Pathogenic importance of intestinal hypermotility in NSAID-induced small intestinal damage in rats.
OBJECTIVE
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin produce damage in the small intestine as a major adverse reaction. We examined the effect of various NSAIDs on intestinal motility and investigated the pathogenic importance of motility changes in the intestinal ulcerogenic response to indomethacin in rats.


METHODS
Animals without fasting were given various NSAIDs (indomethacin 10 mg/kg, diclofenac 40 mg/kg, flurbiprofen 20 mg/kg, naproxen 40 mg/kg) s.c., and in the case of indomethacin, the following parameters were examined in the small intestine 24 h later; the lesion score, the number of enterobacteria and myeloperoxidase (MPO) as well as inducible nitric oxide (iNOS) activity. Intestinal motility was monitored as intraluminal pressure recordings using a balloon under anesthesia.


RESULTS
All NSAIDs tested decreased mucosal PGE(2) levels and produced hemorrhagic lesions in the small intestine, accompanied by intestinal hypermotility. As representative of NSAIDs, indomethacin also increased the extent of enterobacterial invasion and MPO as well as iNOS activity before the occurrence of intestinal damage, and the hypermotility response was observed earlier than the onset of any other event caused by this agent. The intestinal lesions induced by indomethacin were prevented by either supplementation with dmPGE(2), inhibition of bacterial invasion with ampicillin or inhibition of iNOS activity with aminoguanidine, while the hypermotility response was prevented by dmPGE(2) only. In addition, the observed effects of dmPGE(2) were all mimicked by atropine when the intestinal hypermotility was suppressed by this agent.


CONCLUSIONS
These results suggest the pathogenic importance of intestinal hypermotility in the intestinal ulcerogenic response to NSAIDs in rats and show that this event is critical for the occurrence of enterobacterial invasion under PG deficiency, followed by various inflammatory changes and damage in the mucosa. This study also suggests that the antispasmodic drug is protective against NSAID-induced intestinal lesions.
Takeuchi
Koji
K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan. takeuchi@mb.kyoto-phu.ac.jp
Miyazawa
Tohu
T
Tanaka
Akiko
A
Kato
Shinichi
S
Kunikata
Tomonori
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D004008:Diclofenac / Q000009:adverse effects; D015232:Dinoprostone / Q000378:metabolism; D005480:Flurbiprofen / Q000009:adverse effects; D005769:Gastrointestinal Motility / Q000187:drug effects; D007213:Indomethacin / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects; D008297:Male; D009288:Naproxen / Q000009:adverse effects; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D009288:Naproxen; D005480:Flurbiprofen; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015232:Dinoprostone; D007213:Indomethacin