Intestinal protection by lafutidine, a histamine H(2)-receptor antagonist, against indomethacin-induced damage in rats--role of endogenous nitric oxide.
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).


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.
Tanaka
A
A
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
Mizoguchi
H
H
Hase
S
S
Miyazawa
T
T
Takeuchi
K
K
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D018988:Bacterial Translocation; D002211:Capsaicin / Q000494:pharmacology; D004755:Enterobacteriaceae / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009093:Mucus / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009574:Nitro Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014456:Ulcer / Q000139:chemically induced
D000081:Acetamides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D006635:Histamine H2 Antagonists; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D010880:Piperidines; D011725:Pyridines; D009569:Nitric Oxide; C076948:lafutidine; C061872:FK 409; D001120:Arginine; D019001:Nitric Oxide Synthase; D002211:Capsaicin; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin