Intestinal site-dependent susceptibility to chronic indomethacin in the rat: a morphological and biochemical study.
BACKGROUND
The cyclo-oxygenase inhibitor indomethacin induces a pattern of gastrointestinal injury in the rat that is site-dependent. This study compared the extent of injury to different regions of the rat intestine (small intestine, caecum and colon) with the corresponding changes in arachidonic acid metabolism in these areas, following long-term, low-dose indomethachin.


METHODS
Rats (eight per group) received either indomethacin (3 mg.kg/day) or control diet for either 6 or 12 weeks. At termination animals were bled, examined both macroscopically and microscopically for ulcers, and assayed for blood thromboxane B2, intestinal tissue prostaglandin E2 content and production of leukotriene B4. In a further eight animals luminal indomethacin concentrations from the small intestine, caecum and colon were measured following 6 weeks of chronic drug ingestion.


RESULTS
At 6 weeks, macroscopic ulcers were observed in 2/8 (small intestine), 3/8 (caecum) and 1/8 (colon) animals. The corresponding ratios at 12 weeks were 5/8, 8/8 and 0/8. In control animals, a site-dependent gradient of the prostaglandin E2 concentration was found. In indomethacin-dosed animals the intestinal prostaglandin E2 content was reduced significantly in the caecum at 6 weeks, and in all tissues at 12 weeks. An increased leukotriene B4 production was observed in the caecum only, at 12 weeks (P < 0.01), and the blood thromboxane B2 was reduced at both time points (P < 0.05).


CONCLUSIONS
There is a site-dependent gradient of the prostaglandin E2 concentration in the rat intestine. The rat caecum is particularly sensitive to long-term low-dose indomethacin, both in terms of chronic intestinal inflammation and changes in prostanoid metabolism. This site-dependent degree of injury may be associated with a local cyclo-oxygenase inhibition.
Inflammatory Bowel Disease Study Group, University Department of Medicine & Histopathology, Royal Free Hospital School of Medicine, London, UK.
G
G
Nygård
A
A
Anthony
K
K
Khan
S V
SV
Bounds
J
J
Caldwell
A P
AP
Dhillon
R E
RE
Pounder
A J
AJ
Wakefield
D000818:Animals; D003106:Colon / Q000187:drug effects; D004064:Digestive System / Q000187:drug effects*; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects; D007213:Indomethacin / Q000009:adverse effects* / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D010437:Peptic Ulcer / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D007975:Leukotriene B4; D015232:Dinoprostone; D007213:Indomethacin