【作者】 林雪；

【导师】 黄永生；

【作者基本信息】 长春中医药大学 ， 中医内科学（专业学位）， 2013， 博士

【摘要】 高血压病是新疆常见病、高发病之一。高血压病患者在更年期这一特殊生理阶段,其血压波动性较大,临床降压药物疗效较差。导师黄永生教授通过多年的临床实践,基于“因地制宜”的原则,在临床上提出“肝肾阴虚,毒燥伤络”是新疆更年期高血压病发病关键,以地方药、民族药为组方的虚燥更平散治疗更年期高血压病疗效确切。本研究在前期研究的基础上,从文献综述、理论研究及实验研究方面对其进行深入、系统地探究和讨论。文献综述对更年期高血压病的病因病机、辨证分型、辨证论治以及实验研究等从中医学角度进行了系统的总结；对更年期高血压病的病因、诊断、发病机理、治疗现状及研究动态等从西医学角度进行了综述。从中、西医学角度对高血压病、更年期高血压病及病证结合动物模型建立的实验研究进行了综述；对高血压病及更年期高血压病与血管重塑的发病机理、治疗现状及近年来药物干预的实验研究成果及研究动态进行了综述。理论研究基于“因地制宜”原则,阐述西北燥证对新疆更年期高血压病的病因病机、辨证分型、理法方药的影响,提出“肝肾阴虚,毒燥伤络”是其发病关键,从“虚燥论治”是治疗新疆更年期高血压病的基本方法,虚燥更平散是治疗更年期高血压病的有效方药,从而拓宽了中医药防治更年期高血压病的研究思路。实验研究1动物模型实验研究1.1更年期高血压病动物模型复制的实验研究将11月龄SHR大鼠32只随机分为SHR组、假手术组、更年期高血压病造模组,通过手术摘除SHR大鼠卵巢去势后复制更年期高血压病复合动物模型。采用ELISA法检测大鼠血清性激素水平,结果显示,与SHR组及假手术组比较,更年期高血压病造模组大鼠血清E2、T、P降低(P<0.05),血清FSH、LH升高(P<0.05)；在光镜下观察更年期高血压病造模组大鼠阴道涂片细胞学改变,其结果符合大鼠更年期特征,由此评价更年期高血压病复合大鼠模型复制成功。1.2更年期高血压病虚燥证动物模型建立的实验研究将已成模的11月龄更年期高血压病大鼠12只随机分为更年期高血压病组、更年期高血压病虚燥证造模组,并将更年期高血压病虚燥证造模组大鼠置于人工干燥环境中,给予西北燥证食物喂养,施加倒吊及外界铃声刺激,进一步建立更年期高血压病虚燥证动物模型,结果显示,与更年期高血压病组比较,更年期高血压病虚燥证造模组大鼠体重降低,饮水量增加,尿量减少(P<0.05)；采用ELISA法检测大鼠血清神经递质及肝功水平,结果显示,与更年期高血压病组比较,更年期高血压病虚燥证造模组大鼠血清CRH、NE、DA、5-HT、ALT、 AST、E2/T均升高,E2、T降低(P<0.05)；在光镜下观察大鼠肝脏、脾脏、肾上腺、下丘脑组织结构,其结果符合更年期高血压病虚燥证动物模型变化特点,由此评价更年期高血压病虚燥证动物模型的成功建立。1.3更年期高血压病虚燥证对大鼠血管重塑影响的实验研究将13月龄大鼠18只随机分为SHR组、更年期高血压病组、更年期高血压病虚燥证组,另设同月龄WKY组。结果显示,与WKY组比较,SHR组、更年期高血压病组、更年期高血压病虚燥证组大鼠血压水平升高,LD减少,MT、MT/LD增加(P<0.05),且各组大鼠血压水平的升高及腹主动脉血管重构程度呈现WKY组<SHR组<更年期高血压病组<更年期高血压病虚燥证组的趋势；采用ELISA法检测大鼠血清MMP-9、TIMP-1水平,运用免疫组化法及RT-PCR方法检测大鼠TGF-β1以及TGF-β1mRNA在血管中的表达,研究结果表明,与WKY组、SHR组、更年期高血压病组比较,更年期高血压病虚燥证组大鼠血清MMP-9.TIMP一1失衡加重,TGF-β1及TGF-β1mRNA在血管中的表达升高,由此推测,以上两个方面可能是更年期高血压病虚燥证大鼠血管重塑发生发展的病理机制之一,TGF-β1及TGF-β1mRNA的异常高表达可能是毒燥伤络所致更年期高血压病虚燥证大鼠血管重塑的内在病理基础之一。2虚燥更平散对更年期高血压病虚燥证大鼠血管重塑的影响将13月龄更年期高血压病虚燥证大鼠18只随机分为更年期高血压病虚燥证空白组、虚燥更平散组、缬沙坦组,分别灌服等体积蒸馏水、虚燥更平散、缬沙坦胶囊,干预60天后观察下列指标。2.1虚燥更平散对更年期高血压病虚燥证大鼠生物表征、血压及腹主动脉组织结构的影响虚燥更平散能抑制更年期高血压病虚燥证大鼠血压随年龄增长而升高的趋势,与更年期高血压病虚燥证空白组比较,虚燥更平散组大鼠血压在给药10天、20天时逐渐下降,在给药30天后有显著差异,且降压效果平稳持久；与更年期高血压病虚燥证空白组比较,虚燥更平散组大鼠腹主动脉LD增加,MT、MT/LD减少(P<0.05),揭示虚燥更平散通过滋阴润燥、养血通络作用改善更年期高血压病虚燥证大鼠虚燥征象,从而使其降压效果平稳持久,同时能改善更年期高血压病虚燥证大鼠血管内皮脱落以及平滑肌异常增生等病理性损害,由此逆转更年期高血压病虚燥证大鼠腹主动脉血管重构。2.2虚燥更平散对更年期高血压病虚燥证大鼠基质金属蛋白酶及其抑制物的影响本实验采用ELISA法分别检测各组大鼠血清MMP-9、TIMP-1水平,结果显示,与更年期高血压病虚燥证空白组比较,虚燥更平散组大鼠MMP-9、TIMP-1均降低(P<0.05),说明虚燥更平散能降低大鼠外周循环MMP-9水平,并使代偿性升高的TIMP-1降低,恢复MMP-9与TIMP-1动态平衡,减少其对血管基质的降解,从而逆转更年期高血压病虚燥证大鼠的血管重塑。2.3虚燥更平散对更年期高血压病虚燥证大鼠TGF-β1及TGF-β1mRNA在血管中表达的影响通过免疫组化法及RT-PCR方法检测各组大鼠TGF-β1及TGF-β1mRNA在血管中的表达,研究结果表明,虚燥更平散可能通过降低TGF-β1及TGF-β1mRNA在大鼠血管中的表达,实现对更年期高血压病虚燥证大鼠血管重塑的逆转,此结果也为从“虚燥论治”更年期高血压病的有效性提供了实验依据。更多还原

【Abstract】 In the present, Essential Hypertension is one of the most common and the highest incidence disease in xinjiang. Essential Hypertension in the particular history of menopause can performance the fluctuation of blood pressure was larger and the stability of hypertensive drugs was worseer, Professor Huang Yongsheng puted forward the main bases of menopausal hypertension is the maladjustment of liver and kidney and the crux is the damage of superficial venues and lymph vessels by poison, which based on tthe principle of adjust measures to local reference review through many years clinical practices. Professor Huang believed the virtual dry treatment is a valid path in treatting menopausal hypertension and thinked Xu-zao-geng-ping powder has definite effect. The results of this study in order to further develop traditional Chinese medicine research lay the foundation for the prevention and control of menopause climacteric hypertension based on the previous heoretical research and clinical observation experimental research.Reference reviewThe essay systematically summarized the advances of menopausal hypertension with TCM and experimental study as follows, the name of disease, the etiology and pathogenesis, syndrome differentiation with differentiation of symptoms and signs, different treatment with differentiation of symptoms and signs.This Essay reviewed the experimental