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

先前的研究表明，胃的损伤伴随着酸分泌的减少，至少部分由内源性前列腺素（PGs）介导。在本研究中，我们调查内源性一氧化氮（NO）的调节机制中的作用，在胃酸分泌的牛磺胆酸钠（TC）损伤后，在胃。将大鼠胃固定在离体室中并用盐水灌注，在这些条件下，在应用20 mM牛磺胆酸盐（TC）30 min之前和之后测量跨粘膜电位差（PD）、管腔pH和酸分泌。同时管腔内容物中一氧化氮（NO）和Ca^2+增加。预先给予N^G-硝基-L-精氨酸甲酯（L-NAME ;一种NO生物合成抑制剂）以及吲哚美辛（一种环氧合酶抑制剂）不影响PD和pH（基础酸分泌）反应，但对PD和pH（基础酸分泌）反应有显著影响。 ...更多信息 能明显减弱TC对胃酸分泌的抑制作用。在L-NAME存在下，TC损伤后胃酸分泌实际上增加，L-NAME的这种作用不能被氨基胍模拟，并且可以被L-精氨酸拮抗，但不能被D-精氨酸拮抗。用L-NAME或EGTA预处理可抑制损伤胃NO释放的增加，EGTA几乎完全抑制损伤胃内Ca^2+的增加。西咪替丁、FPL-52694（一种肥大细胞稳定剂）或感觉传入阻滞也能抑制L-NAME存在下增强的酸分泌反应。粘蛋白暴露于TC导致管腔组胺输出增加以及胃中粘膜肥大细胞数量减少，FPL-52694或感觉传入阻滞也减轻了这些变化。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，还可能激活酸刺激途径，但后者的作用克服了前者，导致酸分泌减少; 2）胃损伤中的酸刺激是由粘膜肥大细胞释放的组胺介导的，这是一个与辣椒素敏感的感觉神经相互作用的过程，3）胃腔Ca^<2+>的增加是胃对损伤的适应性反应，并在增加NO产生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