Mechanism of acid secretory changes in rat stomach after damage by taurocholate: role of nitric oxide, histamine, and sensory neurons.

The present study was performed to investigate the mechanism underlying the acid stimulatory response in the stomach after damage under the inhibition of nitric oxide (NO) production by N(G)-nitro-L-arginine methyl ester (L-NAME). A rat stomach was mounted in an ex vivo chamber, perfused with saline, and the potential difference (PD) and acid secretion were measured before and after the application of 20 mM taurocholate (TC) for 30 min. Exposure of the stomach to TC caused a PD reduction and a decrease of acid secretion. Pretreatment with L-NAME did not affect basal acid secretion but significantly enhanced the acid secretion in the stomach after damage with TC, without any effect on the PD response. This effect of L-NAME was antagonized by simultaneous administration of L-arginine but not D-arginine. The luminal appearance of NO was significantly increased in the stomach after exposure to TC, and this change was completely blocked in the presence of L-NAME or when EGTA was applied together with TC. The enhanced acid secretory response to TC in the presence of L-NAME was inhibited by pretreatment with cimetidine, FPL-52694 (a mast cell stabilizer), or spantide (a substance P antagonist) or by chemical ablation of capsaicin-sensitive sensory neurons. Mucosal exposure to TC increased histamine output in the lumen and decreased the number of metachromatically staining cells in the stomach, and these changes were also significantly prevented by FPL-52694, spantide, or sensory deafferentation. These results suggest that 1) damage in the stomach may activate the acid stimulatory pathway in addition to the NO-dependent inhibitory mechanism, but the latter effect overcomes the former, resulting in a decrease in acid secretion, 2) the acid stimulation in the damaged stomach may be mediated by histamine released from the mucosal mast cell which may interact with capsaicin-sensitive sensory nerves, and 3) L-NAME unmasks the acid stimulatory response by suppressing the inhibitory mechanism.