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

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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.