气虚血瘀证MCAO大鼠子代的同种证候及疾病趋势诱导形成实验研究
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摘要
目的：
获取气虚血瘀证MCAO(大脑中动脉栓塞)大鼠的子代,探讨该子代大鼠较正常同龄SD大鼠是否更具形成气虚血瘀证候的趋势;并进一步研究该气虚血瘀证MCAO大鼠子代证候造模后,与正常同龄SD大鼠对比,有无形成缺血性卒中前病理生理状态的趋势。
方法：
实验一：采用对SD大鼠进行气虚血瘀证候造模及MCAO卒中造模后,雌雄交配的方法,获取其子代大鼠,再次进行证候造模(证候子代组10只),与同样进行证候造模的正常同龄SD大鼠(证候对照组10只)及无干预因素参与的正常同龄SD大鼠(空白对照组10只)比较,观察其能量代谢指标(乳酸、肌酸激酶、乳酸脱氢酶)的变化水平,并比较三组动物气虚证候、血瘀证候评分及旷场分析、攀网实验、体重等相关动物行为学指标的变化,予以中药“补阳还五汤”进行治疗干预,观察治疗后上述指标的变化情况。
实验二：将获取的前述气虚血瘀证MCAO子代大鼠,进行证候造模处理(证候子代组10只),与同样进行证候造模处理的正常同龄SD大鼠(证候对照组10只)及无干预因素参与的正常同龄SD大鼠(空白对照组10只)比较,观察其血液流变学、血小板膜糖蛋白GPⅡb/Ⅲa、血小板a颗粒膜蛋白CD62P水平及颈内动脉起始处血管内皮病理学变化。
结果：
实验一：造模后,能量代谢指标评价：证候子代组各项能量代谢指标水平均高于其余两对照组,结果差异有统计学意义(P<0.05)；证候对照组与空白对照组比较,各项指标水平也高于空白对照组(P<0.05)。气虚、血瘀证候评分及动物行为学指标评价：治疗干预前,证候子代组与其余两组相比,各项指标评价均有统计学差异(P<0.05),其气虚证候、血瘀证候表现较其余两组明显；证候对照组与空白对照组相比,其气虚证候、血瘀证候表现也较空白对照组明显,各项指标差异亦有统计学意义(P<0.05)。治疗干预后,证候子代组及证候对照组各项评分均有改善,证候子代组与其余两组评价结果比较均有统计学差异(P<0.05)；证候对照组与空白对照组相比,在血瘀证指标、攀网实验指标评价结果上有统计学差异(P<0.05),但在气虚证指标、旷场分析及体重指标上,其结果已无明显统计学差异(P>0.05)。
实验二：证候造模后,证候子代组与其余两组相比,血流变指标、血小板膜糖蛋白GPⅡb/Ⅲa及CD62P水平均有统计学差异(P<0.05),其血液流变学呈明显高粘状态,血小板膜糖蛋白GPⅡb/Ⅲa和CD62P水平也明显高于其他两组；证候对照组与空白对照组相比,血液流变学结果亦有统计学差异(P<0.05),血液黏度呈轻度增高,但其血小板膜糖蛋白GPⅡb/Ⅲa和CD62P水平与空白对照组对比无统计学差异(P>0.05)。证候子代组颈内动脉起始处HE染色可见明显内皮细胞水肿及损伤,均较其余两组有明显改变,证候对照组可见内皮细胞水肿,但程度轻微,不如证候子代组变化明显,空白对照组内皮病理切片未见异常。
结论：
1.获取的气虚血瘀证MCAO大鼠子代及正常同龄SD大鼠都能够在证候造模因素的干预下形成明确的气虚血瘀证候；且气虚血瘀证MCAO大鼠子代与正常同龄SD大鼠相比,在气虚血瘀证候造模的诱导下,更易产生更为明显的气虚血瘀证证候表现。
2.证候造模因素的干预能使气虚血瘀证MCAO大鼠子代及正常同龄大鼠均产生血液高粘滞综合征,并可引起大鼠颈内动脉内皮细胞产生水肿、破坏等病理改变,但血小板功能的活化仅在证候子代组中被观察到,证候对照组无此类改变。且气虚血瘀证MCAO大鼠子代与正常同龄大鼠相比,在气虚血瘀证候造模的诱导下,能够产生更为明显的血液高粘滞综合征及颈内动脉内皮细胞水肿、损伤等病理改变,并且具有肯定的更易形成血栓的趋势。
Objective:
To study index levels of energy metabolism as of filial generation born of the middle cerebral artery occlusion (MCAO) model rats with blood-stasis-due-to-qi-deficiency syndrome (BSDTQDS) as well as normally contemporary SD rats after being syndrome molded and to compare changes in qi-deficiency syndrome grading, blood-stasis syndrome grading and related ethology indexes before/after intervention treatment by a TCM formulation, the Buyanghuanwu Decoction. And next to study index levels of hemorheology, thrombocyte membrane glycoprotein etc. as of filial generation born of the MCAO-model rats with blood-stasis-due-to-qi-deficiency syndrome(BSDTQDS) after being molded as previously stated in Part 1, to observe related pathological transformation as of arteria carotis if any as well as to compare with normally contemporary rats to study whether there is any tendency to result into physiological/pathological status of pre-ischemic stroke for filial generation of the former.
