茯苓甘草汤治疗功能性消化不良胃虚饮停证的理论及实验研究

【作者】 曹峰；

【导师】 傅延龄；

【作者基本信息】 北京中医药大学 ， 中医临床基础， 2009， 博士

【摘要】 功能性消化不良（functional dyspepsia,FD）是临床胃肠道门诊常见病,发病机制欠清,目前认为胃肠道动力障碍是FD主要的病理生理基础。其中有一类功能性消化不良患者表现为胃液体排空减缓,其临床表现类似于中医痞证中胃虚饮停证的表现。有报道显示,约有50%FD患者存在胃液体排空延迟。因此,研究FD胃液体排空延缓的具体病理机制,开发治疗FD的有效安全的方药,已经成为国内外医学界关注的热点。本论文首先对中西医防治FD的进展进行了较为全面的概述,并通过动物实验研究,设计FD胃液体排空延迟的动物模型并对其进行评价。同时观察茯苓甘草汤对FD大鼠胃液体排空及胃底、胃窦及十二指肠中乙酰胆碱酯酶（AChE）、一氧化氮（NO）含量的影响,探讨茯苓甘草汤的作用机制。1文献综述参照古、今中医有关文献对FD的中医病名、病因病机、辨证论治方法、临床及实验研究进展进行了探讨,并对现代医学在FD研究中所取得的进展进行了总结,进一步明确了FD的发病机制、诊断和治疗的研究进展;总结了中医对FD的病因及发病机制、中医诊断及经方治疗FD临床及实验研究进展;并搜集和整理已发表的有关茯苓甘草汤研究报道,阐述了茯苓甘草汤的现代研究进展;最后搜集和整理了近现代著名医家应用茯苓甘草汤的经验及验案。2理论研究理论研究部分首先对功能性消化不良胃虚饮停证的认识进行了理论溯源;其次对茯苓甘草汤的适宜证象进行总结,认为:①心下悸,②四肢不温,③口不渴,④胃中痞满,⑤胃中振水音,⑥不欲饮水,⑦舌淡白,苔薄白而滑,⑧脉沉弦是茯苓甘草汤的主证;随后对茯苓甘草汤方药组成解析,认为生姜是仲景治疗中焦饮停的一味主药。3实验研究3.1实验一目的:探讨建立功能性消化不良胃虚饮停证的动物模型方法并对其进行评价。方法:给予温度为0℃、浓度为0.5mol/L盐酸（用量按0.8ml/100g）灌胃,每日1次,共造模2周。造模完成1周后观察胃液体排空的改变,并与正常组作对照。期间观察两组大鼠饮水、进食量的变化。结果:模型组大鼠出现饮水、进食量减少,与正常组比较差异有显著性意义（P<0.01）,同时胃液体排空明显减缓（P<0.01）。胃部肉眼观察模型组大鼠胃较正常组明显胀满,胃底尤为明显。模型组胃无明显器质性改变,胃黏膜无明显溃疡点及炎症反应。结论:该造模方法操作简便、周期较短,实验条件易于控制,模型表现基本符合FD动物模型胃液体排空障碍的生物学特征,同时也契合中医胃虚饮停证的临床表现,可用于相关的实验研究。3.2实验二目的:观察茯苓甘草汤对功能性消化不良（FD）大鼠胃液体排空的影响,并探讨其作用机制。方法:60只SD大鼠随机分为正常组、模型组、莫沙必利组、生姜组和茯苓甘草汤组。采用盐酸灌胃模型,造模结束后一周观测大鼠胃液体排空。结果:茯苓甘草汤能显著促进FD大鼠胃液体排空。茯苓甘草汤可明显减轻模型组大鼠胃胀满,改善FD大鼠胃底上皮细胞增生,同时还有保护十二指肠黏膜的作用。结论:茯苓甘草汤可对FD大鼠模型均有较好的促进胃液体排空率的作用。3.3实验三目的:观察茯苓甘草汤对FD大鼠胃底、胃窦及十二指肠中一氧化氮（NO）含量的影响,并探讨其作用机制。方法:60只SD大鼠随机分为正常组、模型组、莫沙必利组、生姜组和茯苓甘草汤组。采用盐酸灌胃模型,以硝酸还原酶法测定胃底、胃窦、十二指肠NO的含量,。结果:茯苓甘草汤能显著促进FD大鼠胃液体排空,并可明显降低FD大鼠胃底、胃窦、十二指肠NO含量。结论:茯苓甘草汤可对FD大鼠模型均有较好的促进胃液体排空率的作用,同时茯苓甘草汤可明显降低FD大鼠胃底、胃窦、十二指肠NO含量。提示茯苓甘草汤可能是通过降低NO的含量的作用改善FD大鼠的胃液体排空延迟。3.4实验四目的:观察茯苓甘草汤FD大鼠胃液体排空及胃底、胃窦及十二指肠中乙酰胆碱酯酶（AChE）含量的影响,并探讨其可能的作用机制。方法:60只SD大鼠随机分为正常组、模型组、莫沙必利组、生姜组和茯苓甘草汤组。采用盐酸灌胃模型,化学比色法测定胃底、胃窦、十二指肠AChE的含量。结果:茯苓甘草汤能显著促进FD大鼠胃液体排空,增加胃底、胃窦、十二指肠AChE的含量。茯苓甘草汤能增加大鼠胃肠内AChE的含量,其效果与5-HT₄受体激动剂莫沙必利无明显差别（P>0.05）。结论:茯苓甘草汤可对FD大鼠模型均有较好的促进胃液体排空率的作用,同时茯苓甘草汤可明显降低FD大鼠胃底、胃窦、十二指肠NO含量,增加胃底、胃窦、十二指肠AChE的含量。提示茯苓甘草汤可能是通过升高胃肠AChE的含量,降低NO的含量的综合作用改善FD大鼠的胃液体排空延迟。更多还原

【Abstract】 Functional dyspepsia（FD） is a kind of common disease in gastrointestinal tract clinic,and the pathogenesis is not clear.Recently,it is considered that FD results from the gastrointestinal motility disorder.Delayed gastric liquid emptying is the clinical manifestation of some of the patients with functional dyspepsia similar to epigastric fullness of stomach deficiency and congestion of fluid-retention in syndromes of TCM.It is reported that 50%of the patients with functional dyspepsia have symptom of delayed gastric liquid emptying. Therefore,to study the pathological mechanism of the syndrome of delayed gastric liquid emptying,developing new drugs with effective and safe has become the research hotspot at present.Recent research progresses on prevention and treatment of FD has been performed in the aspects of Chinese medicine and modern medicine,and establishing the animal model of FD with delayed gastric liquid emptying and evaluating it by experimental study.Observe the effect of Fuling Gancao Decoction on gastric liquid emptying and content of nitric oxide and acetylcholine esteras in the gastric fundus,antrum and duodenal tissu of functional dyspepsia rats and investigate the mechanism.1 Reference reviewThe reference review discussed the source of disease name of TCM for FD,etiology and pathogenesis of TCM,selection of therapeutic methods by different stages or according to the differential syndrome diagnosis,advance on the clinical and experimental research as well as the problems lying in the research of TCM and corresponding strategies.We also have summarized the recent research progresses on the FD.In the meanwhile,we further exploited the pathologic characteristics,diagnosis and treatment of FD;summarized etiology and pathogenesis of TCM for FD and application of Classical Prescriptions in clinical and experimental study;Collected and arranged the Literatures and summarized the recent research progresses of Fuling Gancao Decoction;Finally, collected and arranged the literatures of proved cases and clinical experiences of Fuling Gancao Decoction.2 Theoretical studyThe Theoretical study first discussed the source of TCM for stomach deficiency and congestion of fluid-retention in syndromes of FD;Secondly, summarized the indications of Fuling Gancao Decoction,that is:①epigastric throb,②cold hands and feet in syncope,③hydroadipsia,④gastric blockade,⑤gastric splashing sound,⑥no desire for drinks,⑦light white tongue,thin-white and smooth fur,⑧deep and wiry pulse are the indications of Fuling Gancao Decoction;Subsequently,analyzed the composition of Fuling Gancao Decoction,considered that ginger is the main drug which treating congestion of fluid-retention in Middle-Jiao by Zhang Zhongjing.3 Experimental study3.1 Experiment oneObjective:To establish the animal model of FD with delayed gastric liquid emptying and evaluat it.Methods:The model group received 0℃,0.5mol/L Hydrochloric acid by gastric perfusion directly every day in two weeks.The gastric liquid emptying was measured and compared with normal group one week later.During the Period of these three weeks,food-intake and water-intake of each group of rats were measured.Results:The food-intake and water-intake of the model groups were decreased significantly than the normal groups（P<0.01）,and the gastric liquid emptying as delayed significantly than the normal groups（P<0.01）.Stomach was enlarged significantly than the normal groups at visual inspection,especially for the gastric fundus.The stomach organic change