochemistry. In immunohistochemistry, cathepsin A was detected in myocytes of atrial tissue. Ang 1-9 and Ang 1-7 potentiated the effect of an ACE-resistant bradykinin analogue on the B2 receptor in transfected cells expressing human ACE and B2, and in human endothelial cells. Ang 1-9 and 1-7 augmented arachidonic acid and NO release by bradykinin. NO liberation by bradykinin from endothelial cells was potentiated at 10nmol/L concentration by Ang 1-9 and Ang 1-7; at higher concentrations, Ang 1-9 was significantly more active. Both peptides had little activity in absence of bradykinin or ACE. Ang 1-9 and 1-7 potentiated bradykinin action on its B2 receptor at much lower concentrations than their IC50 values with ACE. They probably induce conformational changes in the ACE/B2 receptor complex via interaction with ACE.
Erdös
Ervin G
EG
Department of Pharmacology, University of Illinois College of Medicine at Chicago, Ill 60612-7344, USA. egerdos@uic.edu
Jackman
Herbert L
HL
Brovkovych
Viktor
V
Tan
Fulong
F
Deddish
Peter A
PA
D000803:Angiotensin I / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D002268:Carboxypeptidases / Q000378:metabolism; D043402:Cathepsin A; D004357:Drug Synergism; D006168:Guinea Pigs; D006801:Humans; D006868:Hydrolysis; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D043782:Receptor, Bradykinin B2
D065168:Bradykinin Receptor Antagonists; D043782:Receptor, Bradykinin B2; D000803:Angiotensin I; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C468629:CTSA protein, human; D043402:Cathepsin A; D001920:Bradykinin