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

Abstract

ABSTRACT-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 Nw-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.

Lansoprazole Induces Mucosal Protection through Gastrin Receptor-Dependent Up-Regulation of Cyclooxygenase-2 in Rats

“…The protective effect of lansoprazole was suppressed by functional ablation of capsaicin-sensitive sensory neurons, or prior administration of indomethacin or a selective inhibitor of nitric oxide synthesis. These findings suggest that endogenous PGs, together with capsaicin-sensitive sensory neurons and nitric oxide, mediate PPI-induced gastric mucosal protection (Murakami et al, 1996).…”

“…Cytoprotective effects have been demonstrated by PPIs, including timoprazole, lansoprazole, and others (Ruwart et al, 1984;Okabe et al, 1986;Holm, 1988;Bergmann et al, 1992;Kawano et al, 1992;Fukuda et al, 1995;Murakami et al, 1996;Blandizzi et al, 1999). Studies suggest that PGs are involved in the mucosal protection afforded by lansoprazole (Murakami et al, 1996;Blandizzi et al, 1999).…”

“…Studies suggest that PGs are involved in the mucosal protection afforded by lansoprazole (Murakami et al, 1996;Blandizzi et al, 1999). However, the mechanism responsible for lansoprazole-induced gastric mucosal protection has not yet been determined.…”

“…Proton pump inhibitors (PPIs) are potent antiulcer agents that have both gastric antisecretory and mucosal protective actions (Ruwart et al, 1984;Okabe et al, 1986;Holm, 1988;Bergmann et al, 1992;Kawano et al, 1992;Fukuda et al, 1995;Murakami et al, 1996;Blandizzi et al, 1999). The antisecretory action is due to their inhibitory effects on the H ϩ ,K ϩ -ATPase (proton pump) in parietal cells (Satoh et al, 1989;Nagaya et al, 1990).…”

Lansoprazole Raises Somatostatin, Calcitonin Gene-Related Peptide, and Substance P Levels in Healthy Human Plasma

“…26) PGE 2 also has cytoprotective effects via capsaicinsensitive afferent nerves. 27) Furthermore, Murakami et al 28) reported that the gastric mucosal protective effects of lansoprazole are due to PGs and nitric oxide via an increase in mucosal blood flow. The results of this study supported the hypothesis that the protective effects of lansoprazole are caused by direct or indirect stimulation of capsaicin-sensitive afferent nerves.…”