Signalling pathways and transporters involved in gastroduodenal bicarbonate secretion

1. 可口可乐局部作用于粘膜10分钟后，胃和十二指肠的HCO_3^-分泌均增加。吲哚美辛能完全消除十二指肠反应，乙酰唑胺能部分抑制十二指肠反应，而乙酰唑胺或吲哚美辛能抑制胃反应。可口可乐提高了胃和十二指肠中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HCO_3^-，这种反应可能与碳酸酐酶在细胞内提供HCO_3^-和内源性pg有关，可能与可口可乐溶液的酸性pH有关。PGE2和no -3均能提高小鼠十二指肠HCO_3^-的分泌，EP3和EP4拮抗剂均能抑制PGE2的分泌，而亚甲基蓝则能抑制no -3的分泌。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，长春西汀显著增强了NOR-3的刺激作用，而西洛胺则没有。上述结果表明，PDE1和PDE3参与了十二指肠HCO_3^-分泌的调节，对PGE_2的反应与PDE1和PDE3有关，而对NO的反应主要由PDE1.3调节。no3和8-brcGMP均能剂量依赖性地刺激HCO_3^-的分泌，而亚甲基蓝能抑制对no3的反应。同样，ONO-8711 （EP1拮抗剂）和吲哚美辛能减弱NOR-3或8-br-cGMP诱导的分泌，长春西汀和zaprinast能增强。no -3以抑制亚甲基蓝的方式增加粘膜PGE_2含量。上述结果表明，NO刺激由cGMP介导、由PDE1和PDE5修饰的胃HCO_3^-分泌，并最终由内源性PGE_2通过激活EP1受体介导。

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.