Regulatory mechanism of acid secretory response in the stomach following injury : Role of nitric oxide.

先前的研究表明，胃损伤伴随着酸分泌的减少，至少部分由内源性前列腺素（pg）介导。在本研究中，我们研究了内源性一氧化氮（NO）在牛磺胆酸（TC）损伤后胃酸分泌的调节机制中的作用。将大鼠胃置于离体腔内，灌注生理盐水，在此条件下，测量20 mM牛磺胆酸盐（TC）作用30 min前后的粘膜电位差（PD）、腔内pH和胃酸分泌。粘膜暴露于TC导致PD减少和酸分泌减少，同时一氧化氮（NO）和腔内含量Ca^<2+>增加。先前给予N^ g -硝基- l -精氨酸甲酯（L-NAME，一种NO生物合成抑制剂）和吲哚美辛（一种环加氧酶抑制剂）对PD和pH（基础酸分泌）反应没有影响，但显著减弱了TC对酸分泌的抑制作用。在L-NAME存在的情况下，TC损伤后胃酸分泌确实增强。L-NAME的这种作用不被氨基胍所模仿，并被l -精氨酸而非d -精氨酸联合施用所拮抗。L-NAME预处理或EGTA联合应用均能减弱损伤胃NO释放的增加，EGTA几乎完全抑制腔内Ca^<2+>的增加。L-NAME存在时，增强的酸分泌反应也被西咪替丁、FPL-52694（一种肥大细胞稳定剂）或感觉去传入抑制。粘膜暴露于TC引起胃腔组胺输出增加，同时胃粘膜肥大细胞数量减少，这种变化也通过FPL-52694或感觉脱神经传导减轻。这些结果表明，1)胃损伤除了激活PG-、NO-和Ca^<2+>依赖的抑制机制外，还可能激活酸模拟途径，但后者的作用克服了前者的作用，导致胃酸分泌减少；2)胃损伤的酸刺激是由粘膜肥大细胞释放的组胺介导的，该过程与辣椒素敏感的感觉神经相互作用。3)腔内Ca^<2+>的升高是胃对损伤的适应性反应，并在增加NO生成从而调节胃酸分泌中起作用。少

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 … More 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