Bradykinin stimulates tissue plasminogen activator release from human forearm vasculature through B(2) receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway.
BACKGROUND
Bradykinin stimulates dose-dependent tissue plasminogen activator (tPA) release from human endothelium. Although bradykinin is known to cause vasodilation through B(2) receptor-dependent effects on NO, prostacyclin, and endothelium-derived hyperpolarizing factor production, the mechanism(s) underlying tPA release is unknown.


RESULTS
We measured the effects of intra-arterial bradykinin (100, 200, and 400 ng/min), acetylcholine (15, 30, and 60 microg/min), and nitroprusside (0.8, 1.6, and 3.2 microg/min) on forearm vasodilation and tPA release in healthy volunteers in the presence and absence of (1) the B(2) receptor antagonist HOE 140 (100 microg/kg IV), (2) the NO synthase inhibitor L-N:(G)-monomethyl-L-arginine (L-NMMA, 4 micromol/min intra-arterially), and (3) the cyclooxygenase inhibitor indomethacin (50 mg PO TID). B(2) 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 F(1alpha) (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 B(2) 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.
Brown
N J
NJ
Department of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
Gainer
J V
JV
Murphey
L J
LJ
Vaughan
D E
DE
D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives* / Q000652:urine; D000109:Acetylcholine / Q000008:administration & dosage; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage; D000328:Adult; D001920:Bradykinin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D065168:Bradykinin Receptor Antagonists; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage; D007261:Infusions, Intra-Arterial; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000008:administration & dosage; D010991:Plethysmography; D043782:Receptor, Bradykinin B2; D012039:Regional Blood Flow / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage; D019323:omega-N-Methylarginine / Q000008:administration & dosage
D000319:Adrenergic beta-Antagonists; D065168:Bradykinin Receptor Antagonists; D016861:Cyclooxygenase Inhibitors; D043782:Receptor, Bradykinin B2; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D015121:6-Ketoprostaglandin F1 alpha; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; C065679:icatibant; D019001:Nitric Oxide Synthase; D010959:Tissue Plasminogen Activator; D000109:Acetylcholine; D001920:Bradykinin; D007213:Indomethacin