Protective effect of lafutidine, a novel histamine H2-receptor antagonist, on dextran sulfate sodium-induced colonic inflammation through capsaicin-sensitive afferent neurons in rats.
Lafutidine, a histamine H2-receptor antagonist, exhibits gastric mucosal protective action mediated by capsaicin-sensitive afferent neurons, in addition to a potent antisecretory effect. In this study we examined the effect of lafutidine on dextran sulfate Na (DSS)-induced ulcerative colitis in rats, in relation to capsaicin-sensitive afferent neurons. Experimental colitis was induced in rats by daily treatment with 3% DSS in drinking water for 7 days. Lafutidine, capsaicin, and cimetidine were administered per os twice daily for 6 days. The ulceration area, colon length, and myeloperoxidase (MPO) activity were measured on day 7 after the onset of DSS treatment. DSS caused severe mucosal lesions in the colon, accompanied by an increase in MPO activity as well as a decrease in body weight gain and colon length. Daily administration of lafutidine dose-dependently reduced the severity of DSS-induced colitis and significantly mitigated changes in the colon length and MPO activity. The effects of lafutidine were mimicked by daily administration of capsaicin but not cimetidine and were totally abolished by chemical ablation of capsaicin-sensitive afferent neurons. In contrast, desensitization of afferent neurons significantly worsened the colonic inflammation induced by DSS. It was also found that both lafutidine and capsaicin increased the secretion of mucus in the colonic mucosa. These results suggest that lafutidine is effective against the ulcerative colitis induced by DSS through capsaicin-sensitive afferent neurons. This action might be attributable at least partly to the enhancement of colonic mucus secretion.
Okayama
Mitsuaki
M
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
Tsubouchi
Ryoichi
R
Kato
Shinichi
S
Takeuchi
Koji
K
D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D016264:Dextran Sulfate / Q000633:toxicity; D006635:Histamine H2 Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D000081:Acetamides; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; C076948:lafutidine; D016264:Dextran Sulfate; D009195:Peroxidase; D002211:Capsaicin