Method:
Part 1:Filial generation rats were born through mating between male/female SD rats after BSDTQD syndrome molding and MCAO apoplexy molding and, such subjects were made syndrome molding once again to produce 10 filial generation of syndrome experimental group(SEG) and compared with 10 normally contemporary SD rats by the same syndrome molding in syndrome controlled group(SCG) and other 10 normally contemporary SD rats without any intervention involved in blank controlled group(BCG) to study index change levels of their energy metabolism like lactic acid, creatine kinase and LDH and to compare changes in qi-deficiency syndrome grading, blood-stasis syndrome grading and related ethology indexes like open-field test, net-climbing test before/after intervention treatment by Buyanghuanwu Decoction.
Part 2:Content levels of hemorheology, content level of thrombocyte membrane glycoprotein as GPⅡb/Ⅲa and CD62P plus physiological/pathological status of vascular endothelium at initial section of the arteria carotis interna for filial generation of the MCAO-model rat with BSDTQDS previously stated was surveyed through syndrome molding of 10 filial generation subjects in syndrome experimental group(SEG) and comparison with 10 normally contemporary SD rats in syndrome controlled group(SCG) with the same syndrome molding and other 10 normally contemporary SD subjects in blank controlled group(BCG) without any intervention involved.
Result:
Part 1:Having being molded, related examinations were done as followed.1st, energy metabolism index evaluation, level of each energy metabolism index of the SEG was higher than the two other controlled groups with statistically significant difference. As for SCG and BCG, level of each index as of the former was also higher over the latter. 2nd, qi-deficiency syndrome grading, blood-stasis syndrome grading and assessment of related ethology indexes, before treatment (to speak exactly, this experiment), each index assessment of SEG showed statistically significant difference in comparison with others, and both qi-deficiency syndrome and blood-stasis syndrome of SEG were more serious than controlled groups. Meanwhile, qi-deficiency/blood-stasis syndrome of SCG was more serious than the other and, there was statistically significant difference in each index between groups. After treatment, each assessment was improved as for both SEG and SCG, and assessment of SEG still manifested statistically significant difference with the others. Despite the fact that there were statistical differences in index assessment of blood-stasis syndrome and net-climbing test between controlled groups, results of qi-deficiency syndrome index, open-field test as well as weight index showed no statistically significant difference between them.
Part 2:Having syndrome molding, there were statistically significant differences in hemorheology content level and content level of thrombocyte membrane glycoprotein as GPⅡb/Ⅲa and CD62P as of filial generation in SEG in comparison with the other ones with hemorheology of these subjects showing the state of obviously high blood viscosity and content level of thrombocyte membrane glycoprotein as GPⅡb/Ⅲa and CD62P significantly higher over their counterparts. In contrast to subjects in BCG, there was also statistically significant difference in the change of hemorheology for the ones in SCG with blood showing mildly high viscosity, while there wasn't statistically significant difference in content level of thrombocyte membrane glycoprotein as GPⅡb/Ⅲa and CD62P between such two groups. As for pathology examination on subjects in the three groups, HE coloration at initial section of the arteria carotis interna demonstrated apparent edema/damage in SEG, which proved clear change compared with its counterparts and, endothelial cells were in edema state as of SCG, which was very slight and not obvious as SEG. Furthermore, there was not any abnormality of the pathological section of the endothelium in BCG.
