活血化瘀方对动脉粥样硬化心血瘀证干预作用的实验研究
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摘要
目的：探讨五首活血化瘀代表方对实验性动脉粥样硬化(AS)心血瘀证影响，比较各方作用的异同。
方法：将56只雄性家兔随机分为7组：即正常组、模型组、丹参饮组、血府逐瘀汤组、失笑散组、活络效灵丹组、桃红四物汤组。采用高脂喂饲复制家兔动脉粥样硬化模型，连续63天。实验第30天取血测血脂、载脂蛋白、血液流变学、超氧化物歧化酶（SOD）活力、丙二醛（MDA）含量；从实验第33天起开始灌胃给药，连续30天。实验第63天，取血测血脂、载脂蛋白、血液流变学、超氧化物歧化酶（SOD）活力、丙二醛（MDA）含量；实验结束后观察主动脉、冠状动脉的形态学改变。
结果：实验第30天后，与正常组比较，各造模组家兔血脂增高、血液流变学异常改变、SOD活力下降、MDA含量增加，镜下未见明显改变，造模组间无明显差别。实验第63天后，①模型组与正常组比较：血脂明显增高，血液流变学异常改变，SOD活力下降、MDA含量增加，镜下内膜明显增厚，内含大量多层泡沫细胞，血管内皮细胞坏死脱落，内弹力膜仅少部分残留，有脂质浸润，中膜平滑肌细胞内有大量脂滴，呈泡沫样改变,主动脉斑块面积和灰度明显增加。②血府逐瘀汤能降低家兔血清TC、LDL-c、TG含量、TC/HDL-c、TG/HDL-c比值、apoB100含量；亦能降低家兔全血粘度（低切、高切）、血浆粘度、红细胞比容；明显升高血清SOD活性；明显缩减主动脉斑块面积和灰度，抑制AS病理形态改变。③活络效灵丹能降低家兔血清TC、LDL-c、TG含量、TG/HDL-c比
值，升高血清apoA1、apoA1/apoB100比值；亦能降低家兔全血粘度（低切、高切）、红细胞比容；升高血清SOD活性；缩减主动脉斑块面积和灰度，亦能抑制AS病理形态改变。④丹参饮能降低家兔血清TC、LDL-c含量；亦能降低家兔全血粘度（低切）、红细胞比容；明显升高血清SOD活性；缩减主动脉斑块面积，抑制AS病理形态改变。⑤失笑散能降低家兔血清TC、LDL-c、TG含量；亦能降低家兔红细胞比容；缩减主动脉斑块面积，抑制AS病理形态改变。⑥桃红四物汤能降低家兔血清TG含量；能升高血清apoA1含量；能降低家兔全血粘度（低切）；无明显抑制AS病变的作用。
结论：血脂增高，血液流变学异常改变，自由基代谢异常，这可能是(AS)心血瘀证形成的内在病理机制。五首活血化瘀代表方均具有不同程度地调节降脂、载脂蛋白代谢，改善血液流变状态，提高SOD活性、降低MDA含量，抑制高脂喂饲家兔动脉粥样硬化形成的作用。其中，血府逐瘀汤优于活络效灵丹、丹参饮、失笑散，桃红四物汤疗效最差。为临床辨证论治提供了理论和实验依据。
Objectve： To investigate intervenient effects of five recipes for promoting blood circulation and removing blood stasis on the syndrome of heart blood stasis of atheriosclerosis(AS) .
Methods：56 male white big ear rabbits were randomly divided into 7 groups: normal group,model group, Dan shen yin(DSY) group, Xuefu zhuyu tong (XFZYT) group, Shi xiao san (SXS) group, Huo luo xiao lin dan (HLXLD) group and Tao hong si wu tong (THSWT) group.Besides the normal group,each of the rabbits was fed high cholesterol diet for 63 days. The blood was drawn from the central ear artery to determine serum lipid,apoprotein,hemorheoloy,superoxide dismutase(SOD)activity and the level of malondialdehyde(MDA);The samples of arteries and hearts were taken for the
histopathological changes of the aorta and coronary artery analysis.
Results：Compared with the nomal group, the model group's serum lipid and apoproteinB100 (apoB100), hemorheoloy and the contents of MDA increased; the activity of SOD decreased; a lot of lipid foam cells migrated to the regions of intima and smooth muscle cells(SMC)which associated injuries of internal elastic lamina. Compared with the model group, XFZYT group's levels of TC,TG,LDL-c, apoB100 in serum , whole blood viscosity of high share rate, whole blood viscosity of low share rate, plasma viscosity and hematocrit decreased dramatically; the activity of SOD increased; the area and gray of atherogetic decreased and lesion of the aorta was significantly depressed. HLXLD remarkably decreased the levels of TC ,LDL-c in serum and whole blood viscosity of low share rate, mildly decrease hematocrit; the activity of SOD increased; the area and gray of atherogetic decreased and lesion of the aorta was depressed. DSY decreased whole blood viscosity of high share rate, whole blood viscosity of low share rate, hematocrit, mildly decrease the level of TC and LDL-c in serum, the activity of SOD increased ; the area of atherogetic decreased and lesion of the aorta was depressed. SXS
decreased the levels of TC,TG,LDL-c in serum and hematocrit; the area of atherogetic decreased and lesion of the aorta was slightly depressed. THSWT decreased the level of TG in serum and whole blood viscosity of high share rate, mildly decrease whole blood viscosity of low share rate. the lesion of the aorta was not depressed.
Conclusion：the model group's serum lipid and apoprotein and free radical metabolism became abnormality,blood rheologie characteistics became worse. Perhaps it is the formative mechanism of the syndrome of blood stasis in the heart in AS.The five recipes can modulate it and prevent the development of the AS in varyious degrees. XFZYT is more effective than the others, while THSWT is the worst of the five.
方法：将56只雄性家兔随机分为7组：即正常组、模型组、丹参饮组、血府逐瘀汤组、失笑散组、活络效灵丹组、桃红四物汤组。采用高脂喂饲复制家兔动脉粥样硬化模型，连续63天。实验第30天取血测血脂、载脂蛋白、血液流变学、超氧化物歧化酶（SOD）活力、丙二醛（MDA）含量；从实验第33天起开始灌胃给药，连续30天。实验第63天，取血测血脂、载脂蛋白、血液流变学、超氧化物歧化酶（SOD）活力、丙二醛（MDA）含量；实验结束后观察主动脉、冠状动脉的形态学改变。
结果：实验第30天后，与正常组比较，各造模组家兔血脂增高、血液流变学异常改变、SOD活力下降、MDA含量增加，镜下未见明显改变，造模组间无明显差别。实验第63天后，①模型组与正常组比较：血脂明显增高，血液流变学异常改变，SOD活力下降、MDA含量增加，镜下内膜明显增厚，内含大量多层泡沫细胞，血管内皮细胞坏死脱落，内弹力膜仅少部分残留，有脂质浸润，中膜平滑肌细胞内有大量脂滴，呈泡沫样改变,主动脉斑块面积和灰度明显增加。②血府逐瘀汤能降低家兔血清TC、LDL-c、TG含量、TC/HDL-c、TG/HDL-c比值、apoB100含量；亦能降低家兔全血粘度（低切、高切）、血浆粘度、红细胞比容；明显升高血清SOD活性；明显缩减主动脉斑块面积和灰度，抑制AS病理形态改变。③活络效灵丹能降低家兔血清TC、LDL-c、TG含量、TG/HDL-c比
值，升高血清apoA1、apoA1/apoB100比值；亦能降低家兔全血粘度（低切、高切）、红细胞比容；升高血清SOD活性；缩减主动脉斑块面积和灰度，亦能抑制AS病理形态改变。④丹参饮能降低家兔血清TC、LDL-c含量；亦能降低家兔全血粘度（低切）、红细胞比容；明显升高血清SOD活性；缩减主动脉斑块面积，抑制AS病理形态改变。⑤失笑散能降低家兔血清TC、LDL-c、TG含量；亦能降低家兔红细胞比容；缩减主动脉斑块面积，抑制AS病理形态改变。⑥桃红四物汤能降低家兔血清TG含量；能升高血清apoA1含量；能降低家兔全血粘度（低切）；无明显抑制AS病变的作用。
结论：血脂增高，血液流变学异常改变，自由基代谢异常，这可能是(AS)心血瘀证形成的内在病理机制。五首活血化瘀代表方均具有不同程度地调节降脂、载脂蛋白代谢，改善血液流变状态，提高SOD活性、降低MDA含量，抑制高脂喂饲家兔动脉粥样硬化形成的作用。其中，血府逐瘀汤优于活络效灵丹、丹参饮、失笑散，桃红四物汤疗效最差。为临床辨证论治提供了理论和实验依据。
Objectve： To investigate intervenient effects of five recipes for promoting blood circulation and removing blood stasis on the syndrome of heart blood stasis of atheriosclerosis(AS) .
Methods：56 male white big ear rabbits were randomly divided into 7 groups: normal group,model group, Dan shen yin(DSY) group, Xuefu zhuyu tong (XFZYT) group, Shi xiao san (SXS) group, Huo luo xiao lin dan (HLXLD) group and Tao hong si wu tong (THSWT) group.Besides the normal group,each of the rabbits was fed high cholesterol diet for 63 days. The blood was drawn from the central ear artery to determine serum lipid,apoprotein,hemorheoloy,superoxide dismutase(SOD)activity and the level of malondialdehyde(MDA);The samples of arteries and hearts were taken for the
histopathological changes of the aorta and coronary artery analysis.
