Pharmacological studies on the neuronal and peptidergic regulatory mechanism of gastric mucus secretion and the mucosal defenses

为了阐明神经调节系统在胃粘膜防御机制中的作用，我们用几种动物或组织标本测定了胃粘液和胃酸分泌及粘膜血流量。主要结果如下：1.中枢作用药物通过迷走神经促进胃粘液分泌。M3受体参与了这一反应。2.研究辣椒素敏感神经在胃防御机制中的作用。在几种动物中，辣椒素神经被发现具有胃保护作用。近年来，一氧化氮(NO)在胃功能中的重要作用被提出。结果表明，静脉注射NO供体对胃酸分泌有明显刺激作用，对胃粘液分泌有中度刺激作用。相反，一氧化氮合酶抑制剂抑制了乙醇诱导的胃酸分泌，提示内源性一氧化氮参与了胃酸的分泌。至于胃粘液的分泌，NOS抑制剂对粘液的分泌没有影响。3.前列腺素可促进胃粘液细胞分泌粘液，但刺激作用不如体内制剂。4.EGF类似物MG111对阿司匹林-盐酸或PAF诱导的胃出血有抑制作用，该药对胃酸分泌无明显影响，其保护作用可能与胃防御机制有关。5.应激暴露可引起胃粘膜缺血再灌注，并产生多种自由基。我们发现，血红蛋白的代谢产物胆红素具有自由基清除剂的作用，并对应激诱导的胃损伤具有保护作用。

In order to clarify the neuronal autacoid regulatory system of gastric mucosal defense mechanisms, we measured gastric mucus and acid secretion and mucosal blood flow using several animal or tissue preparations. The main results were as follows : 1. Gastric mucus secretion was increased via the vagus nerves by centrally acting drugs. The muscarinic M3 receptor was involved in this response. 2. The role of capsaicin sensitive nerves in the gastric defense mechanism was studied. In several animal dodels, the capsaicin nerves was found to possess the gastroprotective actions. Recently, the important role of nitric oxide (NO) in gastric functions has been suggested. According to our results, intravenous injection of NO donors markedly stimulated gastric acid secretion, and moderately stimulated gastric mucus secretion. In contrast, inhibitors of NO synthase depressed the bethanechol-induced gastric acid secretion, suggesting an endogenous involvement of NO in gastric acid secretion. As for gastric mucus secretion, NOS inhibitors did not affect the mucus secretion. 3. Prostaglandins induced gastric mucus secretion in gastric mucous cells, but the stimulatory potency was not so great, as comared with that noted in the vivo preparation. 4. MG111, an EGF analog, inhibited the gastric hemorrhage induced by aspirin-HCI or PAF.Since this drug has no action on gastric acid secretion, its protective action would be due to gastric defense mechanism. 5. Stress exposure induces ischemia-reperfusion in the gastric mucosa, which develops several kinds of radicals. We found that bilirubin, a metabolized product of hemoglobin, acts as a radical scavenger, and possesses a protective action against stress-induced gastric lesions.