Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans

Ayaz M. Rahman, Jonathan R. Murrow, Muhiddin A. Ozkor, Nino Kavtaradze, Ji Lin, Christine De Staercke, W. Craig Hooper, Amita Manatunga, Salim Hayek, Arshed A. Quyyumi

Research output: Contribution to journalArticle

6 Scopus citations

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 NG-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 P450-derived epoxides and is inhibited by K+Ca channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.

Original languageEnglish (US)
Pages (from-to)200-208
Number of pages9
JournalJournal of Vascular Research
Volume51
Issue number3
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Keywords

  • Bradykinin
  • Endothelium
  • Endothelium-derived hyperpolarizing factors
  • Fibrinolysis
  • Tissue plasminogen activator

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Rahman, A. M., Murrow, J. R., Ozkor, M. A., Kavtaradze, N., Lin, J., De Staercke, C., Hooper, W. C., Manatunga, A., Hayek, S., & Quyyumi, A. A. (2014). Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans. Journal of Vascular Research, 51(3), 200-208. https://doi.org/10.1159/000362666