Protective effect of lafutidine against indomethacin-induced intestinal ulceration in rats: relation to capsaicin-sensitive sensory neurons.
OBJECTIVE
We examined the prophylactic effect of lafutidine, a novel histamine H(2)-receptor antagonist [(+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyr idyl]oxy- (Z)-2 butenyl]acetamide], on indomethacin-induced small intestinal ulcers in rats and investigated the relation of this action to capsaicin-sensitive sensory neurons.


RESULTS
Subcutaneously administered indomethacin (10 mg/kg) provoked ulceration in the small intestine, mainly the jejunum and ileum, accompanied by increases in myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities as well as the enterobacterial numbers invading the mucosa. Intestinal ulcerogenic response to indomethacin was prevented by 16,16-dimethyl prostaglandin E(2) (10 microg/kg, p.o.) and capsaicin (10 mg/kg, p.o. ) as well as ampicillin (800 mg/kg, p.o.), but not omeprazole (100 mg/kg, p.o.). Likewise, lafutidine (1-10 mg/kg, p.o.), but not cimetidine (100 mg/kg, p.o.), reduced the occurrence of intestinal ulcers in response to indomethacin in a dose-dependent manner, and a significant effect was observed at 3 mg/kg or greater. The protective action of lafutidine as well as capsaicin was almost totally abolished by chemical ablation of capsaicin-sensitive sensory neurons. Both lafutidine and capsaicin significantly suppressed the increases in MPO and iNOS activities as well as enterobacterial numbers in the mucosa. These agents also significantly enhanced mucus secretion in the small intestine.


CONCLUSIONS
These results suggest that lafutidine protects the small intestine against ulceration via stimulation of capsaicin-sensitive sensory neurons. This action may be attributable to inhibition of enterobacterial invasion in the intestinal mucosa, probably by increasing the mucus secretion.
Kato
S
S
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
Tanaka
A
A
Kunikata
T
T
Umeda
M
M
Takeuchi
K
K
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000081:Acetamides / Q000494:pharmacology*; D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007213:Indomethacin / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000294:innervation; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000081:Acetamides; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; C076948:lafutidine; D000667:Ampicillin; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015064:16,16-Dimethylprostaglandin E2; D002211:Capsaicin; D007213:Indomethacin