Related Experiment Videos
Inhibition of nitric oxide synthase induces intestinal mucosal damage and increases mortality in rats treated by
1Department of Urology, Yamanashi Medical University, Japan. wangl@res.yamanashi-med.ac.jp
Introduction:
Despite the beneficial immunosuppressive effects of FK506 during small intestine transplantation, FK506 appears to have direct toxic effects on the intestine. The mechanisms of FK506-induced intestinal damage is unclear, and whether nitric oxide (NO) is involved in the mechanism has not been well defined. This study was designed to evaluate the effects of NG-Nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, on small intestinal damage in rats treated with FK506.
Materials And Methods:
Wistar rats weighing 240-260 g, aged 11 weeks, were administered FK506 (5 mg/kg/day i.m) and/or L-NAME (5 mg/dl in drinking water) for 10 days. Body weight gain, diarrhoea and mortality were observed during experiment. At the end of experiment, the intestinal specimens were excised for histological evaluation. In addition, the effects of L-aginine treatment (1 g/dl in drinking water) were evaluated in this study.
Results:
L-NAME administration time-dependently induced diarrhoea and high mortality in the rats treated with FK506. At the end of 10 days treatment, 7 of 12 rats (58.3%) suffered from diarrhoea and 5 of 12 rats (41.7%) died in the FK506 + L-NAME group (vs. FK506 group, p = 0.05). A significant loss of body weight was also found in the rats treated with FK506 + L-NAME (-52.2 +/- 28.8 g, in FK506 + L-NAME group vs. -14.3 +/- 8.7 g in FK506 group, p = 0.001). In parallel with the severe diarrhoea and high mortality, the loss of villi, hemorrhage and necrosis (grade 5 of pathological damage) was seen in the small intestinal mucosa of rats treated with FK506 + L-NAME. L-arginine treatment in part prevented diarrhoea, mortality and pathological damage of small intestinal mucosa induced by L-NAME.
Conclusions:
Inhibition of NOS induces intestinal mucosal damage and increases mortality in rats treated with FK506. L-arginine treatment can in part prevent the injury induced L-NAME. The present study suggests that NO, as an important protective factor, may be involved in the FK506-induced intestinal damage.
Insights
Inhibition of nitric oxide synthase (NOS) worsens FK506-induced intestinal damage and mortality in rats. Supplementation with L-arginine partially protected against these adverse effects, suggesting nitric oxide (NO) is protective.
Area of Science:
- Gastroenterology
- Pharmacology
- Transplantation Immunology
Background:
- FK506 is crucial for immunosuppression in small intestine transplantation but can cause direct intestinal toxicity.
- The precise mechanisms of FK506-induced intestinal damage remain unclear, with the role of nitric oxide (NO) not well-defined.
Purpose of the Study:
- To investigate the impact of inhibiting NO synthase using NG-Nitro-L-arginine methyl ester (L-NAME) on FK506-induced intestinal damage in a rat model.
- To assess the potential protective effects of L-arginine supplementation.
Main Methods:
- Wistar rats received FK506 and/or L-NAME for 10 days, with observations on body weight, diarrhea, and mortality.
- Intestinal tissues were histologically evaluated, and the effects of L-arginine were assessed.
Main Results:
- L-NAME administration significantly increased diarrhea and mortality in FK506-treated rats.
- FK506 + L-NAME group exhibited severe weight loss, villous loss, hemorrhage, and necrosis in the small intestinal mucosa.
- L-arginine treatment partially mitigated the diarrhea, mortality, and histological damage.
Conclusions:
- Inhibition of NO synthase exacerbates FK506-induced intestinal injury and mortality.
- Nitric oxide (NO) appears to play a protective role in FK506-induced intestinal damage.
- L-arginine demonstrates partial protective effects against L-NAME-induced injury.