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 Citations (Scopus)

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

Fingerprint

Bradykinin
Tissue Plasminogen Activator
Endothelium
Forearm
omega-N-Methylarginine
Intra Arterial Infusions
Fluconazole
Vasodilation
Healthy Volunteers
Nitric Oxide
Tetraethylammonium
Epoxy Compounds
Nitroprusside
Cytochrome P-450 Enzyme System

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans. / Rahman, Ayaz M.; Murrow, Jonathan R; Ozkor, Muhiddin A.; Kavtaradze, Nino; Lin, Ji; De Staercke, Christine; Hooper, W. Craig; Manatunga, Amita; Hayek, Salim; Quyyumi, Arshed A.

In: Journal of Vascular Research, Vol. 51, No. 3, 01.01.2014, p. 200-208.

Research output: Contribution to journalArticle

Rahman, AM, Murrow, JR, Ozkor, MA, Kavtaradze, N, Lin, J, De Staercke, C, Hooper, WC, Manatunga, A, Hayek, S & Quyyumi, AA 2014, 'Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans', Journal of Vascular Research, vol. 51, no. 3, pp. 200-208. https://doi.org/10.1159/000362666
Rahman, Ayaz M. ; Murrow, Jonathan R ; Ozkor, Muhiddin A. ; Kavtaradze, Nino ; Lin, Ji ; De Staercke, Christine ; Hooper, W. Craig ; Manatunga, Amita ; Hayek, Salim ; Quyyumi, Arshed A. / Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans. In: Journal of Vascular Research. 2014 ; Vol. 51, No. 3. pp. 200-208.
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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.",
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T1 - Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans

AU - Rahman, Ayaz M.

AU - Murrow, Jonathan R

AU - Ozkor, Muhiddin A.

AU - Kavtaradze, Nino

AU - Lin, Ji

AU - De Staercke, Christine

AU - Hooper, W. Craig

AU - Manatunga, Amita

AU - Hayek, Salim

AU - Quyyumi, Arshed A.

PY - 2014/1/1

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N2 - 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.

AB - 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.

KW - Bradykinin

KW - Endothelium

KW - Endothelium-derived hyperpolarizing factors

KW - Fibrinolysis

KW - Tissue plasminogen activator

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