16-16-dimethylprostaglandin-e2 and lafutidine

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.. 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.. 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.. 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.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ampicillin; Animals; Anti-Bacterial Agents; Anti-Ulcer Agents; Capsaicin; Cimetidine; Disease Models, Animal; Enterobacteriaceae; Famotidine; Histamine H2 Antagonists; Intestinal Mucosa; Intestine, Small; Male; Mucin-2; Nitric Oxide Synthase Type II; Omeprazole; Peptic Ulcer; Peroxidase; Phenylpropionates; Piperidines; Proton Pump Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sensory Receptor Cells

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.. 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.. 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.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ampicillin; Animals; Capsaicin; Dose-Response Relationship, Drug; Duodenal Ulcer; Histamine H2 Antagonists; Indomethacin; Intestinal Mucosa; Male; Neurons, Afferent; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley

Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor antagonist with gastroprotective activity. The aim of this study was to investigate the property of the gastro-protective activity of lafutidine by examining the effect on ammonia-induced change in transmucosal potential difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent-induced cell damage. Intragastrical application of lafutidine accelerated the recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia solution and the accelerating effect was abolished by chemical deafferentation, but not with indometacin, a cyclooxygenase inhibitor. The application of capsaicin, as a reference compound, significantly promoted the recovery of the ammonia-induced PD reduction and this effect was not altered with indometacin. Lafutidine given intragastrically caused a sustained increase in GMBF in a dose-dependent fashion, which was also completely inhibited in the deafferentated rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin E2, lafutidine did not protect isolated gastric superficial epithelial cells from ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of lafutidine is induced by promoting the restitution of the damaged mucosa after a noxious agent, not by directly protecting the epithelial cells and this effect may be caused through the mechanism of capsaicin-sensitive afferent nerves.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ammonia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Capsaicin; Central Nervous System Depressants; Ethanol; Gastric Mucosa; Histamine H2 Antagonists; Indomethacin; Male; Membrane Potentials; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Administration, Oral; Animals; Anti-Ulcer Agents; Capsaicin; Cimetidine; Denervation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Famotidine; Food; Indomethacin; Male; Nitroarginine; Piperidines; Pyloric Antrum; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Wound Healing

We examined the effect of FRG-8813, a new histamine H2-receptor antagonist, on 1% NH3-induced gastric mucosal lesions and basal gastric mucus production in rats. The effect of FRG-8813 (10 mg/kg) given orally was investigated macroscopically and histochemically compared with that of 16,16-dimethyl prostaglandin E2 (dmPGE2, 2 micrograms/kg) or capsaicin (Cap, 10 mg/kg) in the fundic gland area. FRG-8813, dmPGE2 and capsaicin inhibited the NH3-induced mucosal lesions, and stimulated the mucus secretion 5 min after the administration. Chemical deafferentation abolished the gastroprotective effect of FRG-8813 or Cap and attenuated the increase by FRG-8813, dmPGE2 or Cap in mucus secretion seen after 5 min. These results suggest that FRG-8813 exerts its effect on gastric mucus production partially through the capsaicin-sensitive afferent nerves, like the mechanism involved in gastroprotection, and that the increase in mucus production by FRG-8813 is at least in part responsible for the gastroprotection.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Animals; Anti-Ulcer Agents; Capsaicin; Gastric Mucosa; Histamine H2 Antagonists; Mucus; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley