Protective effect of lafutidine, a histamine H2 receptor antagonist, against loxoprofen-induced small intestinal lesions in rats

• Published in: Journal of gastroenterology and hepatology 2010-05, Vol.25 (s1), p.S111-S118
• Main Authors: Amagase, Kikuko, Ochi, Akimu, Sugihara, Tetsuya, Kato, Shinichi, Takeuchi, Koji
• Format: Article
• Language: English
• Subjects: 16,16-Dimethylprostaglandin E2 - pharmacology; Acetamides - pharmacology; Ampicillin - pharmacology; Animals; Anti-Bacterial Agents - pharmacology; Anti-Ulcer Agents - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Capsaicin - pharmacology; capsaicin-sensitive afferent neurons; Cimetidine - pharmacology; Disease Models, Animal; Enterobacteriaceae - pathogenicity; Famotidine - pharmacology; Gastroenterology. Liver. Pancreas. Abdomen; Histamine H2 Antagonists - pharmacology; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Intestinal Mucosa - pathology; Intestine, Small - drug effects; Intestine, Small - metabolism; Intestine, Small - microbiology; Intestine, Small - pathology; lafutidine; loxoprofen; Male; Medical sciences; Mucin-2 - genetics; mucosal protection; Nitric Oxide Synthase Type II - genetics; Omeprazole - pharmacology; Peptic Ulcer - chemically induced; Peptic Ulcer - metabolism; Peptic Ulcer - microbiology; Peptic Ulcer - pathology; Peptic Ulcer - prevention & control; Peroxidase - metabolism; Pharmacology. Drug treatments; Phenylpropionates; Piperidines - pharmacology; Proton Pump Inhibitors - pharmacology; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Sensory Receptor Cells - drug effects; small intestinal lesion
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/j.1440-1746.2010.06223.x

Background and Aims:  We examined the effect of lafutidine, a histamine H2 receptor antagonist with a mucosal protective action mediated by capsaicin‐sensitive sensory neurons (CSN), on intestinal lesions produced by loxoprofen administration in rats. Methods:  Animals were given loxoprofen (10–100 mg/kg p.o.) and killed 24 h later. Lafutidine (10 and 30 mg/kg), cimetidine (100 mg/kg) or famotidine (30 mg/kg) was given twice p.o. at 0.5 h before and 6 h after loxoprofen. Omeprazole (100 mg/kg) was given p.o. once 0.5 h before. Ampicillin (800 mg/kg) was given p.o. twice at 24 h and 0.5 h before loxoprofen, while 16,16‐dimethyl prostaglandin E2 (dmPGE2; 0.01 mg/kg) was given i.v. twice at 5 min before and 6 h after. Results:  Loxoprofen dose‐dependently produced hemorrhagic lesions in the small intestine, accompanied by invasion of enterobacteria and increased inducible nitric oxide synthase (iNOS) expression as well as myeloperoxidase activity in the mucosa. The ulcerogenic response to loxoprofen (60 mg/kg) was significantly prevented by lafutidine (30 mg/kg), similar to dmPGE2 and ampicillin, and the effect of lafutidine was totally attenuated by ablation of CSN. Neither cimetidine, famotidine nor omeprazole had a significant effect against these lesions. Lafutidine alone increased mucus secretion and reverted the decreased mucus response to loxoprofen, resulting in suppression of bacterial invasion and iNOS expression. In addition, loxoprofen downregulated Muc2 expression, and this response was totally reversed by lafutidine mediated by CSN. Conclusion:  Lafutidine protects the small intestine against loxoprofen‐induced lesions, essentially mediated by the CSN, and this effect may be functionally associated with increased Muc2 expression/mucus secretion, an important factor in the suppression of bacterial invasion.