Inhibition of nitric oxide synthase induces intestinal mucosal damage and increases mortality in rats treated by FK506.
BACKGROUND
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.


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.
Wang
M
M
Department of Urology, Yamanashi Medical University, Japan. wangl@res.yamanashi-med.ac.jp
Kubodera
S
S
Araki
I
I
Takihana
Y
Y
Ueno
A
A
Takeda
M
M
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced / Q000473:pathology; D004326:Drinking; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D007273:Injections, Intramuscular; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007583:Jejunum / Q000187:drug effects* / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D016559:Tacrolimus