胃虚水停动物模型的建立与伤寒论治水三方干预作用研究
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摘要
目的
本实验拟运用中医的理论和方法建立一种新的病证动物模型——胃虚水停证动物模型，并用中医多方对比的方法来反证该动物模型，为中医证候的客观化及经方的临床运用提供科学依据。
方法
1、运用中医的病因学理论，采用大量多次灌服冰水、吹风加饥饿的方法，建立胃虚水停动物模型。实验用昆明种小鼠，40只，雌雄各半，体重22-28g，随机分为空白对照组和模型组两个组。实验组每天用冰水灌胃6次，上下午各三次；每次灌胃前给小鼠用电风扇吹风15分钟，每次灌胃后再用电风扇吹风15分钟；每天上午和下午各断食一次，但不断水，连续造模14天。空白组为健康小鼠，每天给以常规饮食。在建立动物模型完成后一周处死动物进行指标检测。采用饮水量差值测定法测定饮水量，食物量差值测量进食量，用B超机检查胃部的液体潴留情况，采用考马斯亮兰显色法测定胃窦一氧化氮(NO)的含量,以硝酸还原酶法测定组织匀浆中的NO含量。同时,严格按照试剂盒说明书测定蛋白含量，观察胃解剖结构病理切片。
2、选用茯苓甘草汤、七味白术散、痛泻要方三方，以对比治疗的方法来反证该病证动物模型。实验造模同第一个实验，采用饮水量差值测定法测定饮水量，食物量差值测量进食量，断头取血检测血液中的血浆胃动素、血管活性肠肽，用SPSS软件处理统计资料。
3、运用伤寒论治水三方（茯苓甘草汤、苓桂术甘汤、苓桂甘枣汤）对胃虚水停证模型进行对比治疗，以验证茯苓甘草汤的疗效。实验用昆明种小鼠72只，随机分为空白对照组、模型组、痛泻要方组、七味白术散组、茯苓甘草汤组、吗丁啉组，实验造模同第一个实验，造模完成后，给各组动物用相应的中药汤剂（伤寒论治水三方煎液）灌胃治疗，然后采用饮水量差值测定法测定饮水量，食物量差值测量进食量，断头取血检测血液中的血浆及胃窦组织中胃动素、血清中和胃窦组织中胃泌素，用聚合酶链式反应（PCR）测定胃窦组织中胃动素受体和胃泌素受体mRNA的表达。
4、运用伤寒论治水三方（茯苓甘草汤、苓桂术甘汤、苓桂甘枣汤）对胃虚水停证进行预防性治疗，以了解三方对胃虚水停证模型的预防效果。。造模方法同第一个实验，在每次造模前一个小时，用茯苓甘草汤、苓桂术甘汤、苓桂甘枣汤、吗丁啉按小鼠体重每天给以12ml/kg的相应药物灌胃，直到造模结束。然后观察小鼠体征（精神状态、活动度、饮食量、体重变化、大小便、鼠毛光泽度、胃部外形等）并测定血液胃动素、胃泌素含量。
结果
1、观察小鼠体征及检测指标发现，在造模第7天，有部分小鼠出现呕吐，呃逆，胃部出现轻微胀满，胃部触诊听诊有振水感，在第10天，接近半数动物出现呕吐、呃逆，表现有精神萎靡不振，怕冷，喜群卧，活动量明显减少，消瘦，对外界刺激反应不灵敏。在建立模型后的一周内，模型组小鼠毛色略显干枯、大便无明显改变，个别有便溏征象。模型组小鼠的日均饮水量非常显著少于空白对照组（P<0.01），模型组小鼠的饮食量非常显著下降，少于空白组小鼠（P<0.01）。模型组小鼠的胃中甲基橙残留率非常显著高于空白对照组（P<0.01）。B超显示，模型组小鼠胃内有大量液体潴留而未排空，而空白组小鼠胃内则仅有少量液体。模型组小鼠的胃窦NO含量非常显著高于空白组（P<0.01）。模型组小鼠胃较空白组显得胀满，最明显的是胃底部位。肉眼观察，切开后的模型组小鼠胃无明显器质性上的改变，可以看到胃黏膜无明显溃疡点，无糜烂斑块，黏膜颜色比空白对照组偏白。光镜下可以见到模型组小鼠的胃底细胞为鳞状上皮细胞，细胞增生明显，胃底和胃窦细胞间质中有少量炎症细胞浸润，但程度轻微，没有见到其它明显病理学改变。胃底与胃窦都没有发现明显胃粘膜细胞肠化生等器质性病理改变。
2、通过对茯苓甘草汤、七味白术散、痛泻药方的对比治疗发现，茯苓甘草汤组进食量和饮水量较模型组和另外两个药物组增加明显，活动度明显增高。5天的治疗已经使动物基本恢复正常状态。茯苓甘草汤对小鼠胃排空的治疗作用优于七味白术散、痛泻要方、吗丁啉；茯苓甘草汤对血浆胃动素升高作用显著高于七味白术散组、痛泻要方组（（P<0.01或P<0.05），也高于吗丁啉组，而表现出与空白对照组无明显差异。但对于对肠道蠕动有显著抑制作用的血管活性肠肽的降低作用则没有七味白术散、痛泻要方显著，非常显著高于空白对照组（P<0.01）。
3、通过对伤寒论治水三方的对比治疗发现，伤寒论治水三方组小鼠的饮水量和进食量都比模型组显著增加（P<0.01或P<0.05），以茯苓甘草汤组增加最明显（P<0.01）。在血浆胃动素方面各治疗组的胃动素水平都比模型组显著增加（P<0.01或P<0.05），只有茯苓甘草汤的胃动素水平与空白对照组无显著差异，苓桂甘枣汤组胃动素水平非常显著低于空白对照组（P<0.01），苓桂术甘汤组胃动素水平非常显著高于模型组但低于空白对照组水平（P<0.05）。在胃窦组织胃动素方面，显示出与血浆胃动素相似的变化。在血清和胃窦组织胃泌素方面，各治疗组的胃泌素水平均比模型组升高，茯苓甘草汤升高胃泌素的作用最明显。在胃动素受体mRNA的表达方面，与空白对照组相比，模型组的mRNA表达非常显著降低（P<0.01）；与模型组相比，治水三方组的mRNA表达非常显著增高（P<0.01），以茯苓甘草汤增高最为显著。在胃泌素受体mRNA的表达方面，与空白对照组相比，模型组的mRNA表达呈现非常显著升高（P<0.01），与模型组相比，茯苓甘草汤的mRNA表达非常显著降低，苓桂术甘汤的mRNA表达也显著降低，苓桂甘枣汤的mRNA表达与模型组无显著统计学差异（P>0.05）。