Conclusion:
1. Both index assessment and treatment counterevidence suggest that, filial generation born by MCAO rats and normally contemporary rats can be induced to fall into evident BSDTQDS under intervention of syndrome molding factors. What's more, filial generation of the MCAO-model rats with BSDTQDS could be likely led by molding of BSDTQDS to more serious BSDTQDS manifestations than normally contemporary rats.
2. Intervention on syndrome molding factors helps both filial generation of the MCAO-model rats with blood-stasis-due-to-qi-deficiency syndrome and normally contemporary rats fall into myxemia and produce pathological changes like edema, damage, etc. in endothelial cells of arteria carotis interna as for rats, however, increase of thrombocyte adherence function and thrombosis tendency is only found in SEG rather than SCG. Thus comparing to normally contemporary rats, filial generation of the MCAO-model rats with BSDTQDS could be likely induced by molding of BSDTQDS to lead to more obvious myxemia, pathological changes like edema, damage, etc. and the tendency of thrombosis than normally contemporary rats.
获取气虚血瘀证MCAO(大脑中动脉栓塞)大鼠的子代,探讨该子代大鼠较正常同龄SD大鼠是否更具形成气虚血瘀证候的趋势;并进一步研究该气虚血瘀证MCAO大鼠子代证候造模后,与正常同龄SD大鼠对比,有无形成缺血性卒中前病理生理状态的趋势。
方法：
实验一：采用对SD大鼠进行气虚血瘀证候造模及MCAO卒中造模后,雌雄交配的方法,获取其子代大鼠,再次进行证候造模(证候子代组10只),与同样进行证候造模的正常同龄SD大鼠(证候对照组10只)及无干预因素参与的正常同龄SD大鼠(空白对照组10只)比较,观察其能量代谢指标(乳酸、肌酸激酶、乳酸脱氢酶)的变化水平,并比较三组动物气虚证候、血瘀证候评分及旷场分析、攀网实验、体重等相关动物行为学指标的变化,予以中药“补阳还五汤”进行治疗干预,观察治疗后上述指标的变化情况。
实验二：将获取的前述气虚血瘀证MCAO子代大鼠,进行证候造模处理(证候子代组10只),与同样进行证候造模处理的正常同龄SD大鼠(证候对照组10只)及无干预因素参与的正常同龄SD大鼠(空白对照组10只)比较,观察其血液流变学、血小板膜糖蛋白GPⅡb/Ⅲa、血小板a颗粒膜蛋白CD62P水平及颈内动脉起始处血管内皮病理学变化。
结果：
实验一：造模后,能量代谢指标评价：证候子代组各项能量代谢指标水平均高于其余两对照组,结果差异有统计学意义(P<0.05)；证候对照组与空白对照组比较,各项指标水平也高于空白对照组(P<0.05)。气虚、血瘀证候评分及动物行为学指标评价：治疗干预前,证候子代组与其余两组相比,各项指标评价均有统计学差异(P<0.05),其气虚证候、血瘀证候表现较其余两组明显；证候对照组与空白对照组相比,其气虚证候、血瘀证候表现也较空白对照组明显,各项指标差异亦有统计学意义(P<0.05)。治疗干预后,证候子代组及证候对照组各项评分均有改善,证候子代组与其余两组评价结果比较均有统计学差异(P<0.05)；证候对照组与空白对照组相比,在血瘀证指标、攀网实验指标评价结果上有统计学差异(P<0.05),但在气虚证指标、旷场分析及体重指标上,其结果已无明显统计学差异(P>0.05)。
实验二：证候造模后,证候子代组与其余两组相比,血流变指标、血小板膜糖蛋白GPⅡb/Ⅲa及CD62P水平均有统计学差异(P<0.05),其血液流变学呈明显高粘状态,血小板膜糖蛋白GPⅡb/Ⅲa和CD62P水平也明显高于其他两组；证候对照组与空白对照组相比,血液流变学结果亦有统计学差异(P<0.05),血液黏度呈轻度增高,但其血小板膜糖蛋白GPⅡb/Ⅲa和CD62P水平与空白对照组对比无统计学差异(P>0.05)。证候子代组颈内动脉起始处HE染色可见明显内皮细胞水肿及损伤,均较其余两组有明显改变,证候对照组可见内皮细胞水肿,但程度轻微,不如证候子代组变化明显,空白对照组内皮病理切片未见异常。
结论：
1.获取的气虚血瘀证MCAO大鼠子代及正常同龄SD大鼠都能够在证候造模因素的干预下形成明确的气虚血瘀证候；且气虚血瘀证MCAO大鼠子代与正常同龄SD大鼠相比,在气虚血瘀证候造模的诱导下,更易产生更为明显的气虚血瘀证证候表现。
2.证候造模因素的干预能使气虚血瘀证MCAO大鼠子代及正常同龄大鼠均产生血液高粘滞综合征,并可引起大鼠颈内动脉内皮细胞产生水肿、破坏等病理改变,但血小板功能的活化仅在证候子代组中被观察到,证候对照组无此类改变。且气虚血瘀证MCAO大鼠子代与正常同龄大鼠相比,在气虚血瘀证候造模的诱导下,能够产生更为明显的血液高粘滞综合征及颈内动脉内皮细胞水肿、损伤等病理改变,并且具有肯定的更易形成血栓的趋势。
Objective:
To study index levels of energy metabolism as of filial generation born of the middle cerebral artery occlusion (MCAO) model rats with blood-stasis-due-to-qi-deficiency syndrome (BSDTQDS) as well as normally contemporary SD rats after being syndrome molded and to compare changes in qi-deficiency syndrome grading, blood-stasis syndrome grading and related ethology indexes before/after intervention treatment by a TCM formulation, the Buyanghuanwu Decoction. And next to study index levels of hemorheology, thrombocyte membrane glycoprotein etc. as of filial generation born of the MCAO-model rats with blood-stasis-due-to-qi-deficiency syndrome(BSDTQDS) after being molded as previously stated in Part 1, to observe related pathological transformation as of arteria carotis if any as well as to compare with normally contemporary rats to study whether there is any tendency to result into physiological/pathological status of pre-ischemic stroke for filial generation of the former.
