Intra-arterial tumor necrosis factor-alpha impairs endothelium-dependent vasodilatation and stimulates local tissue plasminogen activator release in humans.
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.
Chia
Stanley
S
Department of Cardiology, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK.
Qadan
Motaz
M
Newton
Richard
R
Ludlam
Christopher A
CA
Fox
Keith A A
KA
Newby
David E
DE
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*
D004731:Endotoxins; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009599:Nitroprusside; D010959:Tissue Plasminogen Activator; D000109:Acetylcholine; D001920:Bradykinin