LPS activates inducible NOS (iNOS) expression in the intestine and enhances the production of NO. Endogenous NO has been shown to protect against LPS-induced bowel injury. This study aims to examine the effects of NO donors and NOS inhibitors on LPS-induced shock and bowel injury. Anesthetized adult S.D. rats were injected with LPS (5mg/kg, iv) and the small bowel was removed at 30min or 2h to assess injury. Blood pressure (BP), hematocrit (Hct) and white blood cell (WBC) count were also obtained at baseline and at the the end of the experiment. Some animals were pretreated with one of the following drugs: SMT (S-methylisothiourea, a selective iNOS inhibitor, 4mg/kg, iv), L-NAME (NG-nitro-L-arginine methyl ester, a nonselective NOS inhibitor, 2.5mg/kg, iv), or SIN-1 (3-morpholinosydnonimine, an NO donor, 1mg/kg, iv). Each group had positive and negative controls. We found that LPS at 30min suppressed NOS activity. At 2h, LPS induced iNOS and increased NOS activity. iNOS and NOS inhibitors alone (without LPS) caused an elevation in BP but had no effect on WBC or Hct and caused no bowel injury. NO donor alone (without LPS) caused hypotension and leukopenia as compared to sham operated animals. It had no effect on Hct and did not cause intestinal injury. LPS induced hypotension, leukopenia and hemoconcentration with mild to moderate intestinal injury at 30min. These parameters were all worse at 2h including more severe intestinal injury. At 30min iNOS and NOS inhibitors had no effect on BP, HCT, or WBC, but aggravated intestinal injury. At 2h, iNOS and NOS inhibitors improved the BP, compared to LPS treated animals. However, they had no beneficial effect on intestinal injury. The NO donor at both time points improved Hct and protected against intestinal injury. At 2h the animals pretreated with NO donor had significant recovery of their BP. We conclude that NOS inhibitors aggravate LPS effect at 30min. At 2h NOS inhibitors improved LPS induced hypotension, but failed to ameliorate (and sometimes aggravated) intestinal injury. NO donors protected against LPS-induced shock and small intestinal injury.
