Pathogenic Importance of Intestinal Hypermotility in NSAID-Induced Small Intestinal Damage in Rats

Abstract

Background/Aim: 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 PGE₂ 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 dmPGE₂, inhibition of bacterial invasion with ampicillin or inhibition of iNOS activity with aminoguanidine, while the hypermotility response was prevented by dmPGE₂ only. In addition, the observed effects of dmPGE₂ were all mimicked by atropine when the intestinal hypermotility was suppressed by this agent. Conclusion: 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.

Dopamine D2–Receptor Antagonists Ameliorate Indomethacin-Induced Small Intestinal Ulceration in Mice by Activating α7 Nicotinic Acetylcholine Receptors

“…Indeed, we showed that indomethacin at an ulcerogenic dose enhanced intestinal motility, the response that precedes the onset of intestinal damage as well as various pathogenic events such as enterobacterial invasion, neutrophil activation and iNOS expression (32,39). On the other hand, we confirmed our previous findings that dopamine and its agonist prevented indomethacin-induced small intestinal lesions in mice and these effects were antagonized by D 2 -receptor antagonists.…”

Lafutidine Protects the NSAID-Induced Small Intestinal Lesions Mediated by Capsaicin-Sensitive Afferent Neurons

“…The onset of these lesions was accompanied by the mucosal invasion of enterobacteria and the up-regulation of iNOS expression, those events being similarly observed after indomethacin treatment. We also confirmed that the ulcerogenic response induced by loxoprofen in the small intestine was significantly prevented by pretreatment of the animals with dmPGE 2 as a supplement for PG deficiency or ampicillin as an antibiotic, the same was reported using the intestinal indomethacin-induced intestinal lesions [3][4][5].…”

“…Several factors such as intestinal hypermotility, enterobacteria, neutrophils, nitric oxide (NO), and inducible NO synthase (iNOS) are involved in the pathogenesis of these intestinal lesions [3][4][5][6][7], yet a deficiency of endogenous prostaglandins (PGs) due to cyclooxygenase (COX) inhibition is most important in the background for the intestinal ulcerogenic response to NSAIDs [8][9][10]. Recent clinical studies, using capsule endoscopes or double-balloon endoscopes, confirmed that NSAIDs damage the small intestine in patients at a higher incidence than previously thought.…”

Present status and strategy of NSAIDs-induced small bowel injury

“…The involvement of the following has also been reported important in small bowel injury: the reduction of intestinal mucus due to NSAIDs, microcirculatory disturbances accompanying abnormally increased intestinal motility, NO derived from iNOS, inflammatory cytokines, neutrophil infiltration, and reactive oxygen species [26][27][28][29][30][31]. It is well that NSAIDs do not induce small-bowel injury in germ-free animals [20].…”