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

Abstract

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. 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 B 2 receptor antagonist HOE 140 (100 μg/kg IV), (2) the NO synthase inhibitor l - N G -monomethyl- l -arginine (L-NMMA, 4 μmol/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 1α ( 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.