4、通过伤寒论治水三方对胃虚水停动物模型的预防实验发现，模型组在造模第7天有小鼠出现呃逆，呕吐，胃部触诊听诊有振水感，在第10天，大约有半数出现呕吐、呃逆，表现有精神萎靡不振，怕冷，喜群居而卧，活动量明显减少，消瘦，对外界刺激反应不灵敏，小鼠毛色略显干枯、大便无明显改变，个别有便溏征象。经预防治疗的治水三方组小鼠整体情况比模型组好。茯苓甘草汤组进食量与饮水量较模型组与另外两个药物组明显增强，小鼠活动度虽然有所下降，但仍时不时能与其他小鼠嬉戏、追逐，显示出较为活跃的生命征象，毛色尚光滑不打卷，对外界刺激反应仍然灵敏，比较喜欢实验者从鼠笼外丢进笼内的食物。另外两个中药物组小鼠整体情况尚可，进食与饮水尚可，毛色光泽度有所下降，尚能四处活动觅食，对外界刺激反应比模型组好。吗丁啉组整体情况不佳，精神萎靡，但比模型组稍好，症状轻微。除吗丁啉组以外，各预防组小鼠血浆及组织中MTL含量均比模型组和空白对照升高，以茯苓甘草汤升高最显著；在血清胃泌素方面，各治疗组的胃泌素均比模型组非常显著升高（P<0.01），而且都低于空白对照组，以茯苓甘草汤升高胃泌素的效果最显著。
结论
本实验运用中医理论成功建立胃虚水停证动物模型，该模型造模步骤简便、材料易得、实验仪器要求不高、实验环境易于控制、造模所需时间较短，疾病表现符合胃动力障碍中胃内液体排空时间延长的临床特点，伤寒论治水三方对该模型有一定的治疗作用和预防作用，其中茯苓甘草汤的作用最显著，为茯苓甘草汤治疗胃虚水停证提供了科学依据。
Objective:
The experiment intends to use Chinese medicine theory and methods tobuild a new animal model of the disease-stomach empty water stop animalmodel and multi-contrast method using traditional Chinese medicine todisprove this animal model, as the objective of syndromes and after party toprovide a scientific basis for clinical use.
Methods:
1.The use of traditional Chinese medicine theory of the etiology, the use of alarge number of repeated gavage ice, hair plus hunger ways to build waterempty stomach to stop animal models. Kunming mice experiment,40, maleand female, weighing22-28g, were randomly divided into control group andmodel group two groups. Experimental group fed with ice six times a day,three times in the afternoon; administered to mice before each hair with fansfor15minutes after gavage with fans hair every15minutes; every morningand afternoon, fresh off once, but keep the water continuously modeling14days. Healthy control group mice were given daily routine diet. In the weekafter the completion of the establishment of animal models of animals sacrificed index detection. Determination of the amount of water, measuringthe difference between the amount of food intake, with the B-machineinspection stomach fluid retention cases, using Coomassie brilliant bluechromogenic assay antrum of nitric oxide (NO) levels using the differencebetween the amount of drinking water assay, Determination of nitratereductase in tissue homogenates NO content. Meanwhile, in strict accordancewith the determination of the protein content of the kit instructions, observethe anatomy of the stomach biopsy.
