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夏藤复方对肝火亢盛型高血压大鼠的降压药效评价及作用机制研究

【作者】 王磊

【导师】 李兴广;

【作者基本信息】 北京中医药大学 , 中医临床药学, 2017, 硕士

【摘要】 原发性高血压作为临床高发性心血管疾病,近年来发病人群有年轻化倾向。中医多将高血压归属为眩晕、肝风等中医病名,强调高血压的发生、发展与藏象理论中的肝脏功能失调密切相关。针对年轻化的高血压人群,中医辨证多为肝火亢盛证。夏藤复方是以夏枯草、钩藤为君药,辅以石决明、丹参、川牛膝,针对肝火亢盛证的病因病机,诸药合用,共奏清泻肝火、平肝熄风之功。其对临床上肝火亢盛型高血压患者在降低血压、改善患者症状、减少或延缓并发症等方面具有较好的疗效。然而,夏藤复方的降压机理尚未明确。目的:本课题以“宏观评价药效,微观探讨机理”为指导思想,以稳定的肝火亢盛型高血压大鼠(14至18周龄)病证结合动物模型为基础,以疾病与证候两个层面的量化指标为依据,从疾病与证候两个方面评价夏藤复方的降压药效;探讨夏藤复方对肝火亢盛型高血压大鼠心脏及胸主动脉的组织形态的改变及血管活性物质的影响,以期明确夏藤复方对血压作用的可能机制。方法:1.本实验在前期的研究成果基础上,依据高血压肝火亢盛证宏观体征量表对自发性高血压大鼠进行证候判别,初步筛选出符合肝火亢盛证的SHR大鼠,再结合由中医临床证候标准等效转化而来的可量化的主症及次症宏观指标,确立稳定的肝火亢盛型高血压病证结合模型。2.将45只14周龄肝火亢盛型SHR大鼠,依据收缩压随机分为5组:模型组、硝苯地平缓释片组、夏藤复方高、中、低剂量组;9只WKY大鼠,作为正常对照组。连续灌胃4周,每周进行1次血压测量、旋转耐受实验、旷场实验、易激惹程度评分、次症评分。从疾病层面与证候层面两个方面,对夏藤复方进行降压药效评价。3.给药4周后,取材。取大鼠心脏,称取左心室重量(LVM),计算左心室重量指数(LVMI); HE染色心脏及胸主动脉,在光镜下观察心肌及胸主动脉病理形态的改变。4.酶联免疫吸附测定法(ELISA)检测大鼠血清血管紧张素Ⅱ (ANGⅡ)、去甲肾上腺素(NE)、内皮素(ET)、降钙素基因相关肽(CGRP)、血栓素B2(TXB2)、6-酮-前列腺素F1α (6-Keto-PGF1α)的含量。结果:1.肝火亢盛证模型组与正常组相比收缩压升高,旋转耐受时间缩短,穿格次数增加,易激惹程度评分增加,次症积分增加(P<0. 05)。2.给药4周各组前后比较,夏藤复方高、中、低剂量组均能不同程度的降低或抑制血压升高,以夏藤复方高剂量为最佳(P<0. 05)。夏藤复方高、中、低剂量组对肝火亢盛型大鼠的旋转耐受时间、穿格次数、易激惹程度评分、次症评分也有不同程度的改善。3.给药4周后,观察左心室组织形态,与正常组相比,模型组心肌细胞明显增大且排列紊乱,间隙增宽,炎性细胞浸润在其周围。夏藤复方高、中、低剂量组心肌纤维排列逐渐整齐,炎性细胞浸润逐渐减少,心肌细胞的病理损伤得到不同程度的改善,以夏藤复方高剂量组效果最佳。观察胸主动脉组织形态,与正常组相比,模型组胸主动脉内膜增厚,血管内膜细胞排列紊乱,存在血管壁重构现象。夏藤复方高、中、低剂量组能不同程度地抑制胸主动脉血管壁结构的重构。4.给药4周后,夏藤复方组与模型组相比,能降低血清中ANGⅡ、NE、ET、TXB2的含量,使血清中CGRP含量升高(P<0.05)。结论:1.夏藤复方可有效降低亦或抑制肝火亢盛型SHR的收缩压的进一步升高,同时可显著改善高血压大鼠肝火亢盛证表现出的宏观症状,可使SHR体重增加明显,这体现了中药复方对机体整体调节作用的优势。2.夏藤复方对于心脏组织可有效降低左心室重量指数,减轻SHR心肌肥厚,具有保护心肌细胞损伤,改善心肌纤维重构的作用;对于血管组织具有保护血管内皮的作用。3.夏藤复方降低血清中ANGⅡ、NE、ET、TXB2的含量,使血清中CGRP含量升高,这可能是夏藤复方抑制血压升高及保护心脏、血管靶器官的作用机制。

