Physiological significance of gastric ascorbate secretion system in the gastrointestinal disorders

在大鼠灌流胃中研究了胃抗坏血酸分泌的机制。在所研究的各种多肽激素中，八肽缩胆囊素(CCK-8)以剂量依赖的方式有效地刺激胃抗坏血酸的分泌，而其他激素则无此作用。CCK-8的这种刺激作用明显被CCK受体拮抗剂丙谷胺所阻断，表明胃抗坏血酸的分泌既受体液因素的生理调节，也受神经系统的调节。此外，静脉注射尼古丁1µg/kg可抑制CCK-8诱导的胃抗坏血酸分泌，而15µg/kg可替宁抑制CCK-8诱导的胃抗坏血酸分泌更为有效。这些结果提示香烟烟雾可降低人体胃部抗坏血酸的分泌反应。为解决胃部抗坏血酸分泌的机制，在体外细胞培养系统中进行了进一步的研究。CCK-8和氨基甲胆碱能有效地刺激原代培养的大鼠胃粘膜细胞释放抗坏血酸。我们还证实了抗坏血酸在肠上皮细胞和主动脉内皮细胞中的主动转运。这些结果表明，内源性抗坏血酸是通过胃粘膜细胞之间的转运从血液分泌到胃腔的。为了阐明胃抗坏血酸分泌系统的生理作用，我们观察了内源性抗坏血酸对亚硝胺形成的抑制作用。在禁食期间，亚硝基硫代丙氨酸的形成被有效地抑制，胃中减少的抗坏血酸通过持续的分泌反应得到恢复。这些发现有力地表明，胃中分泌的抗坏血酸作为主要的抗氧化剂发挥着自卫的作用，这种分泌反应与各种胃肠粘膜疾病的发生密切相关。

The mechanism of gastric ascorbate secretion was investigated in the perfused rat stomach. Among various peptide hormones examined, cholecystokinin octapeptide (CCK-8) potently stimulated gastric ascorbate secretion in a dose-dependent manner, but others showed no effect. This stimulation by CCK-8 was apparently abolished by a specific CCK receptor antagonist, proglumide, indicating that gastric ascorbate secretion is physiologically regulatedby humoral factors as well as nervous system. In addition, CCK-8-induced gastric ascorbate secretion was Inhibited by an intravenous administration of nicotine at a dose of 1mug/kg and it was more effectively depressed by cotinine at a dose of 15 mug/kg. These findings suggest that cigarette smoke may reduce the ascorbic acid secretory response in human stomach.Further investigation to solve the mechanism of gastric ascorbic acid secretion was carried out in in vitro cell culture system. The ascorbic acid release from a primary culture of rat gastric mucosal cells was effectively stimulated by CCK-8 and carbachol. We also demonstrated an active transport of ascorbic acid in both intestinal epithelial cells and aortic endothelial cells. These results indicate that endogenous ascorbic acid is secreted from blood to gastric lumen through its transport between these gastric mucosal cells.To clarify the physiological role of gastric ascorbate secretion system, the effect of endogenous ascorbic acid on the Inhibition of nitrosoamine formation was evaluated. The formation of nitrosothioproline was efficiently inhibited during the fasting period and the decreasing amount of gastric ascorbic acid was recovered by a continuous secretory response.These findings strongly indicate that ascorbic acid secreted in the stomach functions as a predominant antioxidant for the self-defense and that this secretory response is crossly associated with the onset of various gastrointestinal mucosal disorders.