Signalling pathways and transporters involved in gastroduodenal bicarbonate secretion

1.胃和十二指肠局部应用可口可乐10分钟，可促进HCO3~-的分泌。十二指肠的这种反应可被消炎痛完全消除，被乙酰唑胺部分抑制，而胃的这种反应可被消炎痛或消炎痛所抑制。可口可乐可增加胃和十二指肠中PGE_2的含量。这些结果表明，可口可乐可诱导胃和十二指肠分泌HCO3~-，这种反应可能与碳酸酐酶介导的细胞内HCO3~-供应和内源性PGs有关，可能与溶液的酸性pH有关。PGE2和NOR-3可促进小鼠十二指肠HCO3~-的分泌，对PGE_2的反应可被EP3和EP4拮抗剂所抑制，而对NOR-3的反应可被亚甲蓝抑制。长春西汀(PDE1抑制剂)和西洛胺(PDE3抑制剂)增强了对PGE2的反应。相比之下，长春西汀可显著增强NOR-3的兴奋作用，而西洛胺则无此作用。这些结果提示，PDE1和PDE3参与十二指肠HCO3-分泌的调节，对PGE_2的反应与PDE1和PDE3有关，而对NO的反应主要受PDE1.3的调节。NOR-3和8-brcGMP均呈剂量依赖性地刺激HCO3~-分泌，亚甲蓝抑制NOR-3的反应。同样，NOR-3或8-br-cGMP诱导的分泌可被EP1拮抗剂ONO-8711和吲哚美辛减弱，并被长春西汀和扎匹司特增强。NOR-3以亚甲基蓝抑制的方式增加粘膜PGE_2含量。这些结果提示，NO可通过细胞内cGMP介导和PDE_1、PDE_5共同调节胃液中HCO3~+的分泌，并通过激活EP1受体最终由内源性PGE_2介导。

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.