2. Glycyrrhiza glabra selection of soups, Qiweibaizhu scatteredTongxieyaofang tripartite contrast to the method of treatment to disprove thedisease animal model. Modeling experiments with the first experiment tomeasure the amount of water, measuring the difference between the amount offood intake, decapitated detect blood in the blood plasma motilin, vasoactiveintestinal peptide assays using the difference between the amount of drinkingwater, processed using SPSS software statistics.
3. Treatise on the use of flood tripartite (Glycyrrhiza glabra soupLingguizhugan soup, Gui Ling Gan KM) certificates on empty stomach tostop water treatment comparison model to verify the efficacy of Poria licoricesoup. Experiment with72mice were randomly divided into control group,model group, Tongxieyaofang group Qiweibaizhu scattered groups, Porialicorice soup group, domperidone group, modeling experiments with the firstexperiment, making after the mold is completed, to the animals in each groupwith the corresponding decoction (Treatise on flood tripartite decoction)gavage treatment, then measured the amount of water, measuring thedifference between the amount of food intake, decapitated blood assay usingthe difference between the amount of drinking water detected in blood plasmaand antral tissue motilin and serum gastrin antral tissue by polymerase chainreaction (PCR) measured antral tissue motilin receptor and gastrin receptor mRNA expression.
4. Treatise on the use of flood tripartite (Glycyrrhiza glabra soupLingguizhugan soup, Gui Ling Gan KM) certificates on empty stomach waterretention preventive treatment, in order to understand the tripartite preventiveeffect of water on empty stomach to stop Syndrome.. Modeling method withthe first experiment, one hour before each modeling with Poria licorice soup,Lingguizhugan soup, Gui Ling Gan KM, domperidone given appropriatemedication daily irrigation by12ml/kg body weight of mice stomach until theend of modeling. Then mice were observed signs (mental status, activity, foodintake, body weight changes, urine, rat Mao Guangze degrees, stomach shape,etc.) and measuring blood motilin and gastrin content.
Results:
1. Observed signs and detect indicators of mice found that in the first sevendays of modeling, some mice were vomiting, hiccups, stomach slight fullness,stomach palpation auscultation with a sense of vibration of water in the first10days, nearly half of the animals vomiting, hiccups, manifestations ofspiritual malaise, chills, like a flock, decreased activity, weight loss,insensitive response to external stimuli. Within a week after the establishmentof the model, the model group were slightly dry coat, no significant change instool, individual signs of loose stools. Average daily water consumption in themodel group mice very significantly less than the control group (P <0.01),food intake model mice decreased very significantly less than the controlgroup of mice (P <0.01). Residual rate of methyl orange stomach model micevery significantly higher than the control group (P <0.01). B-show, there are alot of model mice stomach without emptying fluid retention, while the controlgroup of mice stomach is only a small amount of liquid. Antral NO contentmodel group mice very significantly higher than the control group (P <0.01). Model group compared with the control group of mice stomach fullness seemthe most obvious is the fundus area. The naked eye, cut model mice did notchange significantly after the stomach on organic, you can see no significantgastric ulcer point, no plaque erosion, mucosal white color than the controlgroup. Light microscope can be seen in the model group mice cells and gastricsquamous cell, cell proliferation significantly, between the fundus and antrumin a small amount of interstitial cells of inflammatory cell infiltration, but aslight degree, did not see the other obvious pathology changed. Fundus andantrum have not found significant organic pathology, such as gastric intestinalmetaplasia cells.
2. By Poria licorice soup, Qiweibaizhu Powder, laxative side comparison ofthe treatment of pain found Poria licorice soup and water intake group wassignificantly increased compared with the model group and the other two druggroups, activity was significantly higher.5days of treatment the animals havereturned to normal state. Poria licorice decoction on mice gastric emptyingthan Qiweibaizhu scattered Tongxieyaofang, domperidone; Poria Decoctionon the role of elevated plasma motilin significantly higher Qiweibaizhuscattered groups Tongxieyaofang groups ((P <0.01or P <0.05), higher thandomperidone group, but showed no significant difference with the controlgroup, but the effect on intestinal motility has significantly reduced inhibitionof the vasoactive intestinal peptide no Qiweibaizhu scattered Tongxieyaofangsignificantly, very significantly higher than the control group (P <0.01).
3. By contrast Treatise on flood tripartite treatment found that water intake andfood intake Treatise on flood tripartite group of mice than in the model groupincreased significantly (P <0.01or P <0.05), with Poria licorice soup groupmost significant increase (P <0.01). In plasma motilin aspects than the modelgroup increased significantly (P <0.01or P <0.05) motilin levels for eachtreatment group, no significant difference in motilin levels only Poria licorice soup with the control group, Ling Gui Gan dates Tang group motilin levels arevery significantly lower than the control group (P <0.01), soup groupLingguizhugan motilin levels very significantly higher than the model grouplevel but lower than the control group (P <0.05). Motilin in the antrum tissue,the show and plasma motilin similar changes. Antral gastrin in the serum andorganizational aspects of the treatment groups compared with the model groupincreased gastrin levels, elevated gastrin Poria licorice soup the mostsignificant effect. In expression of motilin receptor mRNA, compared with thecontrol group, mRNA expression of very model group decreased significantly(P <0.01); compared with the model group, mRNA expression of great floodtripartite group was significantly higher (P <0.01), Poria licorice soupincreased the most significant. In terms of gastrin receptor mRNA expression,compared with the control group, mRNA expression in model group showedsignificant increase (P <0.01), compared with the model group, mRNAexpression of Poria licorice soup is very significantly reduced, mRNAexpression Lingguizhugan soup was also significantly reduced, no statisticallysignificant difference (P>0.05) Gui Ling Gan KM mRNA expression with themodel group.
4. By Treatise on empty stomach tripartite flood water retention prevention isfound in animal models, modeling, model group mice showed the first sevendays have hiccups, vomiting, stomach palpation auscultation with a sense ofvibration of water in the first10days, about half of vomiting, hiccups,manifestations of spiritual malaise, chills, gregarious clothes, decreasedactivity, weight loss, insensitive response to external stimuli, slightly dry coatcolor in mice, no significant change in stool, individual loose stools signs.After overall flood prevention treatment group were better than the tripartitemodel group. Poria licorice soup food intake and water intake group comparedwith the model group and the other two drugs was significantly increased, although the degree of mouse activity has declined, but still occasionally playwith other mice, chase, showing signs of a more active life, smooth coat stillnot playing volume, still sensitive to external stimuli, the experimenters preferfood thrown from the squirrel cage outside. In addition the overall situation inthe drug group were still two, eating and drinking is acceptable gloss coatdecline, and can still move around foraging response to outside stimuli betterthan the untreated group. Domperidone group overall poor performance,apathetic, but slightly better than the model group, mild symptoms. In additionto domperidone group, each group of mice prevention MTL levels in plasmaand tissues compared with the model group and control elevated to Porialicorice soup increased the most significant; in terms of serum gastrin, gastrintreatment groups very significantly higher than those in the untreated groupelements (P <0.01), but were lower than the control group, with Poria licoricesoup elevated gastrin most significant effect.
Conclusion:
In this study, the use of traditional Chinese medicine theory successfullyestablished water empty stomach to stop animal model, the model modelingstep is simple, readily available materials, laboratory equipment lessdemanding, easily controlled experimental environment, the shorter the timerequired for modeling, performance in line with gastric motility disordersobstacles stomach emptying liquid prolonged clinical features, Treatise on theflood tripartite model has a therapeutic effect and preventive effect, includingthe role of Poria licorice soup most significant, as Poria decoction of licoricewater empty stomach to stop card offers scientific basis.
本实验拟运用中医的理论和方法建立一种新的病证动物模型——胃虚水停证动物模型，并用中医多方对比的方法来反证该动物模型，为中医证候的客观化及经方的临床运用提供科学依据。
方法
1、运用中医的病因学理论，采用大量多次灌服冰水、吹风加饥饿的方法，建立胃虚水停动物模型。实验用昆明种小鼠，40只，雌雄各半，体重22-28g，随机分为空白对照组和模型组两个组。实验组每天用冰水灌胃6次，上下午各三次；每次灌胃前给小鼠用电风扇吹风15分钟，每次灌胃后再用电风扇吹风15分钟；每天上午和下午各断食一次，但不断水，连续造模14天。空白组为健康小鼠，每天给以常规饮食。在建立动物模型完成后一周处死动物进行指标检测。采用饮水量差值测定法测定饮水量，食物量差值测量进食量，用B超机检查胃部的液体潴留情况，采用考马斯亮兰显色法测定胃窦一氧化氮(NO)的含量,以硝酸还原酶法测定组织匀浆中的NO含量。同时,严格按照试剂盒说明书测定蛋白含量，观察胃解剖结构病理切片。
