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.
Footnotes
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ABBREVIATIONS:
- NSAID
- nonsteroidal anti-inflammatory drug
- ACh
- acetylcholine
- ATR
- atropine
- CAP
- capsaicin
- CIM
- cimetidine
- CSSN
- capsaicin-sensitive sensory neuron
- DIC
- diclofenac
- FAM
- famotidine
- H2-RA
- histamine H2-receptor antagonist
- IND
- indomethacin
- LI
- lesion index
- l-NAME
- N-nitro-l-arginine methyl ester
- LPZ
- lansoprazole
- NO
- nitric oxide
- OPZ
- omeprazole
- PGE2
- prostaglandin E2
- PPI
- proton pump inhibitor
- RAN
- ranitidine
- RPZ
- rabeprazole
- SNP
- sodium nitroprusside
- VEH
- vehicle.
- Received June 14, 2012.
- Accepted July 31, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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