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

本项目的主题集中在通过鸟苷酸环化酶从ECL细胞释放组胺的机制上。结果总结为以下6点：1)一氧化氮（NO）供体刺激小鼠离体胃制剂胃酸分泌。法莫替丁抑制了他们对低剂量而不是高剂量的反应。一氧化氮供体使ECL细胞释放组胺。然而，这些药物抑制胃酸分泌可能是直接作用于胃壁细胞。2) NOS抑制剂抑制了胆碱能药物和胃泌素样肽对酸的分泌反应。因此，一氧化氮从ECL细胞释放组胺可能参与了这些酸分泌反应。3)膜透性cAMP和cGMP使ECL细胞释放组胺。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传导有关。4)非特异性磷酸二酯酶抑制剂IBMX刺激酸性分泌，而v型磷酸二酯酶抑制剂zaprinast对酸性分泌无影响。v型磷酸二酯酶可能在ECL细胞的组胺释放中不起重要作用。5)增加细胞内钙浓度的药物刺激酸分泌。法莫替丁对弱分泌反应有抑制作用，对强分泌反应无阻断作用。这表明ECL细胞对细胞内钙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ECL细胞的组胺释放。肥大细胞与ECL细胞在组胺释放机制上存在明显差异。

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.