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 underlyin g the acid stimulatory response in the stomach after damage under the inhibition of nitric oxide (NO) production by N-G-nitro-L-arginine met hyl ester (L-NAME), A rat stomach was mounted in an ex vivo chamber, p erfused with saline, and the potential difference (PD) and acid secret ion were measured before and after the application of 20 mM taurochola te (TC) for 30 min. Exposure of the stomach to TC caused a PD reductio n and a decrease of acid secretion. Pretreatment with L-NAME did not a ffect basal acid secretion but significantly enhanced the acid secreti on in the stomach after damage with TC, without any effect on the PD r esponse, This effect of L-NAME was antagonized by simultaneous adminis tration 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 E GTA was applied together with TC, The enhanced acid secretory response to TC in the presence of L-NAME was inhibited by pretreatment with ci metidine, 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 lume n and decreased the number of metachromatically staining cells in the stomach, and these changes were also significantly prevented by FPL-52 694, 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 effe ct overcomes the former, resulting in a decrease in acid secretion, 2) the acid stimulation in the damaged stomach may be mediated by histam ine released from the mucosal mast cell which may interact with capsai cin-sensitive sensory nerves, and 3) L-NAME unmasks the acid stimulato ry response by suppressing the inhibitory mechanism.