title: Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga., USA.
authors.forename: Ayaz M
authors.initials: AM
authors.lastname: Rahman
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Murrow
authors.forename: Muhiddin A
authors.initials: MA
authors.lastname: Ozkor
authors.forename: Nino
authors.initials: N
authors.lastname: Kavtaradze
authors.forename: Ji
authors.initials: J
authors.lastname: Lin
authors.forename: Christine
authors.initials: C
authors.lastname: De Staercke
authors.forename: W Craig
authors.initials: WC
authors.lastname: Hooper
authors.forename: Amita
authors.initials: A
authors.lastname: Manatunga
authors.forename: Salim
authors.initials: S
authors.lastname: Hayek
authors.forename: Arshed A
authors.initials: AA
authors.lastname: Quyyumi
mesh_terms: D000328:Adult; D001685:Biological Factors / Q000502:physiology*; D001920:Bradykinin / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D015725:Fluconazole / Q000494:pharmacology; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D019789:Tetraethylammonium / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D024681:Potassium Channels, Calcium-Activated; C067410:endothelium-dependent hyperpolarization factor; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D019789:Tetraethylammonium; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D010959:Tissue Plasminogen Activator; D001920:Bradykinin