title: Exacerbation of nonsteroidal anti-inflammatory drug-induced small intestinal lesions by antisecretory drugs in rats: the role of intestinal motility.
abstract: Antisecretory drugs such as histamine H2-receptor antagonists (H2-RAs) and proton pump inhibitors (PPIs) are commonly used for the treatment of gastric and duodenal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). However, the effects of these drugs on NSAID-induced small intestinal ulcers are not fully understood. The effects of H2-RAs and PPIs on NSAID-induced gastrointestinal lesions and small intestinal motility were examined in rats. Male Wistar rats (180-220 g) were used. Indomethacin (10 mg/kg) was administered orally in fasted or fed rats, and gastrointestinal lesions were examined 24 h after indomethacin administration. Intestinal motility was measured by using a balloon method under urethane anesthesia. Indomethacin produced multiple lesions in the gastric corpus in fasted rats and in the small intestine in fed rats: 1) H2-RAs (cimetidine, ranitidine, and famotidine) and PPIs (omeprazole, lansoprazole, and rabeprazole) markedly inhibited the formation of gastric lesions. 2) The drugs, except for lansoprazole, increased intestinal lesions. 3) H2-RAs augmented the increase in intestinal motility caused by indomethacin, and the effects of H2-RAs on motility and intestinal lesions were markedly inhibited by atropine. 4) Lansoprazole inhibited the formation of intestinal lesions, and the effect was prevented by both pharmacological ablation of capsaicin-sensitive sensory neurons and pretreatment with N-nitro-l-arginine methyl ester, a selective inhibitor of nitric-oxide synthesis. The results suggest that: 1) inhibition of acid secretion by antisecretory drugs may exacerbate NSAID-induced intestinal lesions, 2) H2-RAs further aggravate lesions by increasing intestinal motility via the activation of cholinergic pathways, and 3) lansoprazole protects the intestinal mucosa against NSAID-related ulcerative stimuli.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Division of Pathological Science, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan. h_satoh@mb.kyoto-phu.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satoh
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amagase
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007213:Indomethacin; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000473:pathology*; D007413:Intestinal Mucosa / Q000473:pathology; D007421:Intestine, Small / Q000473:pathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D006635:Histamine H2 Antagonists; D020030:Nitric Oxide Donors; D054328:Proton Pump Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin