【作者】 袁利梅；

【导师】 王清海；

【作者基本信息】 广州中医药大学 ， 中医内科学， 2011， 博士

【摘要】 一、研究背景当今,单纯收缩期高血压(ISH)已经成为威胁人类健康的主要疾病之一,随着我国老年人口数量的不断增加,ISH的发病率在我国亦呈逐渐上升趋势。已有研究证实ISH是老年人群中最常见的高血压亚型,占老年高血压人群半数以上。同时ISH是老年人重要的心血管危险因素之一,其与心血管病的发生率和病死率呈正相关,其心血管并发症的发病率和病死率是血压正常者的3倍,且与早期肾功能损害关系密切。尽管人类已花费了大量人力、财力研究治疗ISH的有效药物,但至目前为止其均存在不可避免的副作用。因此从中医药方面着手,寻求出治疗ISH的有效药物已经成为高血压防治领域的一重要课题。目前为止,虽然已有很多报道治疗ISH的中药制剂,但有关治疗ISH的复方成药及关于这些中药制剂治疗ISH的机制研究未见报道,本课题即打算在此领域作些有益的探索。本研究所用制剂复方芪麻胶囊是王清海教授基于中医基础理论,认真总结现代高血压病的中医辨证分型,结合自己数十载行医经验研制出的经验方。多年临床实践证实复方芪麻胶囊对于高血压,尤其是老年ISH有确切疗效。有研究证明复方芪麻胶囊能有效降低24h、白昼及夜间的血压,减轻血压负荷,对心、脑、肾等靶器官有保护作用。但究竟其通过何种机制起到治疗ISH的作用尚不明确,本课题拟通过临床观察评估复方芪麻胶囊治疗ISH的疗效及安全性,同时通过实验研究初步探讨复方芪麻胶囊治疗ISH的机制。二、实验研究1.目的(1)观察复方芪麻胶囊对ISH大鼠血清中Hcy水平的干预情况,明确复方芪麻胶囊治疗ISH的机制；(2)观察复方芪麻胶囊对实验大鼠血压及血脂相关指标的干预疗效,明确复方芪麻胶囊治疗ISH的机制;(3)从病理学方面明确复方芪麻胶囊改善实验动物动脉硬化的程度,为复方芪麻胶囊治疗ISH提供实验依据。2.方法与内容采用SD大鼠,随机分为6组：健康对照组、空白组对照组、硝苯地平组、复方芪麻胶囊低剂量组、中剂量组和高剂量组。采用WVK模式建立大鼠单纯收缩期高血压模型,采用电镜酶细胞化学和分子生物学及免疫组化等方法,从整体、细胞乃至分子水平探讨复方芪麻胶囊治疗ISH的机制。本实验共分为三个部分。实验一：采用WVK模式制造大鼠单纯收缩期高血压模型,观察复方芪麻胶囊对ISH大鼠血清中Hcy水平的干预情况,明确复方芪麻胶囊治疗ISH的机制。实验二：观察复方芪麻胶囊对大鼠血压及血脂的干预疗效,明确其降压机制。实验三：从病理学角度观察复方芪麻胶囊改善ISH大鼠腹主动脉硬化的程度,探讨复方芪麻胶囊改善动脉粥样硬化的机制。3.结果(1)造模前后血压比较：造模组与健康组大鼠造模后同期收缩压比较,自第三周起,收缩压明显升高,经t检验,P<0.05,差异有统计学意义；造模组与健康组同期舒张压比较,经t检验,P>0.05,差异无统计学意义。造模组造模前后自身收缩压比较,经t检验,P<0.05,差异有统计学意义；造模前后自身舒张压比较,经t检验,P>0.05,差异无统计学意义,说明造模成功。(2)造模后各组与健康组比较,Hcy水平存在着明显差异(P<0.05),说明ISH发生时,血Hcy水平升高。单纯收缩期高血压的发生与高同型半胱氨酸血症密切相关。(3)治疗前后血Hey水平自身比较：低、中、高剂量组存在显著性差异(P<0.05)。说明复方芪麻胶囊能有效降低ISH大鼠血Hcy水平。(4)治疗后与空白组比较：低、中、高剂量组大鼠血Hcy水平均有所下降,其中高剂量组下降最明显,存在显著性差异(P<0.01)。说明复方芪麻胶囊能有效降低ISH大鼠血Hcy水平,疗效呈剂量依赖性。(5)治疗前后收缩压比较：与空白组同期比较,自第一周起硝苯地平组收缩压即见明显降低,经t检验,P<0.01,差异具有统计学意义,而复方芪麻胶囊各剂量组收缩压则自第三周起出现明显下降,中、高剂量组差异具有显著性(P<0.05),具有统计学意义。治疗后第四周,复方芪麻胶囊高剂量组与硝苯地平组血压比较,差异无统计学意义(P>0.05),说明复方芪麻胶囊高剂量降低收缩压疗效与硝苯地平片相当。与空白组同期及治疗前自身比较,复方芪麻胶囊低、中、高剂量组收缩压均明显下降,差异具有统计学意义(P<0.05),其中高剂量组血压下降最明显(P<0.01),说明复方芪麻胶囊降低收缩压的疗效存在着量效关系。(6)治疗前后舒张压比较：与空白组同期和治疗前自身比较,硝苯地平组治疗后舒张压下降明显,经t检验,P<0.05,差异具有统计学意义。复方芪麻胶囊各剂量组治疗后舒张压,与空白组同期及治疗前自身比较,差异无统计学意义(P>0.05),说明复方芪麻胶囊对舒张压影响较小。(7)治疗后各组大鼠血脂水平比较：空白组与健康组比较,TC、TG、LDL-C、LP(a)含量明显升高,存在显著性差异(P<0.05),说明ISH大鼠存在脂代谢紊乱。复方芪麻胶囊各剂量组与空白组比较,TG、TC、LDL、LP(a)含量均明显减低,存在显著性差异(P<0.05),说明复方芪麻胶囊能有效干预ISH大鼠血脂水平。其中复方芪麻胶囊高剂量组下降值最明显,各剂量组间比较,差异具有统计学意义(P<0.05),说明复方芪麻胶囊干预血脂的疗效存在着量效关系。(8)大鼠腹主动脉病理检测结果分析：与健康组比较：空白组大鼠腹主动脉中膜结构、形态见明显改变,增厚明显,说明ISH动物模型复制成功。与硝苯地平组比较,中、高剂量组大动脉中膜结构、形态未见明显改变,中膜增厚不明显；低剂量组中膜纤维结构紊乱,形态不规则,动脉胶原蛋白明显增多,说明复方芪麻胶囊能有效改善ISH大鼠硬化的腹主动脉,起到一定的靶器官保护作用,且改善动脉硬化的程度呈剂量依赖性。4.结论(1)复方芪麻胶囊不仅能有效降低ISH大鼠体内的Hcy水平,且其降低血Hey水平与复方芪麻胶囊呈效量关系。(2)复方芪麻胶囊能明显降低ISH大鼠的收缩压,对舒张压影响较小,但降压疗效存在着效量关系。(3)复方芪麻胶囊能显著降低ISH大鼠血清中TC、TG、LDL-C、LP(a)水平,且其疗效存在着量效关系。。(4)复方芪麻胶囊能有效减轻ISH大鼠腹主动脉的硬化程度,且其疗效与剂量呈依赖性。三、临床研究1.目的观察复方芪麻胶囊对单纯收缩期高血压患者的临床疗效。2.方法与内容采用前瞻性实验性设计方案。遵循随机、对照、单盲原则进行研究。将60例符合中医气虚痰浊型诊断和西医单纯收缩期高血压1、2级标准的患者按1：1随机分为实验组和对照组。治疗组采用复方芪麻胶囊治疗,对照组采用硝苯地平缓释片治疗。通过观察治疗前后血压的变化及中医证候、症状的改变,比较实验组与对照组二者的临床疗效。3.结果(1)治疗后两组患者降压疗效的比较：对照组降压总有效率为86.7%,治疗组降压总有效率为93.3%,两组差异无统计学意义(P>0.05),说明两组患者的降压疗效相当。(2)两组患者治疗前后24h动态血压结果的比较：治疗组与对照组治疗前后24h动态血压自身比较,经t检验,P<0.05,差异有统计学意义,说明复方芪麻胶囊与硝苯地平缓释片均能有效降低血压。两组患者治疗后24h动态血压比较,经t检验,P>0.05,差异无统计学意义,说明复方芪麻胶囊降压疗效与硝苯地平缓释片相当。治疗后两组平滑指数比较,治疗组明显高于对照组,差异有统计学意义(P<0.05),说明复方芪麻胶囊降压作用较硝苯地平缓释片平稳。(3)两组患者中医证候疗效比较：治疗组总有效率93.3%,对照组73.3%,经X2检验P<0.05,差异有统计学意义。(4)两组患者中医症状积分比较：治疗前后自身比较,差异有统计学意义(P<0.05)。治疗组患者治疗前后症状积分差值明显高于对照组,经t检验,P<0.05,差异有统计学意义。(5)两组患者中医症状疗效比较：治疗组眩晕症状总有效率为83.3%,对照组总有效率为50%,两组差异有统计学意义(P<0,05)；治疗组头重症状总有效率为80.8%,对照组总有效率为47.8%,两组差异有统计学意义(P<0,05)；治疗组神疲乏力症状总有效率为89.7%,对照组为60.0%,两组差异有统计学意义(P<0,05)；余各中医症状疗效差异无统计学意义(P>0.05)。4。结论我们通过小样本临床观察,发现复方芪麻胶囊能有效降低1、2级ISH患者的收缩压,对舒张压影响较小,其降压疗效与硝苯地平缓释片相当,同时能明确改善ISH患者血压平滑指数,降压作用较硝苯地平缓释片平稳。其次复方芪麻胶囊在改善气虚痰浊证患者中医证候及中医症状方面疗效优于单纯西药治疗,而且其副作用较少。四、结语1.复方芪麻胶囊能有效降低ISH大鼠体内的Hcy水平,且其降低血Hcy水平与复方芪麻胶囊呈效量关系。2.复方芪麻胶囊能有效降低ISH大鼠收缩压,对舒张压影响较小,但降压疗效存在着量效关系。3.复方芪麻胶囊能有效降低ISH大鼠血TG、TC、LDL-C、LP(a)水平,且其干预疗效存在着量效关系。4.复方芪麻胶囊能有效减轻ISH大鼠腹主动脉的硬化程度,且其疗效与剂量呈依赖性。5.我们通过小样本临床观察,发现复方芪麻胶囊能有效降低1、2级ISH患者的收缩压,对舒张压影响较小,其降压疗效与硝苯地平缓释片相当,同时能明确改善ISH患者血压平滑指数,降压作用较硝苯地平缓释片平稳。其次复方芪麻胶囊在改善气虚痰浊证患者中医证候及中医症状方面疗效优于单纯西药治疗,而且其副作用较少。更多还原

