Intra-arterial tumor necrosis factor-alpha impairs endothelium-dependent vasodilatation and stimulates local tissue plasminogen activator release in humans

Stanley Chia, Motaz Qadan, Richard Newton, Christopher A Ludlam, Keith A A Fox, David E Newby

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

METHODS AND 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.

Original languageEnglish
Pages (from-to)695-701
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume23
Issue number4
DOIs
Publication statusPublished - 1 Apr 2003

Keywords / Materials (for Non-textual outputs)

  • Acetylcholine
  • Adult
  • Brachial Artery
  • Bradykinin
  • Double-Blind Method
  • Endothelium, Vascular
  • Endotoxins
  • Fibrinolysis
  • Humans
  • Injections, Intra-Arterial
  • Interleukin-6
  • Male
  • Nitroprusside
  • Plethysmography
  • Tissue Plasminogen Activator
  • Tumor Necrosis Factor-alpha
  • Vasculitis
  • Vasodilation

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