title: Intra-arterial tumor necrosis factor-alpha impairs endothelium-dependent vasodilatation and stimulates local tissue plasminogen activator release in humans.
abstract: OBJECTIVE
  Inflammation contributes to the pathogenesis of cardiovascular disease, potentially through the actions of proinflammatory cytokines. We assessed the direct effects of local intra-arterial tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and endotoxin on blood flow and endogenous tissue plasminogen activator (t-PA) release in vivo in humans.
  
  
  RESULTS
  In a double-blind, randomized, placebo-controlled trial, blood flow, plasma cytokine, and fibrinolytic parameters were measured using venous occlusion plethysmography and blood sampling. Ten subjects received intrabrachial TNF-alpha, interleukin-6, and endotoxin infusions, and 8 additional subjects received intrabrachial infusions of bradykinin, acetylcholine, and sodium nitroprusside after pretreatment with TNF-alpha. TNF-alpha but not interleukin-6, endotoxin, or placebo caused a gradual and sustained approximately 20-fold increase in plasma t-PA concentrations (P<0.001) that was associated with elevated plasma interleukin-6 concentrations (P<0.05) but without an effect on blood flow or plasminogen activator inhibitor type 1 antigen. Compared with placebo, TNF-alpha pretreatment impaired bradykinin- and acetylcholine-induced vasodilatation (P<0.03) and resulted in a doubling of bradykinin-induced t-PA release (P<0.05).
  
  
  CONCLUSIONS
  Intra-arterial TNF-alpha causes an acute local vascular inflammation that is associated with impaired endothelium-dependent vasomotion as well as a sustained and substantial increase in endothelial t-PA release. TNF-alpha has potentially both adverse vasomotor and beneficial profibrinolytic effects on endothelial function.
authors.affiliation: Department of Cardiology, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Stanley
authors.initials: S
authors.lastname: Chia
authors.forename: Motaz
authors.initials: M
authors.lastname: Qadan
authors.forename: Richard
authors.initials: R
authors.lastname: Newton
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ludlam
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000328:Adult; D001916:Brachial Artery; D001920:Bradykinin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D007269:Injections, Intra-Arterial; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009599:Nitroprusside / Q000008:administration & dosage / Q000494:pharmacology; D010991:Plethysmography; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D014657:Vasculitis / Q000139:chemically induced* / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D004731:Endotoxins; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009599:Nitroprusside; D010959:Tissue Plasminogen Activator; D000109:Acetylcholine; D001920:Bradykinin