2、选用茯苓甘草汤、七味白术散、痛泻要方三方，以对比治疗的方法来反证该病证动物模型。实验造模同第一个实验，采用饮水量差值测定法测定饮水量，食物量差值测量进食量，断头取血检测血液中的血浆胃动素、血管活性肠肽，用SPSS软件处理统计资料。
3、运用伤寒论治水三方（茯苓甘草汤、苓桂术甘汤、苓桂甘枣汤）对胃虚水停证模型进行对比治疗，以验证茯苓甘草汤的疗效。实验用昆明种小鼠72只，随机分为空白对照组、模型组、痛泻要方组、七味白术散组、茯苓甘草汤组、吗丁啉组，实验造模同第一个实验，造模完成后，给各组动物用相应的中药汤剂（伤寒论治水三方煎液）灌胃治疗，然后采用饮水量差值测定法测定饮水量，食物量差值测量进食量，断头取血检测血液中的血浆及胃窦组织中胃动素、血清中和胃窦组织中胃泌素，用聚合酶链式反应（PCR）测定胃窦组织中胃动素受体和胃泌素受体mRNA的表达。
4、运用伤寒论治水三方（茯苓甘草汤、苓桂术甘汤、苓桂甘枣汤）对胃虚水停证进行预防性治疗，以了解三方对胃虚水停证模型的预防效果。。造模方法同第一个实验，在每次造模前一个小时，用茯苓甘草汤、苓桂术甘汤、苓桂甘枣汤、吗丁啉按小鼠体重每天给以12ml/kg的相应药物灌胃，直到造模结束。然后观察小鼠体征（精神状态、活动度、饮食量、体重变化、大小便、鼠毛光泽度、胃部外形等）并测定血液胃动素、胃泌素含量。
结果
1、观察小鼠体征及检测指标发现，在造模第7天，有部分小鼠出现呕吐，呃逆，胃部出现轻微胀满，胃部触诊听诊有振水感，在第10天，接近半数动物出现呕吐、呃逆，表现有精神萎靡不振，怕冷，喜群卧，活动量明显减少，消瘦，对外界刺激反应不灵敏。在建立模型后的一周内，模型组小鼠毛色略显干枯、大便无明显改变，个别有便溏征象。模型组小鼠的日均饮水量非常显著少于空白对照组（P<0.01），模型组小鼠的饮食量非常显著下降，少于空白组小鼠（P<0.01）。模型组小鼠的胃中甲基橙残留率非常显著高于空白对照组（P<0.01）。B超显示，模型组小鼠胃内有大量液体潴留而未排空，而空白组小鼠胃内则仅有少量液体。模型组小鼠的胃窦NO含量非常显著高于空白组（P<0.01）。模型组小鼠胃较空白组显得胀满，最明显的是胃底部位。肉眼观察，切开后的模型组小鼠胃无明显器质性上的改变，可以看到胃黏膜无明显溃疡点，无糜烂斑块，黏膜颜色比空白对照组偏白。光镜下可以见到模型组小鼠的胃底细胞为鳞状上皮细胞，细胞增生明显，胃底和胃窦细胞间质中有少量炎症细胞浸润，但程度轻微，没有见到其它明显病理学改变。胃底与胃窦都没有发现明显胃粘膜细胞肠化生等器质性病理改变。
2、通过对茯苓甘草汤、七味白术散、痛泻药方的对比治疗发现，茯苓甘草汤组进食量和饮水量较模型组和另外两个药物组增加明显，活动度明显增高。5天的治疗已经使动物基本恢复正常状态。茯苓甘草汤对小鼠胃排空的治疗作用优于七味白术散、痛泻要方、吗丁啉；茯苓甘草汤对血浆胃动素升高作用显著高于七味白术散组、痛泻要方组（（P<0.01或P<0.05），也高于吗丁啉组，而表现出与空白对照组无明显差异。但对于对肠道蠕动有显著抑制作用的血管活性肠肽的降低作用则没有七味白术散、痛泻要方显著，非常显著高于空白对照组（P<0.01）。
3、通过对伤寒论治水三方的对比治疗发现，伤寒论治水三方组小鼠的饮水量和进食量都比模型组显著增加（P<0.01或P<0.05），以茯苓甘草汤组增加最明显（P<0.01）。在血浆胃动素方面各治疗组的胃动素水平都比模型组显著增加（P<0.01或P<0.05），只有茯苓甘草汤的胃动素水平与空白对照组无显著差异，苓桂甘枣汤组胃动素水平非常显著低于空白对照组（P<0.01），苓桂术甘汤组胃动素水平非常显著高于模型组但低于空白对照组水平（P<0.05）。在胃窦组织胃动素方面，显示出与血浆胃动素相似的变化。在血清和胃窦组织胃泌素方面，各治疗组的胃泌素水平均比模型组升高，茯苓甘草汤升高胃泌素的作用最明显。在胃动素受体mRNA的表达方面，与空白对照组相比，模型组的mRNA表达非常显著降低（P<0.01）；与模型组相比，治水三方组的mRNA表达非常显著增高（P<0.01），以茯苓甘草汤增高最为显著。在胃泌素受体mRNA的表达方面，与空白对照组相比，模型组的mRNA表达呈现非常显著升高（P<0.01），与模型组相比，茯苓甘草汤的mRNA表达非常显著降低，苓桂术甘汤的mRNA表达也显著降低，苓桂甘枣汤的mRNA表达与模型组无显著统计学差异（P>0.05）。
4、通过伤寒论治水三方对胃虚水停动物模型的预防实验发现，模型组在造模第7天有小鼠出现呃逆，呕吐，胃部触诊听诊有振水感，在第10天，大约有半数出现呕吐、呃逆，表现有精神萎靡不振，怕冷，喜群居而卧，活动量明显减少，消瘦，对外界刺激反应不灵敏，小鼠毛色略显干枯、大便无明显改变，个别有便溏征象。经预防治疗的治水三方组小鼠整体情况比模型组好。茯苓甘草汤组进食量与饮水量较模型组与另外两个药物组明显增强，小鼠活动度虽然有所下降，但仍时不时能与其他小鼠嬉戏、追逐，显示出较为活跃的生命征象，毛色尚光滑不打卷，对外界刺激反应仍然灵敏，比较喜欢实验者从鼠笼外丢进笼内的食物。另外两个中药物组小鼠整体情况尚可，进食与饮水尚可，毛色光泽度有所下降，尚能四处活动觅食，对外界刺激反应比模型组好。吗丁啉组整体情况不佳，精神萎靡，但比模型组稍好，症状轻微。除吗丁啉组以外，各预防组小鼠血浆及组织中MTL含量均比模型组和空白对照升高，以茯苓甘草汤升高最显著；在血清胃泌素方面，各治疗组的胃泌素均比模型组非常显著升高（P<0.01），而且都低于空白对照组，以茯苓甘草汤升高胃泌素的效果最显著。
结论
本实验运用中医理论成功建立胃虚水停证动物模型，该模型造模步骤简便、材料易得、实验仪器要求不高、实验环境易于控制、造模所需时间较短，疾病表现符合胃动力障碍中胃内液体排空时间延长的临床特点，伤寒论治水三方对该模型有一定的治疗作用和预防作用，其中茯苓甘草汤的作用最显著，为茯苓甘草汤治疗胃虚水停证提供了科学依据。
Objective:
The experiment intends to use Chinese medicine theory and methods tobuild a new animal model of the disease-stomach empty water stop animalmodel and multi-contrast method using traditional Chinese medicine todisprove this animal model, as the objective of syndromes and after party toprovide a scientific basis for clinical use.
