title: Bradykinin receptor antagonism and endothelial tissue plasminogen activator release in humans.
abstract: OBJECTIVE
  We sought to assess pharmacodynamic responses to the bradykinin antagonist B9340 and to determine the contribution of the endothelial bradykinin receptor to stimulated tissue plasminogen activator (t-PA) release in humans.
  
  
  RESULTS
  Bilateral forearm blood flow and plasma fibrinolytic variables were measured in 8 volunteers during 100 minutes of intrabrachial infusions of saline placebo, B9340 at 4.5 nmol/min, or B9340 at 13.5 nmol/min. On each occasion, intra-arterial bradykinin (30 to 3000 pmol/min) and substance P (4 to 16 pmol/min) were coinfused for 10 minutes at each dose. To assess the onset and offset of action, 6 additional subjects on 2 occasions received intra-arterial bradykinin (100 pmol/min) for 60 minutes with a coinfusion of either saline placebo or B9340 (13.5 nmol/min) for 12 minutes. During placebo infusion, bradykinin and substance P caused dose-dependent vasodilatation in the infused forearm (P<0.001). B9340 caused a dose-dependent inhibition of bradykinin-induced forearm vasodilatation and t-PA release (P<0.001) without affecting substance P-induced vasodilatation or t-PA release (P=NS). B9340 caused a reversible inhibition of bradykinin-induced vasodilatation (P<0.001) with a rapid onset and offset of action.
  
  
  CONCLUSIONS
  B9340 is a potent, reversible, and selective competitive receptor antagonist of bradykinin-induced vasodilatation and t-PA release in humans.
authors.affiliation: Cardiovascular Research, University of Edinburgh, University of Edinburgh, Royal Infirmary of Edinburgh, UK.
authors.forename: Fraser N
authors.initials: FN
authors.lastname: Witherow
authors.forename: Pamela
authors.initials: P
authors.lastname: Dawson
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ludlam
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000328:Adult; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D012039:Regional Blood Flow / Q000187:drug effects; D012107:Research Design; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
chemical_list: C098525:B 9340; D065168:Bradykinin Receptor Antagonists; D010959:Tissue Plasminogen Activator; D001920:Bradykinin