1 Capsaicin sensitive a erent nerves play an important role in gastric mucosal defensive mechanisms. Capsaicin stimulates a erent nerves and enhances the release of calcitonin gene-related peptide (CGRP), which seems to be the predominant neurotransmitter of spinal a erents in the rat stomach, exerting many pharmacological e ects by a direct mechanism or indirectly through second messengers such as nitric oxide (NO). 2 Lafutidine is a new type of anti-ulcer drug, possessing both an antisecretory e ect, exerted via histamine H 2 receptor blockade, and gastroprotective activities. Studies with certain antagonists or chemical dea erentation techniques suggest the gastroprotective actions of lafutidine to be mediated by capsaicin sensitive a erent nerves, but this is an assumption based on indirect techniques. In order to explain the direct relation of lafutidine to a erent nerves, we conducted the following studies.3 We determined CGRP and NO release from rat stomach and speci®c [ 3 H]-resiniferatoxin (RTX) binding to gastric vanilloid receptor subtype 1 (VR1), which binds capsaicin, using EIA, a microdialysis system and a radioreceptor assay, respectively. 4 Lafutidine enhanced both CGRP and NO release from the rat stomach induced by a submaximal dose of capsaicin, but had no e ect on speci®c [ 3 H]-RTX and capsaicin binding to VR1. 5 In conclusion, our ®ndings demonstrate that lafutidine modulates the activity of capsaicin sensitive a erent nerves in the rat stomach, which may be a key mechanism involved in its gastroprotective action.
We investigated the recurrence of ulcers in rats after treatment with FRG-8813, (±)-2-(furfurylsulfinyl)-N-[4- [4-(piperidinomethyl)-2-pyridyl] oxy-(Z)-2-butenyl] acetamide, a novel histamine H2-receptor antagonist. Chronic gastric ulcers were induced by serosa-searing with a hot metal bar, and the ulcer healing and recurrence after treatment with FRG-8813 or famotidine were evaluated by endoscopy for 160 days. At the dose of 30 mg/kg p.o., once daily, the treatment with FRG-8813 or famotidine for 60 days, which was stopped earlier if the ulcer had healed, accelerated the ulcer healing significantly. A subsequent follow-up study on the healed rats showed that the cumulative recurrence rate of rats healed by FRG-8813 was lower than that of naturally healed rats or rats healed by famotidine. In many cases of rats healed by FRG-8813, the regenerated mucosa was normal in contrast with the control of famotidine-healed animals. The mucosal regeneration index of the gastric ulcer after 10 days’ administration of FRG-8813 was significantly higher than that obtained with famotidine. After cessation of the treatment with famotidine for 7 days, rebound hyperacidity was induced; but such rebound did not occur with FRG-8813. Considering the low recurrence rate of ulcers after FRG-8813 treatment, we suggest that FRG-8813 treatment may provide additional benefits in peptic ulcer therapy.
Abstract.Helicobacter pylori (H. pylori) infection of gastric epithelial cells has been shown to induce interleukin (IL)-8 production, but the signal transduction mechanism leading to IL-8 production has not been clearly defined. Here, we investigate the role of protein kinase C (PKC) in the mechanism of induction of IL-8 release by H. pylori in human gastric epithelial cells. In MKN45 cells, H. pylori-induced IL-8 release was enhanced by treatment with PKC inhibitors (GF109203X and calphostin C) and PKC depletion, which completely inhibited PKC activity. Moreover, PKC inhibitors and PKC depletion increased extracellular signal-regulated kinase (ERK) activity and phosphorylation, but not calcium / calmodulin-dependent protein kinase II (CaMK II) activity, in response to H. pylori infection. PKC activated by H. pylori inhibited activation of ERK induced by H. pylori without affecting the CaMK II activity and negatively regulated IL-8 production in human gastric epithelial cells.
These results suggest that lafutidine inhibits IL-8 release by inhibiting H. pylori adherence to gastric epithelial cells, indicating a novel mechanism by which lafutidine protects against the mucosal inflammation associated with H. pylori infection.
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