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Author Notes:

Corresponding Author: Arshed A. Quyyumi, MD, FRCP Professor of Medicine Emory University School of Medicine 1462 Clifton Rd. NE, Suite F506 Atlanta, GA 30322 Tel: (404) 727-3655 Fax: (404) 712-8785 aquyyum@emory.edu.

Disclosures: none.

Subjects:

Research Funding:

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:

  • 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

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

Tools:

Journal Title:

Journal of Vascular Research

Volume:

Volume 51, Number 3

Publisher:

, Pages 200-208

Type of Work:

Article | Post-print: After Peer Review

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<sup>-1</sup>·l<sup>-1</sup>), and N<sup>G</sup>-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<sup>+</sup><inf>Ca</inf> channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.

Copyright information:

© 2014 S. Karger AG, Basel.

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