Endothelium-Derived Hyperpolarizing Factor Mediates Bradykinin-Stimulated Tissue Plasminogen Activator Release in Humans

• Authors: Ayaz M. Rahman, Emory University; Jonathan Murrow, Emory University; Muhiddin A. Ozkor, Emory University; Nino Kavtaradze, Emory University; Ji Lin, Emory University; Christine De Staercke, Ctr Dis Control & Prevent; W. Craig Hooper, Ctr Dis Control & Prevent; Amita Manatunga, Emory University; Salim Hayek, Emory University; Arshed Quyyumi, Emory University
• Journal Title: Journal of Vascular Research
• Volume: Volume 51, Number 3
• Publisher: Karger Publishers | 2014-01-01, Pages 200-208
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1159/000362666
• Subjects: Health Sciences, General; Health Sciences, Public Health
• Keywords: Science & Technology; Life Sciences & Biomedicine; Physiology; Peripheral Vascular Disease; Cardiovascular System & Cardiology; Bradykinin; Endothelium; Endothelium-derived hyperpolarizing factors; Fibrinolysis; Tissue plasminogen activator; CORONARY-ARTERIES; HUMAN FOREARM; EPOXYEICOSATRIENOIC ACIDS; DEPENDENT HYPERPOLARIZATION; CYTOCHROME P4502C9; TETRAETHYLAMMONIUM IONS; MYOCARDIAL-INFARCTION; POTASSIUM CHANNELS; CIGARETTE-SMOKING; HYDROGEN-PEROXIDE

Abstract

Bradykinin (BK) stimulates tissue plasminogen activator (t-PA) release from human endothelium. Although BK stimulates both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) release, the role of EDHF in t-PA release remains unexplored. This study sought to determine the mechanisms of BK-stimulated t-PA release in the forearm vasculature of healthy human subjects. Methods: In 33 healthy subjects (age 40.3 ± 1.9 years), forearm blood flow (FBF) and t-PA release were measured at rest and after intra-arterial infusions of BK (400 ng/min) and sodium nitroprusside (3.2 mg/min). Measurements were repeated after intra-arterial infusion of tetraethylammonium chloride (TEA; 1 μmol/min), fluconazole (0.4 μmol·min^-1·l^-1), and N^G-monomethyl-L-arginine (L-NMMA, 8 μmol/min) to block nitric oxide, and their combination in separate studies. Results: BK significantly increased net t-PA release across the forearm (p < 0.0001). Fluconazole attenuated both BK-mediated vasodilation (-23.3 ± 2.7% FBF, p < 0.0001) and t-PA release (from 50.9 ± 9.0 to 21.3 ± 8.9 ng/min/100 ml, p = 0.02). TEA attenuated FBF (-14.7 ± 3.2%, p = 0.002) and abolished BK-stimulated t-PA release (from 22.9 ± 5.7 to -0.8 ± 3.6 ng/min/100 ml, p = 0.0002). L-NMMA attenuated FBF (p < 0.0001), but did not inhibit BK-induced t-PA release (nonsignificant). Conclusion: BK-stimulated t-PA release is partly due to cytochrome P<inf>450</inf>-derived epoxides and is inhibited by K⁺<inf>Ca</inf> channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.