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Vol. 294, Issue 2, 605-612, August 2000
Departments of Pharmacology (B.M.M., E.G.E.) and Anesthesiology
(E.G.E.), University of Illinois College of Medicine at Chicago,
Chicago, Illinois
Angiotensin I-converting enzyme (kininase II) inhibitors (ACEis) are
very widely used to treat cardiac conditions and nephropathies, but
some of their beneficial activities cannot be attributed to enzyme
inhibition alone. We investigated the effects of ACEis on the human
bradykinin (BK) B2 receptor expressed in Chinese hamster
ovary cells transfected with the cDNA of human receptor and ACE,
and on human pulmonary endothelial cells that constitutively express
both proteins. BK and its ACE-resistant peptide analog activated the
B2 receptor to release arachidonic acid and elevate [Ca2+]i and subsequently desensitized it. The
release of arachidonic by BK was independent of extracellular
Ca2+. BK enhanced phosphorylation of the immunoprecipitated
B2 receptor but enalaprilat significantly reduced it. ACEi
resensitized the receptor by initiating a cross talk between the
receptor and ACE. Protein kinase C and phosphatase inhibitors
distinguished the signaling by the receptor when activated first by BK
from BK acting on the resensitized receptor. Treatment of cells with 1 µM calphostin, 100 nM staurosporine, 100 nM calyculin, or 500 nM
okadaic acid did not affect either one of the primary actions of BK on
the receptor. Protein kinase C or phosphatase inhibitors, however, blocked the effects of BK on the receptor resensitized by enalaprilat or ramiprilat. The experiments clearly differentiate the primary activation of the receptor by BK from activation of the resensitized receptor after ACEi treatment. The existence of an intermediate component involved in the action of ACEis to enhance release of vasoactive mediators by BK is suggested.
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