Role of capsaicin-sensitive sensory neurons and nitric oxide in the protective effect of lansoprazole, a proton pump inhibitor, on the gastric mucosa in rats.
The mucosal protective effect of lansoprazole, a proton pump inhibitor, was examined in ethanol- and acidified taurocholate-induced rat gastric lesion models. The formation of gastric lesions was markedly inhibited by prostaglandin E2 but hardly inhibited by cimetidine, ranitidine and famotidine. Lansoprazole (3-30 mg/kg, p.o.) inhibited the formation of gastric lesions in a dose-dependent manner, with ID50 values of 8.5 (ethanol) and 4.1 mg/kg, p.o. (acidified taurocholate). The protective effect of lansoprazole was significantly decreased by functional ablation of capsaicin-sensitive sensory neurons or prior administration of indomethacin or N(omega)-nitro-L-arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide (NO) synthesis. The inhibitory effect of L-NAME was antagonized by prior administration of L-arginine, a substrate of endogenous NO, but not D-arginine. The antisecretory effect of lansoprazole on the basal acid secretion in pylorus-ligated rats was not affected by any of these treatments. Lansoprazole (5 and 15 mg/ml) administered directly into the gastric chamber obviously increased both the production of NO in the mucosa and mucosal blood flow, which was prevented by pretreatment with L-NAME. These results suggest that capsaicin-sensitive sensory neurons, NO and prostaglandins are involved in the mucosal protection afforded by lansoprazole possibly via an increase in mucosal blood flow, but are not involved in the antisecretory action of lansoprazole.
Pharmaceutical Research Laboratories III, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
I
I
Murakami
H
H
Satoh
S
S
Asano
R
R
Maeda
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D000431:Ethanol / Q000633:toxicity; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects*; D064747:Lansoprazole; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000627:therapeutic use; D054328:Proton Pump Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013272:Stomach Diseases / Q000139:chemically induced / Q000517:prevention & control*; D013656:Taurocholic Acid / Q000633:toxicity
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D009569:Nitric Oxide; D000431:Ethanol; D013656:Taurocholic Acid; D009853:Omeprazole; D002211:Capsaicin