on March 6, 2003
Published online before print March 6, 2003, doi: 10.1161/01.ATV.0000065195.22904.FA
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Submitted on January 2, 2003
Accepted on January 28, 2003
Intra-Arterial Tumor Necrosis Factor-
Impairs Endothelium-Dependent Vasodilatation and Stimulates Local Tissue Plasminogen Activator Release in Humans
Stanley Chia ;
From the Departments of Cardiovascular Research and Haematology (C.A.L.), University of Edinburgh, Royal Infirmary of Edinburgh, Scotland, UK.
* To whom correspondence should be addressed. 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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