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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:695.)
© 2003 American Heart Association, Inc.

Thrombosis

Intra-Arterial Tumor Necrosis Factor- 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

From the Departments of Cardiovascular Research and Haematology (C.A.L.), University of Edinburgh, Royal Infirmary of Edinburgh, Scotland, UK.

Correspondence to Dr D.E. Newby, Cardiovascular Research, Department of Cardiology, Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh EH3 9YW, Scotland, UK. E-mail d.e.newby{at}ed.ac.uk

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- (TNF-), 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-, interleukin-6, and endotoxin infusions, and 8 additional subjects received intrabrachial infusions of bradykinin, acetylcholine, and sodium nitroprusside after pretreatment with TNF-. TNF- but not interleukin-6, endotoxin, or placebo caused a gradual and sustained 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- 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- 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- has potentially both adverse vasomotor and beneficial profibrinolytic effects on endothelial function.

Key Words: cytokines • endothelium • fibrinolysis • inflammation • vasodilatation

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