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

损伤后胃酸分泌反应的调节机制：一氧化氮的作用。

• 批准号: 08457638
• 负责人: TAKEUCHI Koji
• 金额: $ 0.96万
• 依托单位: Kyoto Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457638/
• 关键词: surface epithelial damage; stomach; acid secretion; nitric oxide; luminal Ca^<2+>; mucosal mast cell; histamine; capsaicin-sensitive sensory neuron; 酸分泌抑制; 修復機転; 粘膜血流

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

以前的研究表明，胃损伤伴随着酸分泌的减少，至少部分是由内源性前列腺素(PGs)介导的。在本研究中，我们探讨了内源性一氧化氮(NO)在牛磺胆酸盐(TC)损伤后胃酸分泌调节机制中的作用。将大鼠胃固定在体外小室中，灌流生理盐水，在此条件下，测定20 mM牛磺胆酸盐(TC)作用30min前后的跨粘膜电位差(PD)、管腔pH和胃酸分泌。粘膜暴露于TC后，PD减少，胃酸分泌减少，肠腔内容物中一氧化氮(NO)和Ca~(2+)升高。预先给予N^G-硝基-L-精氨酸甲酯(L，NO生物合成抑制剂)和吲哚美辛(环氧合酶抑制剂)对PD和pH(基础酸分泌)的反应没有影响，但显著影响…更能减弱TC对胃酸分泌的抑制作用。在L-NAME存在下，经TC损伤后，胃酸分泌明显增强，这种作用不被氨基胍所模拟，可被L-精氨酸拮抗，但不能被D-精氨酸所拮抗。L-NAME或联合应用EGTA可减轻损伤胃组织中NO释放的增加，后者几乎完全抑制损伤胃腔内Ca~(2+)和Gt~(2+)的增加。西咪替丁、肥大细胞稳定剂fpl-52694或感觉去传入也可抑制在L-NAME存在下增强的酸性分泌反应。粘膜暴露于TC可导致胃腔组胺输出增加，同时胃粘膜肥大细胞数量减少，这种变化也可被fpl-52694或感觉去传入减轻。这些结果提示：1)胃损伤除依赖PG-、NO-和Ca~(2+)的抑制机制外，还可能激活酸模拟途径，但后者克服了前者，导致胃酸分泌减少；2)损伤胃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；较少

项目成果

Takeuchi K.et al.: "Role of nitric oxide in mucosal blood flow response and healing of HCI-induced lesions in rat stomachs. Digestion 58:1997,19-27" Digestion. 58. 19-27 (1997)

Takeuchi K.等人：“一氧化氮在粘膜血流反应和 HCI 诱导的大鼠胃损伤愈合中的作用。消化 58：1997,19-27”消化。

Takeuchi K.: "Current Topics in Pharmacology/Regulatory mechanism of acid secretory response in the stomach following injury" Research Trends(ed.Robert Richard)(in press), (1998)

Takeuchi K.：“损伤后胃酸分泌反应的药理学/调节机制的当前主题”研究趋势（罗伯特·理查德编）（出版中），（1998）

Takeuchi K.et al.: "Role of nitric oxide in mucosal blood flow response and healing of HCl-induced lesions in rat stomachs." Digestion. 58. 19-27 (1997)

Takeuchi K.等人：“一氧化氮在粘膜血流反应和 HCl 诱导的大鼠胃损伤愈合中的作用。”

Takeuchi K.: "Current Topics in Pharmacology/Regulatory mechanism of acid secretory response in the stomach following injury." Research Trends(ed.Robert Richard)(in press), (1998)

Takeuchi K.：“药理学/损伤后胃酸分泌反应的调节机制的当前主题。”

Kato S.et al.: "Pathways mediating pentagastrin-induced mucosal blood flow response in rat stomachs." Digestive Diseases and Sciences. 41. 485-491 (1996)

Kato S.et al.：“介导大鼠胃中五肽胃泌素诱导的粘膜血流反应的途径。”