Method:
Part 1:Filial generation rats were born through mating between male/female SD rats after BSDTQD syndrome molding and MCAO apoplexy molding and, such subjects were made syndrome molding once again to produce 10 filial generation of syndrome experimental group(SEG) and compared with 10 normally contemporary SD rats by the same syndrome molding in syndrome controlled group(SCG) and other 10 normally contemporary SD rats without any intervention involved in blank controlled group(BCG) to study index change levels of their energy metabolism like lactic acid, creatine kinase and LDH and to compare changes in qi-deficiency syndrome grading, blood-stasis syndrome grading and related ethology indexes like open-field test, net-climbing test before/after intervention treatment by Buyanghuanwu Decoction.
Part 2:Content levels of hemorheology, content level of thrombocyte membrane glycoprotein as GPⅡb/Ⅲa and CD62P plus physiological/pathological status of vascular endothelium at initial section of the arteria carotis interna for filial generation of the MCAO-model rat with BSDTQDS previously stated was surveyed through syndrome molding of 10 filial generation subjects in syndrome experimental group(SEG) and comparison with 10 normally contemporary SD rats in syndrome controlled group(SCG) with the same syndrome molding and other 10 normally contemporary SD subjects in blank controlled group(BCG) without any intervention involved.
Result:
Part 1:Having being molded, related examinations were done as followed.1st, energy metabolism index evaluation, level of each energy metabolism index of the SEG was higher than the two other controlled groups with statistically significant difference. As for SCG and BCG, level of each index as of the former was also higher over the latter. 2nd, qi-deficiency syndrome grading, blood-stasis syndrome grading and assessment of related ethology indexes, before treatment (to speak exactly, this experiment), each index assessment of SEG showed statistically significant difference in comparison with others, and both qi-deficiency syndrome and blood-stasis syndrome of SEG were more serious than controlled groups. Meanwhile, qi-deficiency/blood-stasis syndrome of SCG was more serious than the other and, there was statistically significant difference in each index between groups. After treatment, each assessment was improved as for both SEG and SCG, and assessment of SEG still manifested statistically significant difference with the others. Despite the fact that there were statistical differences in index assessment of blood-stasis syndrome and net-climbing test between controlled groups, results of qi-deficiency syndrome index, open-field test as well as weight index showed no statistically significant difference between them.