【Abstract】 Today, isolated systolic hypertension has become one of the main diseases of threaten the human health. Along with our country old population quantity’s increase, the ISH disease incidence rate also assumes gradually the trend of escalation in our country. Now some researchs had confirm that ISH is the most common hypertension hypotype in the old age crowd, occupies old age hypertension crowd more than half. Simultaneously ISH is one of senior citizen’s important cardiovascular hazard factors, its and cardiovascular disease’s formation rate and the case fatality rate present are related, his/her the cardiovascular complication’s disease incidence rate and the case fatality rate are blood pressure normal person’s 3 times, and the early kidney function harm relations are close. Although the humanity has spent the massive manpower, the financial resource research to treat ISH the effective medicine, but so far it has the inevitable side effect. Therefore began from the Chinese medicine aspect, to seek treats ISH the effective medicine already to become hypertension to prevent and control the domain an important domain. At present up to, although there already had many reports to traditional Chinese medicine preparation applied to reat ISH,but related treats ISH the compound prescription prepared medicine and closes with these traditional Chinese medicine preparation treats ISH the mechanism research not to see the report, this topic is the plan makes a beneficial exploration in this domain.This research institute uses the preparation Compound Qima Capsules(CQC)is Invented by Professor Wang Qinghai,who based on the Chinese medicine basic theory, summarizes the Chinese medicine dialectical minute which earnestly modern hypertension gets sick, unifies oneself dozens of years to practice medicine the experience to develop after the proven prescription. Many years’clinical practice has confirm that Compound Qima Capsules can descense hypertension Effectively, especially has the accurate curative effect to old ages who with isolated systolic hypertension. But until present there is not any research about the mechanism of Compound Qima Capsules treating isolated systolic hypertension. this study was a beneficial evaluation in this field. Experiment StudyOBJECTIVE:To observe the effect of Compound Qima Capsules(CQC)for the level of Hcy、TC、TG、LDL-C、LP(a) of rice with isolated systolic hypertension(ISH), to evaluate the mechanism of Compound Qima Capsules(CQC) to treatment of ISH by using the experimental model of rats.METHODS:SD rats were randomized into six group:healthy group, blank group, control group, high dose、moderate and low dose group. To establish rats model with the model of WVK, with the medols such as the electron microscopic cytochemistry of enzyme, molecular biologic technique and immunohistochemical technique, to evaluate the mechanism of Compound Qima Capsules (CQC) to treatment of ISH. This study