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Bradykinin potentiation by ACE inhibitors: a matter of metabolism
Author(s) -
Tom Beril,
Dendorfer Andreas,
Vries René de,
Saxena Pramod R,
Jan Danser A H
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704862
Subject(s) - bradykinin , bradykinin receptor , medicine , endocrinology , chemistry , phosphoramidon , calphostin c , neprilysin , angiotensin converting enzyme , ace inhibitor , icatibant , phenylarsine oxide , receptor , protein kinase c , biology , signal transduction , endothelin receptor , biochemistry , enzyme , blood pressure
Studies in isolated cells overexpressing ACE and bradykinin type 2 (B 2 ) receptors suggest that ACE inhibitors potentiate bradykinin by inhibiting B 2 receptor desensitization, via a mechanism involving protein kinase C (PKC) and phosphatases. Here we investigated, in intact porcine coronary arteries, endothelial ACE/B 2 receptor ‘crosstalk’ as well as bradykinin potentiation through neutral endopeptidase (NEP) inhibition. NEP inhibition with phosphoramidon did not affect the bradykinin concentration‐response curve (CRC), nor did combined NEP/ACE inhibition with omapatrilat exert a further leftward shift on top of the ≈10 fold leftward shift of the bradykinin CRC observed with ACE inhibition alone. In arteries that, following repeated exposure to 0.1 μ M bradykinin, no longer responded to bradykinin (‘desensitized’ arteries), the ACE inhibitors quinaprilat and angiotensin‐(1‐7) both induced complete relaxation, without affecting the organ bath fluid levels of bradykinin. This phenomenon was unaffected by inhibition of PKC or phosphatases (with calphostin C and okadaic acid, respectively). When using bradykinin analogues that were either completely or largely ACE‐resistant ([Phe 8 Ψ(CH 2 ‐NH)Arg 9 ]‐bradykinin and [ΔPhe 5 ]‐bradykinin, respectively), the ACE inhibitor‐induced shift of the bradykinin CRC was absent, and its ability to reverse desensitization was absent or significantly reduced, respectively. Caveolar disruption with filipin did not affect the quinaprilat‐induced effects. Filipin did however reduce the bradykinin‐induced relaxation by ≈25–30%, thereby confirming that B 2 receptor‐endothelial NO synthase (eNOS) interaction occurs in caveolae. In conclusion, in porcine arteries, in contrast to transfected cells, bradykinin potentiation by ACE inhibitors is a metabolic process, that can only be explained on the basis of ACE‐B 2 receptor co‐localization on the endothelial cell membrane. NEP does not appear to affect the bradykinin levels in close proximity to B 2 receptors, and the ACE inhibitor‐induced bradykinin potentiation precedes B 2 receptor coupling to eNOS in caveolae.British Journal of Pharmacology (2002) 137 , 276–284. doi: 10.1038/sj.bjp.0704862