Part 2:Having syndrome molding, there were statistically significant differences in hemorheology content level and content level of thrombocyte membrane glycoprotein as GPⅡb/Ⅲa and CD62P as of filial generation in SEG in comparison with the other ones with hemorheology of these subjects showing the state of obviously high blood viscosity and content level of thrombocyte membrane glycoprotein as GPⅡb/Ⅲa and CD62P significantly higher over their counterparts. In contrast to subjects in BCG, there was also statistically significant difference in the change of hemorheology for the ones in SCG with blood showing mildly high viscosity, while there wasn't statistically significant difference in content level of thrombocyte membrane glycoprotein as GPⅡb/Ⅲa and CD62P between such two groups. As for pathology examination on subjects in the three groups, HE coloration at initial section of the arteria carotis interna demonstrated apparent edema/damage in SEG, which proved clear change compared with its counterparts and, endothelial cells were in edema state as of SCG, which was very slight and not obvious as SEG. Furthermore, there was not any abnormality of the pathological section of the endothelium in BCG.
Conclusion:
1. Both index assessment and treatment counterevidence suggest that, filial generation born by MCAO rats and normally contemporary rats can be induced to fall into evident BSDTQDS under intervention of syndrome molding factors. What's more, filial generation of the MCAO-model rats with BSDTQDS could be likely led by molding of BSDTQDS to more serious BSDTQDS manifestations than normally contemporary rats.
2. Intervention on syndrome molding factors helps both filial generation of the MCAO-model rats with blood-stasis-due-to-qi-deficiency syndrome and normally contemporary rats fall into myxemia and produce pathological changes like edema, damage, etc. in endothelial cells of arteria carotis interna as for rats, however, increase of thrombocyte adherence function and thrombosis tendency is only found in SEG rather than SCG. Thus comparing to normally contemporary rats, filial generation of the MCAO-model rats with BSDTQDS could be likely induced by molding of BSDTQDS to lead to more obvious myxemia, pathological changes like edema, damage, etc. and the tendency of thrombosis than normally contemporary rats.
引文
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[1]罗尧岳.气虚血瘀证动物模型的研究述评[J].湖南中医学院学报,2004,24(5)：57-58.
[2]郭建队,杨秀清,陈梅.气虚血瘀证脑梗死动物模型的制作[J].现代中医药,2005,3：123.
[3]王键,赵辉,李净,等.多因素复合制作气虚血瘀证脑缺血动物模型的实验研究[J].中国实验动物学报,2001,(42)：216-220.
[4]尹军祥,田金洲,宋崇顺,等.气虚血瘀证动物模型制作方法与评价[J].中华中医药杂志,2006,21 (7)：424-426.
[5]宋崇顺,廖家桢.气虚证血液流变学的临床观察和实验研究.中医杂志,1981,22(10)：39-41.
[6]李仪奎.中药药理实验方法学[M].上海：上海科学技术出版社,1991：146.
[7]娄金丽,张允岭,郑宏,等.气虚血瘀证动物模型研究的思路与方法[J].北京中医药大学学报,2006,29(2)：87-90.
[8]中国中西医结合研究会活血化瘀专业委员会.血瘀证诊断标准[J].中国中西医结合杂志,1987,3(7)：129.
[9]杨倩春,杨霓芝,陈伯钧,等.黄芪注射液对慢性肾炎气虚血瘀证大鼠模型的药效学研究.广州中医药大学学报,2004,(21)3：196-200
[10]申春悌,曹伟春,曾晓辉.卡通片对心脑血管病血液流变性影响的临床与实验研究.中国中医基础医学杂志,1999,5(11)：26-30
[11]严继贵,凤良元,鄢顺琴.胃得健优化方对气虚血瘀证大鼠血液流变学的影响.福建中医药,2004,35(1)：45-46
[12]施新酋,医用实验动物学[M].西安：陕西科学技术出版社,1989,486.