study results on hypertension experimental animal model, menopausal hypertension experimental animal model, menopausal hypertension yin-deficiency inner dryness syndrome experimental animal model.This Essay also summarized the principle of preventing and treating in menopausal hypertension according to the combine traditional Chinese and western medicine medical point and reviewed the pathogenesis and treatment of menopausal hypertension with vascular remodeling.Theory studyThe disease state was different because the different regions and times by putting the environmental factors into the medical model.This paper dicussed on the influence of northwest drying climate from three aspects:etiology and pathogenesis, syndrome, differentiation with differentiation of symptoms and signs, principle-method-recipe-medicines. We puted forward the main bases of menopausal hypertension was the maladjustment of liver and kidney and the crux was the damage of superficial venues and lymph vessels by poison, then putted forward the valid path of treating menopausal hypertension was "The virtual dry treatment". The application of xu-zao-geng-ping powder was effective agent in the treatment of climacteric hypertension, thus widening the research ideas of TCM prevention.Experimental study1The experimental research of animal model1.1The experimental research of copy the menopause hypertension animal modelRandomly divided11months of32SHR rats into SHR group, control group, menopause hypertension model group, through the removal of SHR rats ovaries copy menopause hypertension animal model, using enzyme-linked immune (ELISA) method to detect the serum sex hormone (E2, FSH, LH, T, P) level, the results show that compare with SHR group and control group, the menopause hypertension rats serum E2, T, P decreased (P＜0.05), serum FSH and LH increased (P＜0.05). Made module rats under light microscopy observation of menopause hypertension rat vaginal smear cytology changes, the result conforms to the characteristics of menopausal rats, proves the ovaries, castration thoroughly, which can be evaluation copy successful copy menopause hypertension rat model. 1.2The experimental research of establish menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal modelRandomly divided11months of12menopause hypertension rats into menopause hypertension group, menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal model group, applying artificial dry environment and using the upside-down stimulation, while giving the northwest dryness syndrome food feeding, further establish the menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal model. Compare with menopause hypertension rats, the weight of menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal model rats lose, water quantity increased, urine volume decreased. Using ELISA method to detect the neurotransmitters and hepatic function of rats, the results show that compare with menopause hypertension rats, the CRH, NE, DA,5-HT, ALT and AST of menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal model group were higher, serum E2, T, E2/T score were lower, the result accord with dryness syndrome animal model evaluation related index changes, then to observe rat liver, spleen, adrenal gland, hypothalamus, histomorphology in line with the characteristic of virtual dryness syndrome animal model changes, which can evaluate menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal model is successfully established.1.3The experimental research of menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal model with vascular remodeling ratsThe only13months of age18rats were randomly divided into SHR and menopause hypertension group, menopause hypertension Yin-deficiency with inner dryness syndrome group, the WKY group. Results show that compared with WKY group, SHR group, menopause hypertension group, the menopause hypertension Yin-deficiency