Results：Compared with the nomal group, the model group's serum lipid and apoproteinB100 (apoB100), hemorheoloy and the contents of MDA increased; the activity of SOD decreased; a lot of lipid foam cells migrated to the regions of intima and smooth muscle cells(SMC)which associated injuries of internal elastic lamina. Compared with the model group, XFZYT group's levels of TC,TG,LDL-c, apoB100 in serum , whole blood viscosity of high share rate, whole blood viscosity of low share rate, plasma viscosity and hematocrit decreased dramatically; the activity of SOD increased; the area and gray of atherogetic decreased and lesion of the aorta was significantly depressed. HLXLD remarkably decreased the levels of TC ,LDL-c in serum and whole blood viscosity of low share rate, mildly decrease hematocrit; the activity of SOD increased; the area and gray of atherogetic decreased and lesion of the aorta was depressed. DSY decreased whole blood viscosity of high share rate, whole blood viscosity of low share rate, hematocrit, mildly decrease the level of TC and LDL-c in serum, the activity of SOD increased ; the area of atherogetic decreased and lesion of the aorta was depressed. SXS
decreased the levels of TC,TG,LDL-c in serum and hematocrit; the area of atherogetic decreased and lesion of the aorta was slightly depressed. THSWT decreased the level of TG in serum and whole blood viscosity of high share rate, mildly decrease whole blood viscosity of low share rate. the lesion of the aorta was not depressed.
Conclusion：the model group's serum lipid and apoprotein and free radical metabolism became abnormality,blood rheologie characteistics became worse. Perhaps it is the formative mechanism of the syndrome of blood stasis in the heart in AS.The five recipes can modulate it and prevent the development of the AS in varyious degrees. XFZYT is more effective than the others, while THSWT is the worst of the five.
引文
[1] 张均田．现代药理实验方法[M] ．北京：中国协和医科大学，北京医科大学联合出版社，1993；1259～1260
[2] 陈可冀．活血化瘀研究与临床[M] ．北京：中国协和医科大学，北京医科大学联合出版社，1993；13～17
[3] 张健元，王会玲，董耀荣，等．双龙丸抗动脉粥样硬化及血管内皮保护作用的临床研究[J]．上海中医药杂志，2001,35(7):14～15
[4] 傅克辛．通脉胶囊治疗冠状动脉粥样硬化性心脏病心绞痛40例临床观察 [J]．河北中医，2001,23(9):657～658
[5] 陈美华，赵红佳，林求诚，等．畅脉乐胶囊消退颈动脉粥样硬化斑块的疗效观察[J]．福建医药杂志，2001,23(5):1～3
[6] 黄河清，李明富．血脉舒抗家兔实验性动脉粥样硬化的研究[J]．中医杂志，1998,39(2):113～115
[7] 谢海林，顾振纶，陈可冀，等．消瘀片对粥样硬化兔血浆ET和血清NO水平的影响[J]．苏州医学院学报，2001,20(3):201～202
[8] 刘亚男，胡涛，曹贵民，等．心复宁V号对家兔实验性动脉粥样硬化血脂、内皮素、一氧化氮的影响[J]．中医药研究，2000,16(2):36～38
[9] 李凤文，刘晓颖，刘红．脉复康对动脉硬化家兔血管内皮损伤的保护作用——光镜和电镜观察[J]．中国中医基础医学杂志，2000,6 (10):38～41
[10] 王南，陈琪，陈秀英，等．脉络通防治动脉粥样硬化的研究[J]．南京中医药大学学报(自然科学版)，2001,17(3):157～158
[11] 李凤文，刘晓颖，张立石，等．水蛭及其复方对实验性动脉粥样硬化家兔主动脉内皮素基因表达的影响[J]．中医杂志，1999,40 (1):50～51
[12] 辛志强，曾旭初，易春涛，等．丹参对冠心病患者血清脂质过氧
化物及超氧化物歧化酶的影响[J]．中国中西医结合杂志，1996,16(5):287～288