includes 3 parts. Part 1:To observe the effect of Compound Qima Capsules (CQC) for the level Hcy to evaluate the he mechanism of Compound Qima Capsules(CQC) to treatment of ISH. Part 2:observation on the effect of Compound Qima Capsules(CQC) on the blood pressure and blood fats, to evaluate the mechanism of decending blood pressure and improves the degre of arteriosclerosis. Part3:by pothology to observe the effect of Compound Qima Capsules(CQC) modifies the degree of arteriosclerosis of mouse, To offer experimental evidence about CQC treat ISH.RESULTS:(1) Comparion about the blood between pre-model and post-model model: compare to the healthy group, the systolic blood pressure level of model groups were markedly increased from the third week, there were significant differences between the two groups(P<0.05); while there was no significant differences between the diastolic pressure. A design of oneself comparion according to pre-model and post-model was performed in different dose groups. There was significant difference in systolic pressure in model group(P<0.05), while there was no significant difference in diastolic pressure. That means it is successful in copy model.(2) Comparion between model group and healthy group:the blood Hey level of model group was markedly increased, there were significant difference s between the two groups(P<0.05), that means The blood Hey level and the ISH occurrence has the close relation.(3) Comparison of the effect of decending blood Hey:the blood level of Hey reduce markedly in the low dose, moderate and high dose group. that means Compound Qima Capsules(CQC) can effectively reduce the level of blood Hey of rats with isolated systolic hypertension(4) Compare to blank group, there was some reduce in the level of blood Hey after post-treatment, especially in high dose group, There were significant differences (P<0.01). that means Compound Qima Capsules (CQC) can reducing the level of blood Hey of ISH rats, while the effect is related to dose.(5)Comparion of systolic pressure pre-treatment and post-treatment: compare to blank group, the systolic pressure of Nifedipine group reduced obviously in the first week, There were significant differences (P<0.01). While the the systolic pressure of CQC groups reduced markedly from the third week,there were significant differences only in model and high dose groups. After treating four weeks, there were no differences in systolic pressure between CQC high dose group and Nifedipine group, that means high dose of CQC has the same efficacy as Nifedipine Tablets in decreasing systolic pressure.Compare to blank group in the same time and pre-treat, systolic pressure has markedly reduced in different dose group, there were significant differences(P<0.05), while reduced most in high dose group (P<0.01). That means the effecy of CQC on decending systolic pressure is related to dose.(6)Comparion of diatolic pressure between blank group and pre-treatment:Compare to blank group in the same time and pre-treatment, diatolic pressure of Nifedipine group reduced markedly, there were significant differences (P<0.05). While there were no significant differences in CQC groups after treatment, compare to blank group in the same time and pre-treatment (P>0.05). That means CQC has little effect on diatlic pressure.