【作者】 李百臣；

【导师】 张伯礼；

【作者基本信息】 天津中医学院 ， 中医内科学， 2004， 博士

【摘要】 本研究主要采用自发性高血压大鼠(SHR)、。肾性血管性高血压犬(RHD)模型，在明确养血清脑颗粒降低血压作用及探索其可能途径的同时，研究了对SHR心脏和肾脏损伤的保护作用。并采用基因芯片技术研究对SHR心脏和肾脏基因表达谱的影响，以探讨其作用的分子机制；在此基础上观察了对正常麻醉犬血流动力学的影响，探讨其对心血管系统的作用。在实验研究的基础上，开展了养血清脑颗粒治疗高血压病的临床研究。其结果如下：1． 养血清脑颗粒对SHR的降压作用1． 1单次灌服养血清脑颗粒，可以使SHR收缩压下降。在给药后约1小时开始显示降压作用，高峰在药后2～4小时之间。2小时后收缩压下降即有显著性差异(P＜0． 05) ，3小时达到降压高峰约9mmHg。中、低剂量组降压趋势与高剂量组相同，但强度不及高剂量组。1． 2连续给药8周，养血清脑颗粒可以抑制SHR收缩压随月龄的增长而增加的趋势。连续给药2周后，高剂量组与模型比较，即有显著性差异(P＜0． 05) ；给药8周后，高剂量组收缩压比模型组低26． 1mmHg，其次中剂量组降低16． 4mmHg，低剂量组降低10． 8mmHg，各剂量组之间有一定的量效关系。2． 养血清脑颗粒降压作用机制研究养血清脑颗粒对SHR血浆RAS的影响：各给药组血浆中Ang Ⅰ没有明显差异。各给药组Ang Ⅱ均有下降趋势，以卡托普利组较为明显，养血清脑颗粒组和牛黄降压丸组也有一定程度的下降，但都没有显著性差异。养血清脑颗粒高剂量组血浆ALD水平明显低于模型组，有显著性差异(P＜0． 001，t=4． 101) 。卡托普利组及牛黄降压丸组血浆ALD水平均低于模型组，亦有显著性差异。3． 养血清脑颗粒对SHR心脏和肾脏损伤的保护作用 中文摘要3.1养血清脑颗粒各剂量组均有降低LVW的作用，高剂量组与模型组比较具有非常显著差异(P<仓01)。各剂量组均有降低Lvw忍W作用，与模型组比较，中剂量组和高剂量组有显著性差异(P<0.05)，高剂量组优于卡托普利组。3.2养血清脑颗粒各剂量组均能降低左心室心肌胶原蛋白的含量和I、111型胶原的比例。其中中剂量组在降低左心室胶原含量方面有显著性差异(P<0.05)，各组在改善I、m胶原比例方面均有显著性差异(P<001)。3.3第22周51任R血清中的cr、ua含量均显著高于正常对照wKY组(P<0.01)。各给药组均明显降低血清Cr、Ua含量，以养血清脑颗粒中、高剂量组最为明显。高剂量组血清Cr水平和模型组比较明显降低并有非常显著性差异(P<0，001，t=2.690);中剂量组血清Cr水平和模型组比较，有显著性差异(P<0.05，t=2.662)。高剂量组血清ua水平和模型组比较明显降低，有显著性差异(P<o，o一，t=2.550);低剂量和模型组比较亦有显著性差异(P<0.05，t=2.452)，其余药组均有下降趋势;牛黄降压丸能显著降低血清BUN水平，有显著性差异(P<005)，其余各组仅有下降趋势。3.4养血清脑颗粒对SHR肾脏组织中RAS的影响。养血清脑颗粒各剂量均能降低肾组织中Ang 11含量，与模型组比较，均有显著性差异，其中剂量有非常显著性差异伊<0.001， t=7.070)。卡托普利组和牛黄降压丸组与模型组比较，也有显著性差异(P<0.05);养血清脑颗粒可以使SHR肾组织中的ALD含量下降，以高、中剂量较为明显，与模型组比较，均有显著性差异，高剂量组印<0.01，卜2.956)，中剂量组(P<0.05，t=2.591)。卡托普利与模型组比较，也有显著性差异(P<0 .05，t=2.706)。4.养血清脑颗粒对SHR心脏和肾脏损伤的保护作用基因图谱研究4.1养血清脑颗粒对SHR心脏基因表达谱的影响:选择SH]良模型组和养血清脑颗粒高剂量组，分别作两张芯片，进行基因表达谱分析.。一初步研究发现，心肌LTBp一2(Latent transforming growth factor binding proteinZ，LTBp一2)、甘氨酸甲基转移酶(Glycine methyltransferase，Gnmt)和p半乳糖昔Q 2.6唾液酸转移酶(Rat beta一galaetoside一alpha 2.6一sialyltransferase)的mRNA表达水平明显下调。上调en36抗原、心脏脂肪酸结合蛋白(heart几tty acid binding protein，Fabp3)、丙酞辅酶Ap多肤(Propionyl eoenZyme A earboxylase，beta polypeptide，pecb) 中文摘要 一一一一-------~~~~~~~~~~---mRNA表达水平。提示养血清脑颗粒可能通过调节多种心脏细胞因子和生物酶的含量及活性，而具有预防和减轻LVI诬的作用。4.2养血清脑颗粒对SHR肾脏基因表达谱的影响。也选择SHR模型组和养血清脑颗粒高剂量组，分别做基因表达谱分析。结果在第一张芯片中差异表达基因有389个，其中下调基因有273个，209个能在Genbank上登陆;上调的基因135个，116个基因能在Genbank上登陆;第二张芯片中差异表达基因有170个，其中下调的基因有120个，87个能在Genbank上登陆;上调的基因50个，42个基因能在Genbank上登陆。5.养血清脑颗粒对RHD的降压作用 单次口服养血清脑颗粒109/kg组，给药后出现有降低血压的?更多还原

