丹芎抑凝饮对家兔血液抗凝作用及血液流变学的影响
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摘要
目的: 对心脏瓣膜置换术后预防栓塞的研究一直是人们重视的课题。血栓形成是由于正常的凝血机制被扰乱而促使某些血细胞和蛋白质被激活相互作用而最终导致血小板-纤维蛋白血栓，它不仅是多细胞类型参与，也是多代谢途径参与的过程。临床上采用维生素K拮抗剂香豆类药物以华法林为代表及抗血小板药物如阿司匹林，潘生丁等口服均有不同程度的不良反应如华法林容易导致出血，妊娠期间服用华法林对胎儿有无致畸作用一直存在争议。而阿司匹林可引起的的消化道的一系列副反应如出血、消化性溃疡等。而且华法林对参与白血栓形成的主要成分血小板并无抑制作用，因此有时配伍用阿司匹林，但阿司匹林对某些诱导剂如ADP诱导的血小板聚集的抑制作用较弱。
近年来，随着对丹参、川芎等传统中药用途的开发研究不断深入，关于其在心血管系统的药理作用的实验依据也不断增多，其作用不仅表现在对心脏收缩力，频率以及血压的调节作用，还表现在通过抑制血小板聚集和抗脂质氧化物对血管内膜的损伤等作用从而抑制血栓形成和预防动脉粥样硬化的发生。这使我们认识到传统中药在防治血栓性疾病中的巨大潜力。祖国医学认为血栓属于血瘀范畴中医的“血瘀”与血小板高聚集状态、血液循环障碍及血栓形成有关而活血化瘀则与抑制血小板功能、改善血液循环障碍，防止血栓形
成或使生成的血栓溶解有着密切的关系。同时气血之间存在着密切的关系，在生理上相互依存，气为血之帅，血为气之母，气滞则血瘀。在活血药中加入补益心气药，使气行则血行。丹芎抑凝饮由我省中医院研制通过选择丹参、川芎、水蛭、红花、桃仁等多味活血化瘀中药与补益心气党参、黄芪、白术、甘草、当归、白芍等中药配伍组成。在临床治疗血栓性疾病中取得了良好的效果。本次拟通过动物实验的方法研究其对家兔内源性、外源性凝血途径、血液流变学的各种参数的研究并将其结果与华法林进行同步比较。以验证此种抗凝中药的抗凝作用以期为其在临床的进一步应用和开发提供实验依据。
方法：对家兔凝血酶原时间(PT)及活化部分凝血活酶时间(APTT)的测定：家兔随24只机分成四组，设空白对照组、阳性对照华法林组，丹芎抑凝饮根据服用中药剂量不同设高低两个剂量组，每组6只。各组按公斤体重灌胃给药。每日一次，连续7天，于第3、5、7天给药后一小时的分别于兔耳部中心动脉取血由ACL-200(美国贝克曼)型智能血液凝集仪检测测量PT、APTT；于第7天取血由血液流变分析仪器LG-R-80（北京世帝科学仪器有限公司）完成全血粘度、血浆粘度、红细胞聚集指数、红细胞变形能力检测；对纤溶活性的影响（优秀球蛋白溶解时间ELT）取家兔随18只随机分成3组，设空白对照组，丹芎抑凝饮根据服用中药剂量不同设高低两个剂量组，每组6只。各组按公斤体重灌胃给药给，每日一次，连续给药7天后，取血，加钙法测定ELT；同样方式，7天后取血应用比浊法测定5分钟内血小板最大聚集率，并计算对血小板的抑制率。
结果：服用丹芎抑凝饮中药组的家兔，PT、APTT逐渐延长，于第3天时取血化验PT、APTT丹芎抑凝饮低高剂量组与空白组间比较无统计学差异(P>0.05)，而服用华法林组的家兔与其他三组相比较PT、APTT显著延长(P<0.05)。服药后第5天丹芎抑凝饮低高剂量组、华法林组与空白组间比较PT、APTT 均显著延长(P<0.05)。丹芎抑凝饮低高剂量组与华法林组无统计学差异(P>.05)。服药后第7天丹芎抑凝饮低高剂量组、华法林组与空白组间比较PT、APTT 均显著延长(P<0.01)。丹芎抑凝饮低高剂量组与华法林组无统计学差异(P>.05)。于第7天取血检测血液流变学的各项指标：华法林组虽然也可以降低血液粘度但在红细胞变形能力上与空白组对照，无统计学差别。丹芎抑凝饮低高剂量组则显示在改善血液流变学各项指标中优于华法林组(P<0.05)。主要表现在降低全血粘度、血浆粘度同时降低红细胞的聚集性，增强了红细胞的变形能力。对于血小板聚集率的比较：结果丹芎抑凝饮低高剂量组对家兔的血小板最大聚集率分别为33.29±4.72%，25.57±3.27 %与空白组比较67.32±5.21%显示明显的抑制血小板聚集的作用(P<0.01)。丹芎抑凝饮对优球蛋白溶解时间低高剂量组118.7±12.6min，109.4±9.8min与空白组145.5±13.9min做对照显著降低(P<0.01)。
结论：实验证明中药组方丹芎抑凝饮可以使PT、APTT显著延长，对凝血过程中存在的内源性和外源性两条途径都存在干预作用。丹芎抑凝饮可显著改善血液流变学各项指标全血粘度、血浆粘度、红细胞聚集指数、红细胞变形指数，并能够显著抑制血小板的聚集。说明其有调节血液的流变性，改善血液的“浓、粘、凝、聚”的倾向等作用，这与祖
国医学所记载的破血逐瘀的理论相一致。丹芎抑凝饮对优球蛋白溶解时间与空白组作对照显著缩短(P<0.01)，其抗凝作用还与增强纤溶酶的活性有关。在丹芎抑凝饮中还包含了多种补益心气的中药党参、黄芪、白术、甘草、当归、白芍等，补气药虽对凝血及纤溶活性无直接影响；但能对活血药起到协同或增强作用。总之丹芎抑凝饮能够显著延长PT、APTT与华法林相当，在改善血液流变学全血粘度、血浆粘度、红细胞聚集指数、红细胞变形指数方面优于华法
Objective: The task to prevent embolism after heart valve repalcement is always paid more attention all the while.Thrombus is induced by boring normal mechanism of blood coagalation and making some blood cell and protein actived.At last the thrombus of platelet-fibrin is formed.It is an complex proedss concluding so many kind of cell and metabolic channel and it has very close realation with hemorrheology. The drug of anti-vitaminK and anti-platele such as warfarin and asprin are applied in clinic.But they all have some side effects,for example, haemorrhage was easily brought on by warfarin. It is disputed if warfarin induces oaf at gestation. Furthermore the platele which is the main component of thrombus is not restrained by warfarin. Asprin results in a series of side effects of alimentary canal such as hemorrhage, canker,etc .