and ulcer,inflammation of gastric mucosa had not been founded in model groups.Conclusion:With the simple operation,short period and easy control of experimental conditions,the model group is in line with the biology characteristic of FD with delayed gastric liquid emptying and stomach deficiency and congestion of fluid-retention in syndromes of tcm,can be used in experimental study.3.2 Experiment twoObjective:To observe the effect of Fuling Gancao Decoction on gastric liquid emptying and investigate the mechanism.Methods:All 60 rats were randomly divided into normal group,model group,mosapride group,ginger group and Fuling Gancao Decoction group.Animal model of FD was set up by gastric perfusion of Hydrochloric acid.A week later, the gastric liquid emptying was measured.Results:Fuling Gancao Decoction could obviously improve the function of gastric emptying liquid.Fuling Gancao Decoction could obviously improve the gasterectasis,reduce the gastric antral epithelial cell proliferation,and protect the duodenal mucosa.Conclusion:Fuling Gancao Decoction had a better effect of improving the function of gastric emptying liquid.3.3 Experiment threeObjective:To observe the effect of Fuling Gancao Decoction on content of nitric oxide and acetylcholine esteras in the gastric fundus,antrum and duodenal tissu of functional dyspepsia rats and investigate the mechanism.Methods:All 60 rats were randomly divided into normal group,model group,mosapride group,ginger group and Fuling Gancao Decoction group.Animal model of FD was set up by gastric perfusion of Hydrochloric acid.The contents of NO in the gastric fundus,antrum and duodenal tissu were measured by nitrate reductase method.Results:Fuling Gancao Decoction could obviously improve the function of gastric emptying liquid,and lowering the NO contents contents in the gastric fundus, antrum and duodenal tissu tissue.Conclusion:Fuling Gancao Decoction had a better effect of improving the function of gastric emptying liquid,and lowering the NO contents in the gastric fundus,antrum and duodenal tissu tissue,suggesting that Fuling Gancao Decoction improve the function of gastric emptying liquid by the effect of lowering NO contents in the gastrointestinal tract.3.4 Experiment fourObjective:To observe the effect of Fuling Gancao Decoction on gastric liquid emptying and content of acetylcholine esteras in the gastric fundus,antrum and duodenal tissu of functional dyspepsia rats and investigate the mechanism.Methods:All 60 rats were randomly divided into normal group,model group,mosapride group,ginger group and Fuling Gancao Decoction group.Animal model of FD was set up by gastric perfusion of Hydrochloric acid.The contents of AChE in the gastric fundus,antrum and duodenal tissu were measured by chemical colorimetric method.Results:Fuling Gancao Decoction could obviously improve the function of gastric emptying liquid,and heighten AChE contents in the gastric fundus,antrum and duodenal tissu tissue.Fuling Gancao Decoction could heighten AChE contents in the gastrointestinal tract,which was similar to the 5-HT₄ receptor agonist mosapride.Conclusion:Fuling Gancao Decoction had a better effect of improving the function of gastric emptying liquid,and lowering the NO contents and heighten AChE contents in the gastric fundus,antrum and duodenal tissu tissue,suggesting that Fuling Gancao Decoction improve the function of gastric emptying liquid by the comprehensive effect of lowering NO contents and heighten AChE contents in the gastrointestinal tract.更多还原