[13]庞树玲,高金亮.中年大鼠气虚血瘀证的模拟及其机制探讨[J].天津中医学院学报,1997,16(3)：28-31.
[14]王键,胡建鹏.缺血性中风气虚血瘀证动物模型的初步研究[J].安徽中医学院学报,1999,18(2)：46-49.
[15]赵辉,王键.试论多因素复合制作病证结合动物模型思路[J].安徽中医学院学报,2001,20(5)：57-59.
[16]Julio H, Gareia J. Experimental ischemie stroke Areview. Stroke.1984, 15:5
[17]Alexisne, Dietriehwd, greenej, et al. Nonoc elusive common carotidartery thrombosis in the rat results in reversible seneor motorandeognitive behaviora defieits. Stroke 1995,26(12):2338-2346
[18]Maeraeim. new models of focal cerebral ischaemia. Br j clin Pharmacol.1992,34(4):302-308
[19]Koizumi J, Yoshida Y, Nakazawa Tet al. Experimental studies of ischemic brain edemaa new experimental model of cerebral embdish in rats in which recirculation can be introduced in the ischemic area. J Stroke,1986,8:1
[20]EZLonga, PRWeinstein, SCarlson, et al. Reversible middle cerebra lartery occlusion without craniectomy in rats [J]. Stroke,1989,20:84-91.
[21]郭移海,黄韧,连至诚,等.中医实验动物学[M].广州：暨南大学出版社,1999.154.
[22]田金洲,王永炎,时晶,等。证候模型研究的思路[J]。北京中医药大学学 报,2005,5：2527
[23]李净,王键。益气活血法改善气虚血瘀证局灶性脑缺血再灌注模型鼠生物学特征的有效性评价[J]。中国中医基础医学杂志,2003,9(4)：22-25
[24]扈新刚,张允岭,柳洪胜,等。气虚血瘀证大鼠表征观察与分析[J]。北京中医药大学学报,2006,29(12)：807-810
[25]田金洲,王永炎,徐意,等。血瘀证动物模型的种类、评价与研究[J]。北京中医药大学学报,2006,29(6)：396-400
[26]Gretarsdottk S, Svehabjomsdottk S, Jonsson HE et al. Localization of a susceptibility gene for common forms of stroke to 5al2 Am J Hum Genet.2002.70:593-603.
[27]张成.基因多态性与缺血性脑血管病[J].实用医院临床杂志,2008,5(2)：30-32.
[28]凌锋,刘承基,等.脑血管病理论与实践2007[M].北京：人民卫生出版社,2007：31.
[29]HASSNA, MARKUS H S. Genetics and ischemicstroke[J]. Brain,2000.123: 1784-1812.
[30]Rubattu S, LeeMA, De Pao lis P, etal. A ltered structure, regulation and function of the gene encoding atrial natriuretic peptide in the stroke prone spontaneously hypertensive rat [J].Circ Res,1999,85: 900-905.
[31]Woffle, A. P., Matzke,M. A. Epigenetics regulation through repression. Science.1999,286:481-486.
[32]Jeff D. A alfs and Robert E. Kingeston et al. What does'chromatin remodeling'mean T rends in Biochem ical science2000,548-555.
[33]黄超峰.基因型和基因表型[J]生物学通报.2003(11)：10-12
[34]Hugh Morgan. Jost p reis, V ardhman Rakyan and EmmaWhitelaw, Inheritance:not only DNA, L ife Science 2001,131:32-36.
[35]RubattuS, VolpeM, KreutzR, etal. Chromosomalmapping of quantitative trait loci contributing to stroke inarat model of com-plex human disease [J]. NatGenet,1996,13:429-434.
[36]JeffsB, ClarkJS, AndersonNH, etal. Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus [J]. NatGenet,1997,16:364-367.
[37]李钰铭.动物模型在中风遗传学中的应用研究[J]西部医学.2006 (9)：666-668
[38]RASTENYTE D, TCOMILEHTO J, SARTI C, Genetics of stroke—a review[J]. J of Neurol Sci,1998,153:132-145.
[39]De Pao lis P, Rubattu S, LombardiA, etal. Functional analysis of a pro ANP molecular variant in the stroke-p rone spontaneously hypertensive rat.13th Scientific Meeting of the International Society of Hypertension, M ilan 2003[J].J Hypertens,2003,21(Suppl 4):S239.
