Nitric oxide, histamine, and sensory nerves in the acid secretory response in rat stomach after damage.

Abstract

The stomach normally responds to mucosa-damaging agents by decreasing acid secretion, but this acid response turn from "inhibition" into "stimulation" when the production of nitric oxide (NO) is inhibited by NG-nitro-L-arginine methyl ester (L-NAME). We investigated the mechanism underlying stimulation of acid secretion in the stomach after damage with taurocholate (TC) in the presence of L-NAME. A rat stomach was mounted in an ex vivo chamber and perfused with saline, and the potential difference (PD), luminal pH, and acid secretion were measured before and after application of 20 mM TC for 30 min. Exposure of the stomach to TC caused a reduction in PD, an increase in luminal pH, and a decrease in acid secretion. Pretreatment with L-NAME did not affect basal acid secretion but significantly increased secretion after damage with TC, without any effect on PD. This effect of L-NAME was antagonized by co-administration of L-arginine but not D-arginine. The luminal appearance of NO was also increased after exposure of the stomach to TC, a phenomenon completely blocked by L-NAME, or when EGTA was applied together with TC. The enhanced acid secretory response in the presence of L-NAME was inhibited by prior administration of cimetidine, FPL-52694 (a mast cell stabilizer), 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 mucosal mast cells in the stomach. These changes were prevented by FPL-52694 or sensory neuronal ablation. These results suggest that (a) damage in the stomach may activate acid stimulation in addition to an NO-dependent inhibitory mechanism but that the latter effect overcomes the former, resulting in a decrease in acid secretion, (b) acid stimulation in the damaged stomach may be mediated by histamine released from the mucosal mast cells, a process that may interact with capsaicin-sensitive sensory nerves, and (c) L-NAME unmasks the acid stimulatory response by suppressing the inhibitory mechanism.