【Abstract】 Essential hypertension is a high incidence of cardiovascular disease. In recent years, the incidence of young people tend to. Chinese medicine will be attributed to high blood pressure for dizziness,liver and other Chinese medicine name, emphasizing the occurrence and development of hypertension and Tibetan theory of liver function disorders are closely related.For the young people with high blood pressure, TCM syndrome is mostly anger. Xiateng compound is based on Prunella vulgaris,Uncaria Steven Medicine,supplemented by Cassia,Salvia, Achyranthes bidentata, for the anger of hyperthyroidism etiology and pathogenesis, all drugs combined, played a total of Qinghu anger, Which has good clinical efficacy in lowering blood pressure, improving patient symptoms, reducing or delaying complications, and so on.However, the mechanism of lowering blood pressure is not clearObjective:Guided by the idea of "macroscopic evaluation of drug efficacy and microscopic exploration" and Based on the quantitative model of disease and syndromes,this study was based on the animal model of stagnation of anastomosing hypertensive rats (14 to 18 weeks old), and from the aspects of disease and syndrome To evaluate the effect of Xiateng compound on the changes of heart and thoracic aorta and the effect of vasoactive substances in rats with anger hyperactivity hypertension. To explore the possible mechanism of Xiateng compound for reducing blood pressureMothods:1. In this study, based on the previous research results, according to the high blood pressure hyperactivity syndrome macro-scale scale of spontaneously hypertensive rats to identify the syndrome, the initial screening to meet the anger of the SHR rats, and then by the standard of clinical syndrome equivalent to the quantification of the main symptoms and secondary macroeconomic indicators,the establishment of a stable type of anger hyperactivity hypertension syndrome model.2. 45 rabbits with 14 weeks of age were randomly divided into 5 groups: model group,nifedipine sustained release group,high,medium and low dose group,9 WKY rats,As a normal control group. Continuous administration for r 4 weeks, weekly blood pressure measurement,rotation tolerance test,open field experiment,easy to provoke degree score,secondary disease score. From the aspect of disease and syndromes, the efficacy of antihypertensive efficacy was evaluated.3 .After 4 weeks of administration, the material was taken. Left ventricular mass (LMI)was calculated and the left ventricular mass index (LVMI) was calculated. The heart and thoracic aorta were stained with HE and the myocardium and thoracic aorta were observed under light microscope Pathological changes.4.ELISA method detection of rat serum angiotensin Ⅱ (ANG Ⅱ), norepinephrine (NE),endothelin (ET), calcitonin gene related peptide (CGRP) thromboxane B2 (TXB2), 6- keto prostaglandin F1 (6-Keto-PGF1 alpha) content.Results:1. Anger hyperactivity syndrome model group compared with normal group, systolic blood pressure, rotation tolerance time shortened, in case the increase in the number of irritability score increased, secondary symptoms increased (P<0.05).2.Before and after administration for 4 weeks, the high, middle and low dose groups of Xiateng compound could reduce or inhibit the blood pressure in different degrees, and the highest dose of compound was the best (P<0.05). Xiateng compound high, middle and low dose groups of rats with hyperactivity of liver fire type rotation tolerance time, the number of crossing line, irritability score, secondary symptom score has been improved to some extent.3.After 4 weeks of administration, the left ventricular tissue morphology was observed.Compared with the normal group, the cardiomyocytes in the model group were significantly increased and the disorder was observed. The gap between the cells was widened and the inflammatory cells were infiltrated around the tissue. The myocardial fibers of the high,medium and low dose groups were gradually neat, the infiltration of inflammatory cells was gradually reduced, and the pathological damage of myocardium was improved to some extent.The effect of the high dose group was the best. The morphology of thoracic aorta was observed. Compared with the normal group, the intima of the thoracic aorta was thickened,the proliferation of vascular smooth muscle cells, the arrhythmia of vascular endothelial cells were disturbed, and the reconstruction of vascular wall structure was observed. The high,medium and low dose groups of Xiateng compound can inhibit the reconstruction of vascular wall structure.4. After 4 weeks of administration, the contents of ANGⅡ NE, ET and TXB2 in serum were decreased compared with the model group, and the content of CGRP in serum was increased (P <0.05).Conclusion:1 Xiateng compound can effectively reduce or inhibit the anger of hyperthyroidism SHR systolic blood pressure to further increase, and can significantly improve the hypertensive rats with anger manifestations of macro-symptoms, can make SHR weight gain significantly,which reflects the traditional Chinese medicine compound On the overall role of the body to adjust the advantages.2. Xiateng compound for heart tissue can effectively reduce the left ventricular weight index, reduce the SHR cardiac hypertrophy, with the protection of myocardial cell damage,improve the role of myocardial fiber remodeling; for vascular tissue to protect the vascular endothelium.3.Xiateng compound can reduce the levels of ANG, NE, ET and TXB2 in serum, and increase the content of CGRP in serum, which may be the mechanism of inhibiting blood pressure and protecting the heart and blood vessels.

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