Expression of inducible nitric oxide synthase and effects of L-arginine on colonic nitric oxide production and fluid transport in patients with "minimal colitis".
OBJECTIVE
Some patients with idiopathic, chronic diarrhoea have minimal, non-specific colonic inflammation. As nitric oxide (NO) acts as a secretagogue in the colon, we studied the expression of inducible NO synthase (iNOS) in mucosal biopsies and the effects of NOS stimulation on colonic transfer of fluid and output of NO in patients with "minimal colitis".


METHODS
Twelve patients with idiopathic, chronic diarrhoea and "minimal colitis" and 6 healthy volunteers were included in the study. Expression of iNOS in colonic mucosal biopsies was quantified by Western blot analysis and localized by immunohistochemistry. The effects of topical L-arginine or placebo on colonic net fluid transfer and nitrite/nitrate (NOx) output were assessed during "steady state" perfusion of the whole colon. Concentrations of NOx were measured by Griess' assay.


RESULTS
The expression of iNOS was increased 10-fold (p<0.01) in patients with "minimal colitis" compared with that in healthy volunteers and localized to the colonic epithelium. Colonic absorption of fluid was impaired (mean (SEM) 1.5 (0.2) versus 3.0 (0.2) ml/min, p<0.001) and the output of NOx was increased (47 (4) nmol/min versus <37 nmol/min, p<0.05) in patients with "minimal colitis" compared with that in healthy volunteers. Luminal L-arginine (20 mM) reduced colonic absorption of fluid in both groups (95% confidence intervals (CIs) 21-50% in patients with "minimal colitis" versus 4-18% in healthy volunteers), but an increase in NOx output was detectable only in the group of patients (8-106%). In time control experiments, colonic net transfer rates of fluid and outputs of NOx were unaffected by placebo.


CONCLUSIONS
In patients with idiopathic, chronic diarrhoea and histopathological evidence of "minimal colitis", colonic absorption of fluid is impaired, while epithelial expression of iNOS and mucosal production of NO is enhanced. It could be speculated that NO in excess contributes to the diarrhoea observed in "minimal colitis".
Perner
Anders
A
Department of Gastroenterology, Herlev Hospital, and University of Copenhagen, Denmark.
Andresen
Lars
L
Normark
Michel
M
Fischer-Hansen
Birgit
B
Rask-Madsen
Jørgen
J
D000328:Adult; D001120:Arginine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D015153:Blotting, Western; D001826:Body Fluids / Q000378:metabolism*; D046728:Colitis, Microscopic / Q000188:drug therapy / Q000378:metabolism*; D003113:Colonoscopy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D010477:Perfusion
D015415:Biomarkers; D009569:Nitric Oxide; D001120:Arginine; D052247:Nitric Oxide Synthase Type II