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Signalling pathways and transporters involved in gastroduodenal bicarbonate secretion

参与胃十二指肠碳酸氢盐分泌的信号通路和转运蛋白

基本信息

批准号：
18590248
负责人：
TAKEUCHI Koji
金额：
$ 2.5万
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 (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

1. Coca-Cola topically applied to the mucosa for 10 min increased HCO_3^- secretion in both the stomach and the duodenum. The response in the duodenum was totally abolished by indomethacin and partially inhibited by acetazolamide, while the response in the stomach was inhibited by acetazolamide or indomethacin. Coca-Cola increased PGE_2 contents in both the stomach and the duodenum. These results suggest that Coca-Cola induces HCO_3^- secretion in both the stomach and duodenum, and the responses may be attributable to both the intracellular supply of HCO_3^-, by the aid of carbonic anhydrase, and endogenous PGs, probably related to the acidic pH of the solution.2. PGE2 and NOR-3 increased HCO_3^- secretion in the mouse duodenum in vitro, and the response to PGE_2 was inhibited by both EP3 and EP4 antagonists, while that to NOR-3 was inhibited by methylene blue. Vinpocetine (PDE1 inhibitor) and cilostamide (PDE3 inhibitor) potentiated the response to PGE2. By contrast, the stimulatory action of NOR-3 was significantly potentiated by vinpocetine but not cilostamide. These results suggested that PDE1 and PDE3 are involved in the regulation of duodenal HCO_3^- secretion and that the response to PGE_2 is associated with both PDE1 and PDE3, while the response to NO is mainly modulated by PDE1.3. Both NOR-3 and 8-brcGMP dose-dependently stimulated HCO_3^- secretion, and the response to NOR-3 was inhibited by methylene blue. Likewise, the secretion induced by NOR-3 or 8-br-cGMP was attenuated by ONO-8711 (EP1 antagonist) as well as indomethacin and potentiated by both vinpocetine and zaprinast. NOR-3 increased the mucosal PGE_2 content in a methylene blue-inhibitable manner. These results suggest that NO stimulates gastric HCO_3^- secretion mediated intracellularly by cGMP and modified by both PDE1 and PDE5, and this response is finally mediated by endogenous PGE_2 via the activation of EP1 receptors.

1.在胃和十二指肠粘膜上涂抹可口可乐10分钟可增加HCO_3 ~-的分泌。十二指肠的反应被吲哚美辛完全消除，乙酰唑胺部分抑制，而胃的反应被乙酰唑胺或吲哚美辛抑制。可口可乐使胃和十二指肠中PGE_2含量增加。这些结果表明，可口可乐可诱导胃和十二指肠分泌HCO_3^-，这种效应可能是由碳酸酐酶和内源性PG共同作用的结果，而内源性PG可能与溶液的酸性pH有关. PGE_2和NOR-3可增加小鼠离体十二指肠HCO_3 ~-的分泌，其作用可被EP_3和EP_4拮抗剂所抑制，而NOR-3的作用可被亚甲蓝所抑制。长春新碱（PDE 1抑制剂）和西洛酰胺（PDE 3抑制剂）加强对PGE 2的反应。相比之下，NOR-3的刺激作用被长春新碱而不是西洛酰胺显著增强。结果提示，PDE_1和PDE_3参与了十二指肠HCO_3 ~-分泌的调节，对PGE_2的反应与PDE_1和PDE_3有关，而对NO的反应主要受PDE_1的调节。NOR-3和8-brcGMP均呈剂量依赖性地刺激HCO_3 ~-的分泌，而NOR-3的作用可被亚甲蓝抑制。同样，NOR-3或8-br-cGMP诱导的分泌被ONO-8711（EP 1拮抗剂）以及吲哚美辛减弱，并被长春新碱和扎匹司特增强。NOR-3可使粘膜PGE_2含量升高，且呈亚甲基蓝染色阳性。提示NO刺激胃HCO_3 ~-的分泌是由cGMP介导的，并经PDE_1和PDE_5修饰，最后由内源性PGE_2通过激活EP_1受体介导。