| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1997: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Previous studies have revealed that damage in the stomach is accompanied by a decrease of acid secretion, mediated at least partly by endogenous prostaglandins (PGs). In the present research, we investigated the role of endogeneous nitric oxide (NO) in 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 under these conditions transmucosal 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 significa
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ntly 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 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 cell 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, the changes also being mitigated by FPL-52694 or sensory deafferentation. These results suggest that 1) damage in the stomach may activate acid simulatory 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 damaged 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. Less
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