(7) Comparion of blood fats pre-treatment and post-treatment:the level of TC、TG、LDL-C、LP(a) increases markedly of the control groups compares to the blank groups, that means existent fat metabolic disorder in rats with isolated systolic hypertension. Compare to blank group, the level of blood TG、TC、LDL、LP(a) reduce obviously, there were significant differences, that means CQC can effectively interven level of blood fats of ISH rats. But it reduced most in the high dose group, comparion among different dose groups, there were significant differences, that means the effecy of CQC on decending blood fats level is related to dose.(8) The pathology test result of rats’abdomen aorta:Compares with the healthy group:the blank group aorta tunica media vasorum structure, the shape see obvious change, the accumulation are obvious, showed that the ISH animal model duplicates successfully. Compares to the Nifedipine group, the medium and high dose group has not seen the obvious change, the tunica media vasorum accumulation are not obvious; The low dose group aorta tunica media vasorum structure, the shape see the obvious change, explained that the compound prescription qi hemp capsule improvement arteriosclerosis the degree and the dosage have the close relation.CONCLUSION:(1) The Compound Qima Capsules can reduce the level of blood Hey of rats with isolated systolic hypertension, and its effect is related to the quantity.(2) The compound Qima Capsules can decend the systolic pressure obviously of rats with ISH, and has little influence on dialotid pressure, but the effect in reducing blood pressure has the effect quantity relations.(3) The Compound Qima Capsules can reduce the level of blood fats of rats with isolated systolic hypertension, and the effect is related to the dose.(4) CQC can effectively reduce the sclerosis degree of aortaventralis with ISH, and the effect is related to dose. Clinical StudyOBJECTIVE:To observe the clinic effect of Compound Qima Capsules (CQC) for the treatment of isolated systolic hypertension (ISH) with Qi deficiency and phlegm turbidity.METHODS:A prospective study was done of Qi deficiency and phlegm turbidity in 60 patients with ISH under the randomized, controlled and single-blind rules. These patients were randomized into control and experimental groups in 1:1 proportion. These patients in experimental group received CQC; while the patients in control group received extended-release Nifedipine Tablets.To compare the clinic efficiency to the patients in control and experimental groups by observing the change of hypertension and the change of traditional Chinese medicine syndrome and symptom before and after treatment.RESULTS:(1) Comparion of the efficacy to blood pressure after treatment:the results of therapy were assessed as follows:the general effective rate being 86.7% in treatmental group, while 93.3% in control group, there was not significant differences between the two groups (P>0.05). It means that the two groups has same effect.(2) Compare of the results of 24h ambulatory blood pressure:A design of oneself comparison according to pre-treatment and post-treatment was performed in both groups. There was significant differences in each group(P<0.05). The comparisons of 24h ambulatory blood pressure between two groups after treatment:there was not significant differences between the two groups(P>0.05). It illustrates that the two groups has same effect. The compariison in smoothness index between two groups after treatment:there was significant differences between two groups,that means the effect of CQC is moderater than Nifedipine Tablets.