THE RELATIONSHIPS AMONG NITRIC-OXIDE PRODUCTION, BACTERIAL TRANSLOCATION, AND INTESTINAL INJURY AFTER ENDOTOXIN CHALLENGE IN-VIVO

Background: This study examines the hypothesis that there is a relatio nship among endotoxin-induced bacterial translocation (BT) and increas ed nitric oxide (NO) production and that inhibition of excessive NO pr oduction with N-G-monomethyl-L-arginine (L-NMMA) is beneficial. Method s: Rats received 0, 1, or 4 mg/kg endotoxin intraperitoneally, and 6 o r 18 hours later, they were killed and BT, NO production (as reflected in nitrite/nitrate levels), and calcium-dependent nitric oxide syntha se and calcium-independent nitric oxide synthase (iNOS) activities wer e measured in tissues (ileum, liver, and mesenteric lymph nodes) and b lood, In a second set of experiments, the animals received the NOS inh ibitor L-NMMA (100 mg/kg) intravenously either 15 minutes before or 2 hours after endotoxin challenge (4 mg/kg) and the same parameters were measured. Results: The incidence of BT was higher in rats receiving 4 mg/kg endotoxin (62.5%) than in the control group (0%, p < 0.05), and the 1 mg/kg endotoxin group had intermediate incidence (25%), The ani mals receiving 4 mg/kg endotoxin had higher tissue (mesenteric lymph n odes, liver) and blood nitrite/ nitrate levels than the control or 1 m g/kg endotoxin groups, The increased NO production was mainly attribut able to an elevated level of iNOS activity, The administration of L-NM MA before but not after endotoxin challenge reduced iNOS activity, NO production, and BT to control levels at 6 hours but not 18 hours after endotoxin administration. Conclusion: Endotoxin-induced mucosal injur y and BT are associated with iNOS activity and increased NO production , Inhibition of iNOS activity with L-NMMA before treatment prevented e ndotoxin-induced heal mucosal injury and BT.