(Hypertension. 1999;33:835-843.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Enhancement of Bradykinin and Resensitization of Its B2 Receptor
Presented in part at the 13th Annual Scientific Meeting of the American Society of Hypertension, New York, NY, May 13–16, 1998, and published in abstract form (Am J Hypertens. 1998;11:239A).
From the Departments of Pharmacology (B.M., P.A.D., H.L.J., E.G.E.) and Anesthesiology (E.G.E.), University of Illinois College of Medicine at Chicago.
Correspondence to Ervin G. Erdös, MD, Department of Pharmacology (M/C 868), University of Illinois–Chicago, 835 S Wolcott Ave, Chicago, IL 60612. E-mail EGErdos{at}uic.edu
Abstract—We studied the
enhancement of the effects of bradykinin B2 receptor
agonists by agents that react with active centers of
angiotensin-converting enzyme (ACE) independent of
enzymatic inactivation. The potentiation and the desensitization and
resensitization of B2 receptor were assessed by measuring
[3H]arachidonic acid release and
[Ca2+]i mobilization in Chinese hamster ovary
cells transfected to express human ACE and B2 receptor, or
in endothelial cells with constitutively expressed ACE
and receptor. Administration of bradykinin or its ACE-resistant
analogue desensitized the receptor, but it was resensitized
(arachidonic acid release or
[Ca2+]i mobilization) by agents such as
enalaprilat (1 µmol/L). Enalaprilat was inactive in the absence
of ACE expression. La3+ (100 µmol/L) inhibited the
apparent resensitization, probably by blocking the entry of
extracellular calcium. Enalaprilat resensitized the receptor via ACE to
release arachidonic acid by bradykinin at a lower
concentration (5 nmol/L) than required to mobilize
[Ca2+]i (1 µmol/L). Monoclonal
antibodies inhibiting the ACE N-domain active center and polyclonal
antiserum potentiated bradykinin. The snake venom peptide BPP5a and
metabolites of angiotensin and bradykinin
(angiotensin-[1–9], angiotensin-[1–7],
bradykinin-[1–8]; 1 µmol/L) enhanced
arachidonic acid release by bradykinin.
Angiotensin-(1–9) and -(1–7) also resensitized the
receptor. Enalaprilat potentiated the bradykinin effect in cells
expressing a mutant ACE with a single N-domain active site. Agents that
reacted with a single active site, on the N-domain or on the C-domain,
potentiated bradykinin not by blocking its inactivation but by inducing
crosstalk between ACE and the receptor. Enalaprilat enhanced signaling
via ACE by G
i in lower concentration than by
Gq-coupled receptor.
Key Words: angiotensin-converting enzyme inhibitors • kininase II • endothelial cells • G proteins • [Ca2+]i • arachidonic acid • angiotensin-(1–9)
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