【Abstract】 To investigate the antihypertension effect of YXQN on Spontaneous Hypertension Rat (SHR) and RHD(2K1C), and search for YXQN’s protective effect on SHR heart and kidney. By the gene chip, study the gene express of the heart and kidney and the machannism of the protection. And by the anaesthesia normal dog, observe the effection of the YXQN, in order to find the effection on the system of the heart and the vessel. The results are the following: Result:1. The antihypertension effect of YXQN on Spontaneous Hypertension Rat (SHR) (l)Treating with YXQN one time can reduce the blood pressure of SHR. Onehour after YXQN was treated we observed the effect of reducing blood pressure and the peak is after 2 to 4 hours. The blood pressure reduced significantly after 2 hours and the peak is after 3 hours about 9mmHg. The middle and low dose groups also reduce the blood pressure but not yet to the extent of that of high dose group.(2) Different dose groups of YXQN can reduce the blood pressure of SHR. Two weeks after YXQN was treated continuously, the blood pressure is reduced significantly in high dose group compared with model group. YXQN can prevent the development of blood pressure while rats grows.2. The machanism of the antihypertension effect of YXQNThe effect of YXQN on the RAS of SHR: There is no difference on Ang I in the plasma of all the groups. Ang II of all treated groups reeuced, but there is no significiance compared with the model. The ALD content of high dose of YXQN reduced significiacly compare with the model.3. The protective effect of YXQN on the heart and kedney of the SHR(1) Different dose groups of YXQN can reduce LVW and the effect is significant between high dose group and model group. They also can reduce the ratio of LVW to BW and the effect of middle and high dose groups is significant compared with model group. The effect of high dose group is better than Captopril Tablets group.(2) Different groups can reduce contain of left ventricular myocardial collagen and type I to type III collagen ratio. The effect of middle dose group is significant inreducing contain of collagen. The effect of all groups is significant in reducing ratio of type I to type III collagen.(3) The content of Cr and Ua in the plasma of 22-week-old SHR rose siginificiancly compared with the normal group. Differet dose groups can reduce their content, the high dose and the middle dose is better than the other. The content of Cr of the high dose group reduced signifiacely compared with the model group so did the middle dose group. The content of Ua of the high dose group reduced signifiacely compared with the model group so did the low dose group.(4) The effect of YXQN on the RAS of the SHR kidney. All dose groups of YXQN can signifiancely reduce the content of Ang II in the kidney of SHR compared with the model group. The high and the middle dose groups of YXQN can signifiancely reduce the content of ALD in the kidney of SHR compared with the model group.4.The study of the protection effect of YXQN on the damaging heart and kidney of SHR by the gene expression.(1) The genes latent transforming growth factor binding protein 2 (LTBP-2), glycine methyltransferase (Gnmt) and rat beta-galactoside-alpha 2.6-sialyltransferase in YXQN group were expressed in lower level than in model group. The genes CD36 antigen, heart fatty acid binding protein (Fabp3) and propionyl Coenzyme A carboxylase beta polypeptide (Pccb) in YXQN group was expressed in higher level than in model group. They may play an important role in preventing LVH.(2) The first gene chip showed that 389 genes were difference expession. Among them, 273 genes expressed in low level, while 135 genes expressed in high level. On the second gene chip, the number of difference expession gene was 170. 120 genes expressed in low level, and 50 genes expressed in high level.5. The antihypertension effect of YXQN on RHD (2K1C)Treating YXQN by Mouth one time (lOg/kg), the pressure of the conscious RHD decreased without changes in the heart r更多还原