with inner dryness syndrome group rats blood pressure levels, LD, MT and MT/LD increased (P＜0.05); Using ELISA method to detect the rat serum levels of MMP-9and TIMP-1level, using immunohistochemical method and RT-PCR detection rat TGF-β1and TGF-β1 mRNA expression in blood vessels, the research results show that compared with WKY group、SHR group、menopause hypertension group,the menopause hypertension Yin-deficiency with inner dryness syndrome group imbalance is aggravating, TGF-β1and TGF-β1mRNA expression in blood vessels, thus speculated that the above two aspects may be menopause hypertension virtual dryness syndrome occurrence and development of vascular remodeling in rats is one of the pathological mechanism, TGF-β1and TGF-β1mRNA expression might be poisonous dry injury is caused by menopause hypertension virtual dryness syndrome is one of the characteristics of vascular remodeling in rats.2The Effects of Xu-zao-geng-ping powder on vascular remodeling in menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal modelThe13months of menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal model rats18were randomly divided into menopause hypertension Yin-deficiency with inner dryness syndrome black group, Xu-zao-geng-ping powder group and valsartan group. Respectively to the irrigation uniform such as distilled water volume more flat, Xu-zao-geng-ping powder and valsartan capsule after60days, observe the following indicators.2.1The effect of Xu-zao-geng-ping powder on biological characterization in rats, the impact of blood pressure and vascular structure in menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal modelXu-zao-geng-ping powder can inhibit menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal blood pressure with age and the rising trend, and menopause hypertension after30days from the drug virtual dry the blank group comparison, there were significant differences, and antihypertensive effect smooth and durable compare with menopause hypertension Yin-deficiency with inner dryness syndrome blank group. The Xu-zao-geng-ping powder can raise LD value, low MT (P＜0.05), improve the dry signs through nourishing Yin for moistening dryness, nourishing blood for dredging collaterals, so as to make it smooth step-down lasting, at the same time can improve the vessels tissue injury in Yin-deficiency with inner dryness syndrome experimental animal model rats.2.2The effect of Xu-zao-geng-ping powder on MMP-9, TIMP-1in menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal modelThis experiment adopts the enzyme-linked method between groups of rats was detected in serum level of MMP-9and TIMP-1. Results show that comparing with menopause hypertension Yin-deficiency with inner dryness syndrome blank group, the MMP-9and TIMP-1values of Xu-zao-geng-ping powder group are lower (P＜0.05), shows that Xu-zao-geng-ping powder can reduce rat peripheral circulation MMP-9level, lower the compensatory increase of TIMP-1, MMP-9and TIMP-1dynamic balance, reduce its degradation of vascular matrix, thereby reversing climacteric hypertension dryness syndrome of vascular remodeling in rats.2.3The effect of xu-zao-geng-ping powder on TGF-β1in abdominalis aorta tissue and TGF-β1mRNA in thoracic aorta tissue of menopause hypertension Yin-deficiency with inner dryness syndrome experimental animal modelBy immune-histochemical method and RT-PCR method for detection of each rat TGF-β1expression and TGF-β1mRNA expression in ratery tissue. Results show that Xu-zao-geng-ping powder may adjust the TGF-β1and TGF-β1mRNA expression in ratery tissue, relieve menopause hypertension virtual dry blood vessel tissue injury in rats, the implementation of menopause hypertension virtual dry reversal of vascular remodeling in rats, the results for "virtual dry treatment" menopause climacteric hypertension virtual effectiveness of dry syndrome in rats provides experiment basis.更多还原