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Departments of 1 Pharmacology and 2 Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois 60612
Kininase I-type carboxypeptidases
convert native kinin agonists for B2 receptors into
B1 receptor agonists by specifically removing the
COOH-terminal Arg residue. The membrane localization of
carboxypeptidase M (CPM) and carboxypeptidase D (CPD) make them ideally
situated to regulate kinin activity. Nitric oxide (NO) release from
human lung microvascular endothelial cells (HLMVEC) was measured
directly in real time with a porphyrinic microsensor. Bradykinin
(1-100 nM) elicited a transient (5 min) peak of generation of NO
that was blocked by the B2 antagonist HOE 140, whereas
B1 agonist des-Arg10-kallidin caused a small
linear increase in NO over 20 min. Treatment of HLMVEC with 5 ng/ml
interleukin-1
and 200 U/ml interferon-
for 16 h upregulated
B1 receptors as shown by an approximately fourfold increase
in prolonged (>20 min) output of NO in response to
des-Arg10-kallidin, which was blocked by the B1
antagonist des-Arg10-Leu9-kallidin.
B2 receptor agonists bradykinin or kallidin also generated prolonged NO production in treated HLMVEC, which was significantly reduced by either a B1 antagonist or carboxypeptidase
inhibitor, and completely abolished with a combination of
B1 and B2 receptor antagonists. Furthermore,
CPM and CPD activities were increased about twofold in membrane
fractions of HLMVEC treated with interleukin-1 and
interferon- compared with control cells. Immunostaining localized CPD primarily in a perinuclear/Golgi region, whereas CPM was on the
cell membrane. These data show that cellular kininase I-type carboxypeptidases can enhance kinin signaling and NO production by
converting B2 agonists to B1 agonists,
especially in inflammatory conditions.
carboxypeptidase M; carboxypeptidase D; bradykinin B2
receptor; interleukin 1-; interferon-
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