Methods:
1.The use of traditional Chinese medicine theory of the etiology, the use of alarge number of repeated gavage ice, hair plus hunger ways to build waterempty stomach to stop animal models. Kunming mice experiment,40, maleand female, weighing22-28g, were randomly divided into control group andmodel group two groups. Experimental group fed with ice six times a day,three times in the afternoon; administered to mice before each hair with fansfor15minutes after gavage with fans hair every15minutes; every morningand afternoon, fresh off once, but keep the water continuously modeling14days. Healthy control group mice were given daily routine diet. In the weekafter the completion of the establishment of animal models of animals sacrificed index detection. Determination of the amount of water, measuringthe difference between the amount of food intake, with the B-machineinspection stomach fluid retention cases, using Coomassie brilliant bluechromogenic assay antrum of nitric oxide (NO) levels using the differencebetween the amount of drinking water assay, Determination of nitratereductase in tissue homogenates NO content. Meanwhile, in strict accordancewith the determination of the protein content of the kit instructions, observethe anatomy of the stomach biopsy.
2. Glycyrrhiza glabra selection of soups, Qiweibaizhu scatteredTongxieyaofang tripartite contrast to the method of treatment to disprove thedisease animal model. Modeling experiments with the first experiment tomeasure the amount of water, measuring the difference between the amount offood intake, decapitated detect blood in the blood plasma motilin, vasoactiveintestinal peptide assays using the difference between the amount of drinkingwater, processed using SPSS software statistics.
3. Treatise on the use of flood tripartite (Glycyrrhiza glabra soupLingguizhugan soup, Gui Ling Gan KM) certificates on empty stomach tostop water treatment comparison model to verify the efficacy of Poria licoricesoup. Experiment with72mice were randomly divided into control group,model group, Tongxieyaofang group Qiweibaizhu scattered groups, Porialicorice soup group, domperidone group, modeling experiments with the firstexperiment, making after the mold is completed, to the animals in each groupwith the corresponding decoction (Treatise on flood tripartite decoction)gavage treatment, then measured the amount of water, measuring thedifference between the amount of food intake, decapitated blood assay usingthe difference between the amount of drinking water detected in blood plasmaand antral tissue motilin and serum gastrin antral tissue by polymerase chainreaction (PCR) measured antral tissue motilin receptor and gastrin receptor mRNA expression.
4. Treatise on the use of flood tripartite (Glycyrrhiza glabra soupLingguizhugan soup, Gui Ling Gan KM) certificates on empty stomach waterretention preventive treatment, in order to understand the tripartite preventiveeffect of water on empty stomach to stop Syndrome.. Modeling method withthe first experiment, one hour before each modeling with Poria licorice soup,Lingguizhugan soup, Gui Ling Gan KM, domperidone given appropriatemedication daily irrigation by12ml/kg body weight of mice stomach until theend of modeling. Then mice were observed signs (mental status, activity, foodintake, body weight changes, urine, rat Mao Guangze degrees, stomach shape,etc.) and measuring blood motilin and gastrin content.
Results:
1. Observed signs and detect indicators of mice found that in the first sevendays of modeling, some mice were vomiting, hiccups, stomach slight fullness,stomach palpation auscultation with a sense of vibration of water in the first10days, nearly half of the animals vomiting, hiccups, manifestations ofspiritual malaise, chills, like a flock, decreased activity, weight loss,insensitive response to external stimuli. Within a week after the establishmentof the model, the model group were slightly dry coat, no significant change instool, individual signs of loose stools. Average daily water consumption in themodel group mice very significantly less than the control group (P <0.01),food intake model mice decreased very significantly less than the controlgroup of mice (P <0.01). Residual rate of methyl orange stomach model micevery significantly higher than the control group (P <0.01). B-show, there are alot of model mice stomach without emptying fluid retention, while the controlgroup of mice stomach is only a small amount of liquid. Antral NO contentmodel group mice very significantly higher than the control group (P <0.01). Model group compared with the control group of mice stomach fullness seemthe most obvious is the fundus area. The naked eye, cut model mice did notchange significantly after the stomach on organic, you can see no significantgastric ulcer point, no plaque erosion, mucosal white color than the controlgroup. Light microscope can be seen in the model group mice cells and gastricsquamous cell, cell proliferation significantly, between the fundus and antrumin a small amount of interstitial cells of inflammatory cell infiltration, but aslight degree, did not see the other obvious pathology changed. Fundus andantrum have not found significant organic pathology, such as gastric intestinalmetaplasia cells.
