MOLSIDOMINE INCREASES ENDOTOXIC SURVIVAL AND DECREASES CYTOKINE PRODUCTION

We hypothesized that nitric oxide (NO) may exert feedback regulatory c ontrol over cytokine production and improve survival in endotoxin (ETX ) shock. To test this hypothesis, we evaluated the pre-endotoxin effec t of the NO donor molsidomine (MOL) on circulating tumor necrosis fact or (TNF), interleukin (II)-1, and IL-6 levels, the production of these cytokines in the perfused liver, and endotoxic lethality in mice. Mal e 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 mt or SAL, for either the determination of plasma cytokine level s by enzyme-linked immunosorbent assays or for use in the perfused liv er assessment of cytokine production. MOL treatment significantly redu ced the post-ETX circulating levels of TNF to 84%, IL-l 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-l, and 54 % less IL-6 over a 2 h perfusion, as compared with SAL-treated ETX con trols. 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.