(3) Compare of the efficacy to traditional Chinese medicine syndrome between control and experimental group:the general effective rate being 93.3% in treatmental group; the general effective rate being 73.3% in control group, there were significant differences between the two groups(P<0.05).(4) Compare of the scores of traditional Chinese clinical symptoms between control and experimental group:A design of oneself comparison according to pre-treatment and post-treatment was performed in both groups. There were significant differences between pre-treatment and post-treatment in each group (P<0.05). The value between pre-treatment and post-treatment in experimental group had significant difference to that in control group(P<0.05).(5) Compare of the traditional Chinese medicine symptom between control and experimental group:the general effective rate to god tired strength being 89.7% in experimental group, while 60.0% in control group. there were significant differences between the two groups (P<0,05). The general effective rate to head heaviness being 80.8% in experimental group, while 47.8% in control group. there were significant differences between the two groups(P<0,05). the genenral effective rate to dizziness being 83.3% in experimental group, while 50% in control group. there were significant differences between the two groups(P<0,05).There were no significant differences of other symptom between the two groups(P>0.05).CONCLUSION:Through the observation of treatment of Compound Qima Capsules for for the treatment of 1.2 leve isolated systolic hypetension(ISH)with Qi deficiency and phlegm turbidity, we found that CQC has the same efficacy as Nifedipine Tablets in decreasing blood pressure,and has litter influence in dialotic pressure. But the improvement of traditional Chinese medicine syndrome and symptom, specially god tired strength、head heaviness and dizziness, is significantly increased in experimental group tha in control group. we also found that Compound Qima Capsule has lower side effect, so as to has a good prospect of application and extension.CONCLUDING:(1) The Compound Qima Capsules can reduce the level of blood Hcy of rats with isolated systolic hypertension, and its effect is related to the quantity.(2) The compound Qima Capsules can decend the systolic pressure obviously of rats with ISH, and has little influence on dialotid pressure,but the effect in reducing blood pressure has the effect quantity relations.(3) The Compound Qima Capsules can reduce the level of blood fats of rats with isolated systolic hypertension, and the effect is related to the dose.(4) CQC can effectively reduce the sclerosis degree of aortaventralis with ISH, and the effect is related to dose.(5) Through the observation of treatment of Compound Qima Capsules for for the treatment of 1.2 leve isolated systolic hypetension(ISH)with Qi deficiency and phlegm turbidity, we found that CQC has the same efficacy as Nifedipine Tablets in decreasing blood pressure, and has litter influence in dialotic pressure. But the improvement of traditional Chinese medicine syndrome and symptom, specially god tired strength、head heaviness and dizziness, is significantly increased in experimental group tha in control group. we also found that Compound Qima Capsule has lower side effect, so as to has a good prospect of application and extension.更多还原