[40]Vesely DL. A trial natriuretic pep tide prohormone gene expression hormones and diseases that up regulate its expression [J].IUBMB Life, 2002,53:153-159.
[41]Ikeda M, KohnoM, Takeda T. Inhibition by cardiac natriuretic pep tides of rat vascular endo thelial cellmigration[J].Hyperten2sion,1995, 26:401-405.
[42]Kook H, Itoh H, Cho iBS, etal. Physiological concentration of atrial natriuretic peptide induces endo thelial regeneration in vitro [J].Am J Physiol,2003,284:H1388-H1397.
[43]梁颖茵,陈松林,张成.脑血管病的遗传学[J].Cerebrovasc Dis Foreign Med Sci,2004,12. (6):466-469.
[44]Duggirala R, GonzalezVC,0'L eary DH, etal. Genetic basis of variation of caro tid artery wall thickness[J]. Stroke,1996,27: 833-837.
[45]SzolnokiZ, SomogyvariF, SzolicsM, etal. Common genetic mutations as possible aetiological factors in stroke.EurNeurol,2001, 145:119-120.
[46]GreenD. Thrombophilia and stroke. Top Stroke Rehabil,2003,1021-33.
[47]王先梅,严睿,杨丽霞,等.复合环境因素诱导大鼠脑卒中机体防御基因表达的改变及意义[J].中华医学遗传学杂志,2003,(20)：143-146.
[2]郭建队,杨秀清,陈梅.气虚血瘀证脑梗死动物模型的制作[J].现代中医 药,2005,3：123.
[3]王键,赵辉,李净,等.多因素复合制作气虚血瘀证脑缺血动物模型的实验研究[J].中国实验动物学报,2001,(42)：216-220.
[4]尹军祥,田金洲,宋崇顺,等.气虚血瘀证动物模型制作方法与评价[J].中华中医药杂志,2006, 21(7)：424-426.
[5]田金洲,王永炎,时晶,等。证候模型研究的思路[J]。北京中医药大学学报,2005,5：25-27
[6]张爱林,徐秋萍,孙建宁.不同厂家的银杏制剂对冷水负重游泳模型小鼠保护作用的比较研究.中国中医药信息杂志,2004, 11(1)：31-32
[7]宋崇顺,廖家桢.气虚证血液流变学的临床观察和实验研究.中医杂志,1981,22(10)：39-41.
[8]李仪奎.中药药理实验方法学[M].上海：上海科学技术出版社,1991：146.
[9]娄金丽,张允岭,郑宏,等.气虚血瘀证动物模型研究的思路与方法[J].北京中医药大学学报,2006,29(2)：87-90.
[10]中国中西医结合研究会活血化瘀专业委员会.血瘀证诊断标准[J].中国中西医结合杂志,1987,3(7)：129.
[11]杨倩春,杨霓芝,陈伯钧,等.黄芪注射液对慢性肾炎气虚血瘀证大鼠模型的药效学研究.广州中医药大学学报,2004,(21)3：196-200
[12]申春悌,曹伟春,曾晓辉.卡通片对心脑血管病血液流变性影响的临床与实验研究.中国中医基础医学杂志,1999,5(11)：26-30
[13]严继贵,凤良元,鄢顺琴.胃得健优化方对气虚血瘀证大鼠血液流变学的影响.福建中医药,2004,35(1)：45-46
[14]施新酋,医用实验动物学[M].西安：陕西科学技术出版社,1989,486.
[15]庞树玲,高金亮.中年大鼠气虚血瘀证的模拟及其机制探讨[J].天津中医学院学报,1997,16(3)：28-31.
[16]王键,胡建鹏.缺血性中风气虚血瘀证动物模型的初步研究[J].安徽中医学院学报,1999,18(2)：46-49.
[17]李净,王键。益气活血法改善气虚血瘀证局灶性脑缺血再灌注模型鼠生物学特征的有效性评价[J]。中国中医基础医学杂志,2003,9(4)：22-25
[18]田金洲,王永炎,徐意,等。血瘀证动物模型的种类、评价与研究[J]。北京中医药大学学报,2006,29(6)：396-400
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