2. By Poria licorice soup, Qiweibaizhu Powder, laxative side comparison ofthe treatment of pain found Poria licorice soup and water intake group wassignificantly increased compared with the model group and the other two druggroups, activity was significantly higher.5days of treatment the animals havereturned to normal state. Poria licorice decoction on mice gastric emptyingthan Qiweibaizhu scattered Tongxieyaofang, domperidone; Poria Decoctionon the role of elevated plasma motilin significantly higher Qiweibaizhuscattered groups Tongxieyaofang groups ((P <0.01or P <0.05), higher thandomperidone group, but showed no significant difference with the controlgroup, but the effect on intestinal motility has significantly reduced inhibitionof the vasoactive intestinal peptide no Qiweibaizhu scattered Tongxieyaofangsignificantly, very significantly higher than the control group (P <0.01).
3. By contrast Treatise on flood tripartite treatment found that water intake andfood intake Treatise on flood tripartite group of mice than in the model groupincreased significantly (P <0.01or P <0.05), with Poria licorice soup groupmost significant increase (P <0.01). In plasma motilin aspects than the modelgroup increased significantly (P <0.01or P <0.05) motilin levels for eachtreatment group, no significant difference in motilin levels only Poria licorice soup with the control group, Ling Gui Gan dates Tang group motilin levels arevery significantly lower than the control group (P <0.01), soup groupLingguizhugan motilin levels very significantly higher than the model grouplevel but lower than the control group (P <0.05). Motilin in the antrum tissue,the show and plasma motilin similar changes. Antral gastrin in the serum andorganizational aspects of the treatment groups compared with the model groupincreased gastrin levels, elevated gastrin Poria licorice soup the mostsignificant effect. In expression of motilin receptor mRNA, compared with thecontrol group, mRNA expression of very model group decreased significantly(P <0.01); compared with the model group, mRNA expression of great floodtripartite group was significantly higher (P <0.01), Poria licorice soupincreased the most significant. In terms of gastrin receptor mRNA expression,compared with the control group, mRNA expression in model group showedsignificant increase (P <0.01), compared with the model group, mRNAexpression of Poria licorice soup is very significantly reduced, mRNAexpression Lingguizhugan soup was also significantly reduced, no statisticallysignificant difference (P>0.05) Gui Ling Gan KM mRNA expression with themodel group.
4. By Treatise on empty stomach tripartite flood water retention prevention isfound in animal models, modeling, model group mice showed the first sevendays have hiccups, vomiting, stomach palpation auscultation with a sense ofvibration of water in the first10days, about half of vomiting, hiccups,manifestations of spiritual malaise, chills, gregarious clothes, decreasedactivity, weight loss, insensitive response to external stimuli, slightly dry coatcolor in mice, no significant change in stool, individual loose stools signs.After overall flood prevention treatment group were better than the tripartitemodel group. Poria licorice soup food intake and water intake group comparedwith the model group and the other two drugs was significantly increased, although the degree of mouse activity has declined, but still occasionally playwith other mice, chase, showing signs of a more active life, smooth coat stillnot playing volume, still sensitive to external stimuli, the experimenters preferfood thrown from the squirrel cage outside. In addition the overall situation inthe drug group were still two, eating and drinking is acceptable gloss coatdecline, and can still move around foraging response to outside stimuli betterthan the untreated group. Domperidone group overall poor performance,apathetic, but slightly better than the model group, mild symptoms. In additionto domperidone group, each group of mice prevention MTL levels in plasmaand tissues compared with the model group and control elevated to Porialicorice soup increased the most significant; in terms of serum gastrin, gastrintreatment groups very significantly higher than those in the untreated groupelements (P <0.01), but were lower than the control group, with Poria licoricesoup elevated gastrin most significant effect.
Conclusion:
In this study, the use of traditional Chinese medicine theory successfullyestablished water empty stomach to stop animal model, the model modelingstep is simple, readily available materials, laboratory equipment lessdemanding, easily controlled experimental environment, the shorter the timerequired for modeling, performance in line with gastric motility disordersobstacles stomach emptying liquid prolonged clinical features, Treatise on theflood tripartite model has a therapeutic effect and preventive effect, includingthe role of Poria licorice soup most significant, as Poria decoction of licoricewater empty stomach to stop card offers scientific basis.
