Protective effect of lafutidine, a histamine H2 receptor antagonist, against loxoprofen-induced small intestinal lesions in rats.
OBJECTIVE
We examined the effect of lafutidine, a histamine H(2) 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 E(2) (dmPGE(2); 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 dmPGE(2) 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.


CONCLUSIONS
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.
Amagase
Kikuko
K
Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan. amagase@mb.kyoto-phu.ac.jp
Ochi
Akimu
A
Sugihara
Tetsuya
T
Kato
Shinichi
S
Takeuchi
Koji
K
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000081:Acetamides / Q000494:pharmacology*; D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D004195:Disease Models, Animal; D004755:Enterobacteriaceae / Q000472:pathogenicity; D015738:Famotidine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D055262:Mucin-2 / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009853:Omeprazole / Q000494:pharmacology; D010437:Peptic Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D010666:Phenylpropionates; D010880:Piperidines / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects
D000081:Acetamides; D000900:Anti-Bacterial Agents; D000897:Anti-Ulcer Agents; D006635:Histamine H2 Antagonists; C524628:Muc2 protein, rat; D055262:Mucin-2; D010666:Phenylpropionates; D010880:Piperidines; D054328:Proton Pump Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; C040656:loxoprofen; C076948:lafutidine; D015738:Famotidine; D000667:Ampicillin; D002927:Cimetidine; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D009853:Omeprazole; D015064:16,16-Dimethylprostaglandin E2; D002211:Capsaicin