title: Molsidomine increases endotoxic survival and decreases cytokine production.
abstract: 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.
authors.affiliation: Department of Surgery, University of Illinois at Chicago 60012, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Kumins
authors.forename: J
authors.initials: J
authors.lastname: Hunt
authors.forename: R L
authors.initials: RL
authors.lastname: Gamelli
authors.forename: J P
authors.initials: JP
authors.lastname: Filkins
mesh_terms: 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
chemical_list: D016207:Cytokines; D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008981:Molsidomine