Abstract 17825: Endothelium-Derived Hyperpolarizing Factor Mediates Bradykinin Stimulated Tissue Plasminogen Activator Release In the Human Forearm Vasculature
Background: Bradykinin stimulates vasodilation and tissue plasminogen activator (tPA) release from the human endothelium. Although bradykinin vasodilates by releasing both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF), the role of EDHF in tPA release remains unexplored. Tetraethylammonium chloride (TEA) was employed to inhibit K+ca channels and fluconazole to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis, both known EDHF pathways. We hypothesized that EDHF mediates bradykinin-stimulated tPA release.
Methods: In 34 healthy subjects (age 40.3±11 years, 62% male) forearm blood flow (FBF) and net tPA release (arterio-venous difference) was measured at rest, and after intra-arterial infusions of bradykinin (400ng/min) and sodium nitroprusside (3.2 mg/min). Measurements were repeated after intra-arterial infusion of TEA (1 μmol/min), fluconazole (0.4 μmol.min−1.L−1), and NG-monomethyl-L-arginine (L-NMMA, 8 μmol/min) to block nitric oxide, and their combination in separate studies.
Results: Bradykinin significantly increased net tPA release across the forearm (63-fold increase, P<0.0001). Fluconazole partly attenuated both the bradykinin-mediated vasodilation (−23.3±2.7% FBF, P<0.0001) and tPA release (from 50.9±9.0 to 21.3±8.9 ng/min/100ml, P=0.001). TEA attenuated FBF (−14.4±3.1%, P=0.002) and abolished bradykinin-stimulated tPA release (from 25.3±5.9 to −5.5±5.8 ng/min/100ml, P=0.01). L-NMMA attenuated FBF (−19.6±5.7%, P<0.0001), but did not inhibit bradykinin-induced tPA release (18.8±8.6 ng/min/100ml, P=0.17). Net tPA release was not affected by sodium nitroprusside.
Conclusions: Bradykinin-stimulated tPA release is partly due to cytochrome P450-derived epoxides, and is completely inhibited by K+ca channel blockade. Thus, bradykinin stimulates both EDHF-dependent vasodilation and tPA release. Abnormalities in the EDHF signaling pathway may contribute to both abnormal vasodilation and increased thrombotic risk, and needs to be further studied.
- © 2010 by American Heart Association, Inc.