Bradykinin Stimulates Tissue Plasminogen Activator Release From Human Forearm Vasculature Through B 2 Receptor–Dependent, NO Synthase–Independent, and Cyclooxygenase-Independent Pathway

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Abstract
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 F1α (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.