Molsidomine increases endotoxic survival and decreases cytokine production.
We hypothesized that nitric oxide (NO) may exert feedback regulatory control over cytokine production and improve survival in endotoxin (ETX) shock. To test this hypothesis, we evaluated the pre-endotoxin effect of the NO donor molsidomine (MOL) on circulating tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6 levels, the production of these cytokines in the perfused liver, and endotoxic lethality in mice. Male BDF mice weighing 28-32 g were administered either 100 mg/kg MOL or saline (SAL) i.p. Thirty minutes later, the mice received either 50 mg/kg Salmonella enteriditis ETX or SAL i.p. Mice were killed at 90 min after ETX or SAL, for either the determination of plasma cytokine levels by enzyme-linked immunosorbent assays or for use in the perfused liver assessment of cytokine production. MOL treatment significantly reduced the post-ETX circulating levels of TNF to 84%, IL-1 to 65%, and IL-6 to 56%, as compared with SAL-treated ETX controls. Endotoxic livers from MOL-pretreated mice produced 82% less TNF, 88% less IL-1, and 54% less IL-6 over a 2 h perfusion, as compared with SAL-treated ETX controls. MOL pretreatment also decreased lethality in ETX shock from 90 to 50% (p < .05). Therefore, NO may provide a beneficial effect during sepsis by inhibiting hepatic cytokine production, and thus providing survival benefits.
Kumins
N H
NH
Department of Surgery, University of Illinois at Chicago 60012, USA.
Hunt
J
J
Gamelli
R L
RL
Filkins
J P
JP
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000008:administration & dosage / Q000633:toxicity; D007375:Interleukin-1 / Q000097:blood / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008981:Molsidomine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000494:pharmacology; D012772:Shock, Septic / Q000503:physiopathology*; D013534:Survival / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008981:Molsidomine