(Circulation. 2000;102:2190.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Bradykinin Stimulates Tissue Plasminogen Activator Release From Human Forearm Vasculature Through B2 Receptor–Dependent, NO Synthase–Independent, and Cyclooxygenase-Independent Pathway
From the Departments of Medicine and Pharmacology (N.J.B., J.V.G., L.J.M., D.E.V.), Vanderbilt University Medical Center, and the Nashville Veteran’s Administration Medical Center (D.E.V.), Nashville, Tenn.
Background—Bradykinin stimulates dose-dependent tissue plasminogen activator (tPA) release from human endothelium. Although bradykinin is known to cause vasodilation through B2 receptor–dependent effects on NO, prostacyclin, and endothelium-derived hyperpolarizing factor production, the mechanism(s) underlying tPA release is unknown.
Methods and Results—We measured the effects of
intra-arterial bradykinin (100, 200, and 400 ng/min),
acetylcholine (15, 30, and 60 µg/min), and nitroprusside (0.8, 1.6,
and 3.2 µg/min) on forearm vasodilation and tPA release in healthy
volunteers in the presence and absence of (1) the B2
receptor antagonist HOE 140 (100 µg/kg IV), (2) the NO
synthase inhibitor
L-NG-monomethyl-L-arginine
(L-NMMA, 4 µmol/min intra-arterially), and (3) the
cyclooxygenase inhibitor
indomethacin (50 mg PO TID). B2 receptor
antagonism attenuated vasodilator (P=0.004) and tPA
(P=0.043) responses to bradykinin, without attenuating
the vasodilator response to nitroprusside (P=0.36).
L-NMMA decreased basal forearm blood flow (from 2.35±0.31 to
1.73±0.22 mL/min per 100 mL, P=0.01) and blunted
the vasodilator response to acetylcholine (P=0.013) and
bradykinin (P=0.07, P=0.038 for forearm
vascular resistance) but not that to nitroprusside
(P=0.47). However, there was no effect of L-NMMA on
basal (P=0.7) or bradykinin-stimulated tPA release
(P=0.45). Indomethacin decreased urinary
excretion of the prostacyclin metabolite
2,3-dinor-6-keto-prostaglandin F1
(P=0.04). The vasodilator response to
endothelium-dependent (P=0.019 for
bradykinin) and endothelium-independent
(P=0.019) vasodilators was enhanced during
indomethacin administration. In contrast, there was no
effect of indomethacin alone (P=0.99) or
indomethacin plus L-NMMA (P=0.36) on
bradykinin-stimulated tPA release.
Conclusions—These data indicate that bradykinin stimulates tPA release from human endothelium through a B2 receptor–dependent, NO synthase–independent, and cyclooxygenase-independent pathway. Bradykinin-stimulated tPA release may represent a marker for the endothelial effects of endothelium-derived hyperpolarizing factor.
Key Words: bradykinin • endothelium • endothelium-derived factors • nitric oxide synthase • plasminogen activators
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