Histamine Release Mechanism from ECL Cells of Gastric Mucosa via Guanylate Cyclase and its Related Pharmacological Features

本课题的主要研究内容是ECL细胞通过鸟苷酸环化酶释放组胺的机制。结果表明：1）一氧化氮（NO）供体刺激小鼠离体胃的胃酸分泌。法莫替丁可抑制对低剂量的反应，但对高剂量无抑制作用。NO供体使ECL细胞释放组胺。但这些药物可能通过直接作用于胃壁细胞而抑制胃酸分泌。2）NOS抑制剂可抑制胆碱能药物和胃泌素样肽引起的胃酸分泌反应。因此，NO可能参与了ECL细胞释放组胺的过程。3）ECL细胞释放组胺是由cAMP和cGMP引起的。这一发现表明，鸟苷酸环化酶，以及腺苷酸环化酶，与组胺释放的细胞内信号。4）IBMX，一种非特异性磷酸二酯酶抑制剂，刺激酸分泌，但扎普司特，V型磷酸二酯酶抑制剂，对酸分泌没有影响。V型磷酸二酯酶可能在ECL细胞释放组胺中不起重要作用。5）增加细胞内钙离子浓度的药物刺激酸分泌。法莫替丁可抑制弱分泌反应，但不阻断强分泌反应。提示ECL细胞对胞内钙离子浓度的敏感性高于壁细胞。6）内源性NO和外源性NO均抑制肥大细胞内ECL细胞释放组胺。肥大细胞释放组胺的机制明显不同于ECL细胞。

The theme of the present project has been focused on histamine release mechanism from ECL cells via guanylate cyclase. The results are summarized in the following six point :1) Nitric oxide (NO) donors stimulated gastric acid secretion in the mouse isolated stomach preparation. The response to their low doses, but not to their high doses, was inhibited by famotidine. The NO donors produced histamine release from ECL cells. However, these drugs inhibited gastric acid secretion probably by a direct action on gastric parietal cells.2) Acid secretory responses to cholinergic agents and gastrin like peptides were inhibited by treatment with NOS inhibitors. Therefore, histamine release from ECL cells by NO may be involved in these acid secretory responses.3) Membrane permeable cAMP and cGMP produced histamine release from ECL cells. This finding suggests that guanylate cyclase, as well as adenylate cyclase, is associated with intracellular signaling of histamine release.4) IBMX, a nonspecific phophodiesterase inhibitor, stimulated acid secretion, but zaprinast, a V-typed phosphodiesterase inhibitor, had no effect on acid secretion. V-typed phosphodiesterase may not play a significant role in histamine release from ECL cells.5) Treatment with drugs which increase intracellular calcium concentration stimulated acid secretion. The weak secretory response was inhibited by famotidine, but the strong response was not blocked. This finding suggests that ECL cells have higher sensitivity to intracellular calcium concentration than parietal cells.6) Both of endogenous NO and exogenous NO inhibited histamine release from ECL cells in mast cells. Mast cells was apparently different from ECL cells in histamine releasing mechanism.