Nitric oxide synthase inhibitor ameliorates oral total parenteral nutrition-induced barrier dysfunction

The expression of inducible nitric oxide synthase (iNOS) is increased in th e intestine and results in mucosal damage after endotoxin challenge. Althou gh the oral administration of total parenteral nutrition (TPN) solution pro motes bacterial translocation (BT) and increases the intestinal permeabilit y, the role of NO in the nutrition-induced loss of mucosal barrier function remains unclear. The distribution of fluorescein isothiocyanate-dextran (F ITC-dextran, 4400) across the lumen of small intestine in rat was examined to investigate the role of NOS activity on the intestinal permeability unde r oral TPN feeding. Fifty-one rats were randomly divided into 4 groups. Gro up I (control group) was fed with rat chow, group II received TPN solution orally. Groups III and IV received TPN solution supplemented with NOS inhib itors. On day 9, FITC-dextran was injected into the intestinal lumen. After 30 min, blood samples were taken from portal vein and analyzed for plasma FITC-dextran level by fluorescence spectrophotometry. Samples of small inte stine were frozen and sectioned in a cryostat for morphological and NOS his tochemical studies. Homogenates of small intestine were used for NOS activi ty measurement. The plasma level of FITC-dextran showed a significant incre ase (P < 0.05) in rats fed with oral TPN compared with the control ones. Su pplement with NOS inhibitors significantly decreased the intestinal permeab ility in groups III and IV compared with group II. Similarly, the total NOS activities showed a significant 2-fold increase (Pi 0.05) in group II, and NOS inhibitors decreased the elevated NOS activity. These data suggest tha t oral TPN feeding for 9 days leads to an increase in permeability to dextr an and the total NOS activity of small intestine, and both induction of the intestinal permeability and NOS activity were inhibited by treatment with NOS inhibitors. Addition of S-methylisothiourea (SMT), an iNOS selective in hibitor, profoundly inhibited 66% of the induced iNOS activity (P < 0.05) a nd reduced 74% of the diet-induced increase in intestinal permeability (P < 0.05) in group II. The induced permeability change in rats receiving oral TPN is mainly due to the activity of intestinal mucosal iNOS. The induction of iNOS is an important mediator for intestinal barrier dysfunction. Admin istration of SMT, which specifically decreases iNOS activity, is useful in the prevention of diet-induced barrier failure.