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

• Type of Material: Article
• 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
• Language: English
• Date: 2014-01-01
• Publisher: Karger Publishers
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 S. Karger AG, Basel.
• Final Published Version (URL): http://dx.doi.org/10.1159/000362666
• Title of Journal or Parent Work: Journal of Vascular Research
• ISSN: 1018-1172
• Volume: 51
• Issue: 3
• Start Page: 200
• End Page: 208
• Grant/Funding Information: National Institutes of Health Research Grant RO1 HL79115, and in part by PHS Grant UL1 RR025008 from the Clinical and Translational Science Award Program, and PHS Grant M01 RR00039 from the General Clinical Research Center program, National Institutes of Health, National Center for Research Resources, the British Cardiovascular Society Research Fellowship, National Blood Foundation, NIH NRSA T32 Training Grant, American College of Cardiology Foundation Keating Fellowship, and the American Heart Association Beginning Grant-in-Aid
• Keywords: Bradykinin; Cardiovascular System & Cardiology; Endothelium-derived hyperpolarizing factors; POTASSIUM CHANNELS; EPOXYEICOSATRIENOIC ACIDS; CYTOCHROME P4502C9; CORONARY-ARTERIES; Peripheral Vascular Disease; Fibrinolysis; HUMAN FOREARM; Life Sciences & Biomedicine; DEPENDENT HYPERPOLARIZATION; CIGARETTE-SMOKING; Science & Technology; Physiology; TETRAETHYLAMMONIUM IONS; MYOCARDIAL-INFARCTION; Tissue plasminogen activator; Endothelium; HYDROGEN-PEROXIDE
• Research Categories: Health Sciences, Public Health; Health Sciences, General

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.