ABSTRACT We investigated the regulatory mechanism of acid secretion in the stomach after damage with taurocholate (TC). 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 the application of 20 mM taurocholate (TC) for 30 min. Mucosal exposure to TC caused a reduction in PD and a decrease in acid secretion, together with an increase of nitric oxide (NO) as well as Ca 2+ in luminal contents. Prior administration of N G-nitro-L-arginine methyl ester (L- NAME; an inhibitor of NO biosynthesis) as well as indomethacin (a cyclooxygenase inhibitor) did not affect PD and pH (basal acid secretion) responses, but significantly attenuated the inhibitory effect of TC on acid secretion. In the presence of L-NAME the acid secretion was actually enhanced in the stomach after damage with TC. This effect of L-NAME was not mimicked by aminoguanidine and antagonized by co-administration of L-arginine but not D-arginine. The increase of NO release in the damaged stomach was attenuated by pretreatment with L-NAME or co-application of EGTA, and the latter almost totally inhibited the increase of Ca 2+ in the lumen. The enhanced acid secretory response in the presence of L-NAME was also inhibited by cimetidine, FPL-52694 (a mast stabilizer) or sensory deafferentation. Mucosal exposure to TC caused an increase of luminal histamine output together with a decrease in the number of mucosal mast cells in the stomach. These changes were prevented by FPL-52694 or sensory deafferentation. These results suggest the 1) damage in the stomach may activate acid stimulatory pathway in addition to a PG -, NO -, and Ca 2+-dependent inhibitory mechanism, but the latter effect overcomes the former, resulting in a decrease in acid secretion, 2) acid stimulation in the damage stomach is mediated by histamine released from the mucosal mast cell, a process interacting with capsaicin-sensitive sensory nerves, and 3) the increase of luminal Ca 2+ is an adaptive response of the stomach to damage and plays a role in increasing NO production and hence in regulating acid secretion.
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