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Intestinal protection by lafutidine, a histamine H(2)-receptor antagonist, against indomethacin-induced damage in rats--role of endogenous nitric oxide.
Med Sci Monit. 2001 Sep-Oct; 7(5):869-77.MS

Abstract

BACKGROUND

We previously reported that lafutidine ((I)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2-butenyl] acetamide), a novel histamine H(2)-receptor antagonist, protects the small intestine against indomethacin-induced damage, mediated by capsaicin-sensitive afferent neurons (CSN).

MATERIAL AND METHODS

In the present study, we investigated whether or not the protective action of lafutidine against indomethacin-induced intestinal damage is mediated by endogenous nitric oxide (NO). Male SD rats were given indomethacin (10 mg/kg, s.c), killed 24 hr later, and the small intestinal mucosa was examined. Lafutidine (10 mg/kg) and capsaicin (10 mg/kg) was given p.o. twice 0.5 hr before and 9 hr after indomethacin. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME: 10 mg/kg) or the selective iNOS inhibitor aminoguanidine (10 mg/kg) was given s.c. 1 hr before lafutidine, while L-arginine (200 mg/kg) was given i.p. 10 min before L-NAME.

RESULTS

Indomethacin produced severe lesions in the small intestine, accompanied by increases in enterobacterial translocation in the mucosa. Both lafutidine and capsaicin significantly reduced the severity of these lesions, together with suppression of bacterial translocation. The protective action of lafutidine as well as capsaicin was almost totally abolished by L-NAME but not aminoguanidine, in a L-arginine-sensitive manner. Both lafutidine and capsaicin significantly increased intestinal mucus secretion, and these effects were also attenuated by prior administration of L-NAME. The exogenous NO donor NOR-3 prevented indomethacin-induced intestinal lesions at the dose that stimulated the mucus secretion and inhibited the bacterial translocation.

CONCLUSIONS

These results suggest that lafutidine protects the small intestine against indomethacin-induced damage, the action being dependent on CSN and mediated by endogenous NO produced by cNOS. The protective action of lafutidine may be attributable to suppression of the bacterial translocation following indomethacin, probably due to stimulation of intestinal mucus secretion.

Authors+Show Affiliations

Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11535926

Citation

Tanaka, A, et al. "Intestinal Protection By Lafutidine, a Histamine H(2)-receptor Antagonist, Against Indomethacin-induced Damage in Rats--role of Endogenous Nitric Oxide." Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, vol. 7, no. 5, 2001, pp. 869-77.
Tanaka A, Mizoguchi H, Hase S, et al. Intestinal protection by lafutidine, a histamine H(2)-receptor antagonist, against indomethacin-induced damage in rats--role of endogenous nitric oxide. Med Sci Monit. 2001;7(5):869-77.
Tanaka, A., Mizoguchi, H., Hase, S., Miyazawa, T., & Takeuchi, K. (2001). Intestinal protection by lafutidine, a histamine H(2)-receptor antagonist, against indomethacin-induced damage in rats--role of endogenous nitric oxide. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, 7(5), 869-77.
Tanaka A, et al. Intestinal Protection By Lafutidine, a Histamine H(2)-receptor Antagonist, Against Indomethacin-induced Damage in Rats--role of Endogenous Nitric Oxide. Med Sci Monit. 2001 Sep-Oct;7(5):869-77. PubMed PMID: 11535926.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intestinal protection by lafutidine, a histamine H(2)-receptor antagonist, against indomethacin-induced damage in rats--role of endogenous nitric oxide. AU - Tanaka,A, AU - Mizoguchi,H, AU - Hase,S, AU - Miyazawa,T, AU - Takeuchi,K, PY - 2001/9/6/pubmed PY - 2002/1/18/medline PY - 2001/9/6/entrez SP - 869 EP - 77 JF - Medical science monitor : international medical journal of experimental and clinical research JO - Med Sci Monit VL - 7 IS - 5 N2 - BACKGROUND: We previously reported that lafutidine ((I)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2-butenyl] acetamide), a novel histamine H(2)-receptor antagonist, protects the small intestine against indomethacin-induced damage, mediated by capsaicin-sensitive afferent neurons (CSN). MATERIAL AND METHODS: In the present study, we investigated whether or not the protective action of lafutidine against indomethacin-induced intestinal damage is mediated by endogenous nitric oxide (NO). Male SD rats were given indomethacin (10 mg/kg, s.c), killed 24 hr later, and the small intestinal mucosa was examined. Lafutidine (10 mg/kg) and capsaicin (10 mg/kg) was given p.o. twice 0.5 hr before and 9 hr after indomethacin. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME: 10 mg/kg) or the selective iNOS inhibitor aminoguanidine (10 mg/kg) was given s.c. 1 hr before lafutidine, while L-arginine (200 mg/kg) was given i.p. 10 min before L-NAME. RESULTS: Indomethacin produced severe lesions in the small intestine, accompanied by increases in enterobacterial translocation in the mucosa. Both lafutidine and capsaicin significantly reduced the severity of these lesions, together with suppression of bacterial translocation. The protective action of lafutidine as well as capsaicin was almost totally abolished by L-NAME but not aminoguanidine, in a L-arginine-sensitive manner. Both lafutidine and capsaicin significantly increased intestinal mucus secretion, and these effects were also attenuated by prior administration of L-NAME. The exogenous NO donor NOR-3 prevented indomethacin-induced intestinal lesions at the dose that stimulated the mucus secretion and inhibited the bacterial translocation. CONCLUSIONS: These results suggest that lafutidine protects the small intestine against indomethacin-induced damage, the action being dependent on CSN and mediated by endogenous NO produced by cNOS. The protective action of lafutidine may be attributable to suppression of the bacterial translocation following indomethacin, probably due to stimulation of intestinal mucus secretion. SN - 1234-1010 UR - https://www.unboundmedicine.com/medline/citation/11535926/Intestinal_protection_by_lafutidine_a_histamine_H_2__receptor_antagonist_against_indomethacin_induced_damage_in_rats__role_of_endogenous_nitric_oxide_ L2 - https://www.medscimonit.com/download/index/idArt/508530 DB - PRIME DP - Unbound Medicine ER -