Anti-secretory 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 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. Intestinal motility was measured 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 both by pharmacological ablation of capsaicin-sensitive sensory neurons and pretreatment with L-NAME, a selective inhibitor of NO synthesis. The results suggest that 1) inhibition of acid secretion by anti-secretory drugs may exacerbate NSAID-induced intestinal lesions, 2) H2-RAs further aggravate lesions by increasing intestinal motility via activation of cholinergic pathways, and 3) lansoprazole protects the intestinal mucosa against NSAID-related ulcerative stimuli.
- acid secretion
- gastrointestinal toxicology
- histamine receptors
- intestinal motility
- non-steroidal anti-inflammatory drugs (NSAIDs)
- Received June 14, 2012.
- Revision received July 25, 2012.
- Accepted July 31, 2012.
- The American Society for Pharmacology and Experimental Therapeutics