Effects of nitric oxide synthase inhibition on intestinal damage in rats with experimental necrotizing enterocolitis.

In the inflamed intestinal mucosa of necrotizing enterocolitis (NEC), nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) may contribute to the pathogenesis of local intestinal damage. To study the importance of iNOS for the pathogenesis of NEC, the effects of selective (aminoguanidine, AG) and nonselective (L-nitroarginine methyl ester, L-NAME) iNOS inhibitors on intestinal morphologic changes were assessed in neonatal rats with experimental NEC. The neonatal rats were randomized into one of the five treatment groups. The control group consisted of rats that were breast-fed. The NEC group, consisting of neonates separated from their mothers, were gavaged with a special rodent formula to produce NEC. Rats in the sham, the AG, and the L-NAME groups were gavaged in a similar fashion to those in the NEC group; in addition, they were treated with 0.9 % saline, 10 mg/kg/day AG, and 10 mg/kg/day L-NAME, respectively. The rats were sacrificed on day 4, and the last 4 cm of terminal ileum was harvested for morphological studies and detection of nitrite and nitrate levels in tissue. The animals in the NEC and sham groups showed various degrees of intestinal inflammatory changes and increased tissue levels of nitrite and nitrate compared to those in the control group. Both AG and L-NAME treatment decreased the tissue levels of these nitrogen oxides, but the inflammatory changes of the intestine appeared to be attenuated only in the AG treated animals. L-NAME treatment did not improve the intestinal damage and increased mortality. These results may indicate that NO synthesized by iNOS plays a pathogenic role in formula-fed induced NEC and that inhibition of iNOS improves intestinal inflammatory damage.