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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 publication




Journal article


Arterioscler thromb vasc biol

Publication Date





695 - 701


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