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[40]李鹏，张澍田，于中麟等.消化不良患者胃窦胃体内镜表现及病理对比研究[J].中国实用内科杂志，2005，25(10)：899-901.
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[42]任丽梅，张坚，栗鹏等.功能性消化不良患者胃窦壁内NO含量与胃排空关系的探讨[J].基础医学与临床，2003，23(增刊)：62-64.
[43]Chen JD，Co E，Liang J，etc.Patterns of gastric myoelectrical activity inhuman subjects of different ages[J].Am J Physiol，1997，272(5Pt1)：1022-1027.
[44]Levanon D， Zhang M， Orr WC， etc.Effects of meal volume andcomposition on gastric myoelectrical activity [J]. Am J Physiol，2009，274(2Pt1)：430-434.
[45]谢胜，税典奎.旋复代赭汤对胃动力低下大鼠血液及组织中MTL、GAS及VIP含量的影响.第二十一届全国中西医结合消化系统疾病学术会议暨国家级中西医结合消化系统疾病新进展学习班论文汇编.2009,7(23)
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[52]税典奎,谢胜.旋复代赭汤对胃动力低下大鼠血液及组织中GAS、SP及SS含量的影响.第二十一届全国中西医结合消化系统疾病学术会议暨国家级中西医结合消化系统疾病新进展学习班论文汇编.2009,7(23)
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[1]郑小伟.中医动物模型的研制方法与评价[J].中国医药学报，2008，12(3)：45-46
[2]阐甸喜.用耗气破气理论塑造脾气虚动物模型[J].吉林中医药，2010，(2)：32-34
[3]王米渠.先天肾虚证造模种鼠子代行为的遗传实验研究[J].中医杂志，2008，39(9)：56-57
[4]郑小伟.模拟“迟脉”实验动物模型的研究[J].浙江中医学院学报，2012，14(6)：29-31
[5]周奇志.实验性“脾虚证”大鼠脑内单胺递质的变化及其择时治疗效应[J].成都中医药大学学报，2008，21(3)：36-37
[6]欧敏.血虚家兔模型红细胞变形性与SODLPO变化的实验研究[J].辽宁中医杂志，2009，23(3)：19-21
[7]区永欣.卫气生理病理的研究[J].中医杂志，2011，35(8)：490-492
[8]朱升朝.体弱易感动物模型按摩治疗的实验研究[J].中医杂志，2008，39(2)：11-12
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[13]王彩霞.Alzheime：型痴呆大白鼠病证结合模型的实验研究[J].辽宁中医杂志，2010，22(9)：42-43
[14]吕爱平.肾虚痹证(类风湿性关节炎)发病机理研究[J].中医杂志，2010，36(8)：49-52
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[16]龙新生.加味真武汤注射剂对充血性心力衰竭少阴病阳虚水停证兔血浆内皮素的影响[J].中国中医药科技2008，5(3)：13-15
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[1]郑小伟.中医动物模型的研制方法与评价[J].中国医药学报，2008，12(3)：45-46
[2]阐甸喜.用耗气破气理论塑造脾气虚动物模型[J].吉林中医药，2010，(2)：32-34
[3]王米渠.先天肾虚证造模种鼠子代行为的遗传实验研究[J].中医杂志，2008，39(9)：56-57
[4]郑小伟.模拟“迟脉”实验动物模型的研究[J].浙江中医学院学报，2012，14(6)：29-31
[5]周奇志.实验性“脾虚证”大鼠脑内单胺递质的变化及其择时治疗效应[J].成都中医药大学学报，2008，21(3)：36-37
[6]欧敏.血虚家兔模型红细胞变形性与SODLPO变化的实验研究[J].辽宁中医杂志，2009，23(3)：19-21
[7]区永欣.卫气生理病理的研究[J].中医杂志，2011，35(8)：490-492
[8]朱升朝.体弱易感动物模型按摩治疗的实验研究[J].中医杂志，2008，39(2)：11-12
[9]孙福立.试用睡眠剥夺方法建立心虚证的动物模型[J].中西医结合杂志，2008，39(2)：11-13
[10]申冬珠.中西医结合动物实验模型研制问题的探讨[J].中国中西医结合杂志，2011，14(2)：19-21
[11]许周振.论“证”的动物模型研究的缺陷性中医药信息[J]，中医杂志，2008，(3)：4-6
[12]王秋.家兔“温病阴虚热盛证”动物模型的实验研究[J].辽宁中医杂志，2010，22(9)：42-45
[13]王彩霞.Alzheime：型痴呆大白鼠病证结合模型的实验研究[J].辽宁中医杂志，2010，22(9)：42-43
[14]吕爱平.肾虚痹证(类风湿性关节炎)发病机理研究[J].中医杂志，2010，36(8)：49-52
[15]蔡文就.实验性MDDM大鼠模型及其胰岛素抵抗的初步研究[J].广州中医药大学学报，2011，14(2)：87-88
[16]龙新生.加味真武汤注射剂对充血性心力衰竭少阴病阳虚水停证兔血浆内皮素的影响[J].中国中医药科技2008，5(3)：13-15
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