Prolonged exposure of rat aorta to low levels of endotoxin in vitro results in impaired contractility. Association with vascular cytokine release.
Treatment of volunteers or animals with endotoxin in vivo results in reduced vascular reactivity to catecholamines. Endotoxin also causes liberation of the vasoactive cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF) from vascular smooth muscle and endothelial cells in culture. This study tested whether defects in contractility could be induced in isolated vascular tissue by prolonged exposure to endotoxin (1-100 ng/ml) in vitro, and whether IL-1 and TNF release by blood vessels is altered during the establishment of endotoxin induced contractile dysfunction. A concentration of endotoxin as low as 1 ng/ml suppressed contractions to norepinephrine (NE) and KCl; aortic sensitivity to NE also decreased. The presence of serum constituents or an intact endothelium were not necessary for endotoxin-induced vascular suppression. Aortas incubated with endotoxin liberated IL-1 and TNF in a dose-dependent fashion. The addition of dexamethasone or indomethacin during the incubations generally suppressed release of the cytokines and improved tissue reactivity to NE. The endotoxin-induced diminished vascular contraction and augmented IL-1 and TNF liberation required de novo protein synthesis; tissue incubated with endotoxin plus actinomycin D was completely shielded from the influence of endotoxin on vascular reactivity to NE. The association between endotoxin-induced vascular cytokine release and diminished contraction suggests a possible role for cytokines derived from the vasculature in the regulation of contractile function.
McKenna
T M
TM
Casualty Care Research Department, Naval Medical Research Institute, Bethesda, Maryland 20814.
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D004731:Endotoxins / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D008855:Microscopy, Electron, Scanning; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
D004731:Endotoxins; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D003907:Dexamethasone; D009638:Norepinephrine; D007213:Indomethacin