[13] 严晓红，欧阳静萍，涂淑珍，等．当归对氧化低密度脂蛋白致内皮细胞分泌一氧化氮下降和细胞间粘附分子-1表达升高的影响[J]．中国病理生理杂志，2001,16(1):16～17
[14] Robenfire M,Coletti AT,MoscaL. Treatment strategies for management of serum Lipids: lessons leamed from Lipid metabolism, recent clinical triads,and a experience with the HMG coA reductase inhibitors [J] Prog cardiovasc Dis,1998,41:95～116
[15] Hackmen A,Abe Y, Insall W,etal. levels of soluble cell adhesion molecudes in patients with dyslipidaemia [J] Circulation,1996,93:1 334～338
[16] Hiltunen TP,luoma JS,Nikkari T,etal. expression of LDL receptor,VLDL receptor,LDL receptor-related protein,and scavenger receptor in rabbit atheroscle rotic lesion [J]. Circulation 1998,97:1079～086
[17] 张明，霍海洋，李占全，等.甘油三酯/高密度脂蛋白胆固醇比值对冠心病诊断价值的探讨[J].中华心血管病杂志，2000,28(1):33～35
[18] 郑春雷．活络效灵丹加味治疗高血脂症80例[J]．陕西中医，2002,23（1）:56～57
[19] 毛建业，马菊英．桃红四物汤治疗高血脂症临床观察[J]．中国社区医师，2002,18（1）:36～37
[20] 金鸣．桃红四物汤抑制交愿蛋白交联透明质酸解聚和脂质过氧化作用的研究[J]．中国中药杂志，1994,19(11):680～682
[21] 伍小燕．失笑滴丸与失笑散的药理作用比较[J]．中成药， 1996,18（10）:33～35
[2] 陈可冀．活血化瘀研究与临床[M] ．北京：中国协和医科大学，北京医科大学联合出版社，1993；13～17
[3] 张健元，王会玲，董耀荣，等．双龙丸抗动脉粥样硬化及血管内皮保护作用的临床研究[J]．上海中医药杂志，2001,35(7):14～15
[4] 傅克辛．通脉胶囊治疗冠状动脉粥样硬化性心脏病心绞痛40例临床观察 [J]．河北中医，2001,23(9):657～658
[5] 陈美华，赵红佳，林求诚，等．畅脉乐胶囊消退颈动脉粥样硬化斑块的疗效观察[J]．福建医药杂志，2001,23(5):1～3
[6] 黄河清，李明富．血脉舒抗家兔实验性动脉粥样硬化的研究[J]．中医杂志，1998,39(2):113～115
[7] 谢海林，顾振纶，陈可冀，等．消瘀片对粥样硬化兔血浆ET和血清NO水平的影响[J]．苏州医学院学报，2001,20(3):201～202
[8] 刘亚男，胡涛，曹贵民，等．心复宁V号对家兔实验性动脉粥样硬化血脂、内皮素、一氧化氮的影响[J]．中医药研究，2000,16(2):36～38
[9] 李凤文，刘晓颖，刘红．脉复康对动脉硬化家兔血管内皮损伤的保护作用——光镜和电镜观察[J]．中国中医基础医学杂志，2000,6 (10):38～41
[10] 王南，陈琪，陈秀英，等．脉络通防治动脉粥样硬化的研究[J]．南京中医药大学学报(自然科学版)，2001,17(3):157～158
[11] 李凤文，刘晓颖，张立石，等．水蛭及其复方对实验性动脉粥样硬化家兔主动脉内皮素基因表达的影响[J]．中医杂志，1999,40 (1):50～51
[12] 辛志强，曾旭初，易春涛，等．丹参对冠心病患者血清脂质过氧
化物及超氧化物歧化酶的影响[J]．中国中西医结合杂志，1996,16(5):287～288
[13] 严晓红，欧阳静萍，涂淑珍，等．当归对氧化低密度脂蛋白致内皮细胞分泌一氧化氮下降和细胞间粘附分子-1表达升高的影响[J]．中国病理生理杂志，2001,16(1):16～17
[14] Robenfire M,Coletti AT,MoscaL. Treatment strategies for management of serum Lipids: lessons leamed from Lipid metabolism, recent clinical triads,and a experience with the HMG coA reductase inhibitors [J] Prog cardiovasc Dis,1998,41:95～116
[15] Hackmen A,Abe Y, Insall W,etal. levels of soluble cell adhesion molecudes in patients with dyslipidaemia [J] Circulation,1996,93:1 334～338
[16] Hiltunen TP,luoma JS,Nikkari T,etal. expression of LDL receptor,VLDL receptor,LDL receptor-related protein,and scavenger receptor in rabbit atheroscle rotic lesion [J]. Circulation 1998,97:1079～086
[17] 张明，霍海洋，李占全，等.甘油三酯/高密度脂蛋白胆固醇比值对冠心病诊断价值的探讨[J].中华心血管病杂志，2000,28(1):33～35
[18] 郑春雷．活络效灵丹加味治疗高血脂症80例[J]．陕西中医，2002,23（1）:56～57
[19] 毛建业，马菊英．桃红四物汤治疗高血脂症临床观察[J]．中国社区医师，2002,18（1）:36～37
[20] 金鸣．桃红四物汤抑制交愿蛋白交联透明质酸解聚和脂质过氧化作用的研究[J]．中国中药杂志，1994,19(11):680～682
[21] 伍小燕．失笑滴丸与失笑散的药理作用比较[J]．中成药， 1996,18（10）:33～35