Lately along with the study of salvia milliorhiza and ligusticum wallichii franch in-depth evidence for they do good to cardiovascular system become more and more.It can prevent thormbus through restraining platelet assembling. It is said that thrombus has relation with fettle of platelet assembling by
Chinese iatrology.And that huoxuehuayu could restain platelet assembling, improve blood circulation and restrain platelet assembling. We supprose to select some Cinese medical herbs which has the effect of anticoafalation and cardioqi-nourishing technique. That we could make Danxiong Yiningyin (DX).Through the animal experiment choose some parameter which could reflect the anticoagalation and hemorrheology.We observe the effect of Danxiong Yiningyin in comparsion with warfarin in order to provide experimental data for the development and application of the two drugs in clinic .
Methods:Choose pure bred twenty-four rabbits (2.2± 0.5kg).Divide them into four groups at radom. Every group has six rabbit.The four group include Danxiong Yiningyin low high group warfarin group and control group. The Chinese medical herbs of the root of red rooted salvia, chuanxiong, honghua,etc, provided by Hebei medical material company. Then make it into hydromel.Warfarin was made into power and mixed pured water into solution.Accroding to the weighth each rabbit take the drugs every day. Take the blood and then examine the PT,APTT at third, fifth, seventh day by appartus ACL-200(America backman).Examine the hemorrheologic at the seventh day by appartus LG-R-80 automatic blood analyzer（Beijing shidi company）.Examine the rate of platelet assembling max and ELT at the seventh day too. All data was tested with spss10.0 software. Numberical variable data were wxpressed mean( stand deviation.P value<0.05 was considered
statistically signifiant difference.
Result: Results showed that Dxiong Yiningyin could significantly prolong PT,APTT in rabbit which take it.The third day the PT,APTT of Dxiong Yiningyin low and high group were simliar with control group.No significantly different- ce(P>0.05)showed.but That compared with warfarin group, has significantly difference(P<0.05).At fifth day the Dxiong Yiningyin low and high group.No significant difference has found in two Chinese medical herbs(P>0.05). Compared with control group It has significant difference(P<0.05).Compare with warfarin group no significant difference was observed(P>0.05).At the seventh day no significant difference has found in two Chinese medical herbs(P>0.05).Compared with control group It has significant difference(P<0.05). Compare with warfarin group, no significant difference was observed(P>0.05).Take blood to examine the hemorrheologic parameters. Whole blood viscosity, plasm viscosity and erythrocyte deformed index lowered obviously as compared with warfarin group(P<0.05). The platele Amax in the DX group was 33.29±4.72%, 25.57±3.27 % and that Compare with control group significant difference was observed(P<0.05) in ELT.
Conclousion: Through the animal experiment DX could significantly prolong PT,APTT in rabbit.It illuminates that DX interfere with endogenesis and exterior approach in cruor process. DX had a mor
近年来，随着对丹参、川芎等传统中药用途的开发研究不断深入，关于其在心血管系统的药理作用的实验依据也不断增多，其作用不仅表现在对心脏收缩力，频率以及血压的调节作用，还表现在通过抑制血小板聚集和抗脂质氧化物对血管内膜的损伤等作用从而抑制血栓形成和预防动脉粥样硬化的发生。这使我们认识到传统中药在防治血栓性疾病中的巨大潜力。祖国医学认为血栓属于血瘀范畴中医的“血瘀”与血小板高聚集状态、血液循环障碍及血栓形成有关而活血化瘀则与抑制血小板功能、改善血液循环障碍，防止血栓形
成或使生成的血栓溶解有着密切的关系。同时气血之间存在着密切的关系，在生理上相互依存，气为血之帅，血为气之母，气滞则血瘀。在活血药中加入补益心气药，使气行则血行。丹芎抑凝饮由我省中医院研制通过选择丹参、川芎、水蛭、红花、桃仁等多味活血化瘀中药与补益心气党参、黄芪、白术、甘草、当归、白芍等中药配伍组成。在临床治疗血栓性疾病中取得了良好的效果。本次拟通过动物实验的方法研究其对家兔内源性、外源性凝血途径、血液流变学的各种参数的研究并将其结果与华法林进行同步比较。以验证此种抗凝中药的抗凝作用以期为其在临床的进一步应用和开发提供实验依据。
方法：对家兔凝血酶原时间(PT)及活化部分凝血活酶时间(APTT)的测定：家兔随24只机分成四组，设空白对照组、阳性对照华法林组，丹芎抑凝饮根据服用中药剂量不同设高低两个剂量组，每组6只。各组按公斤体重灌胃给药。每日一次，连续7天，于第3、5、7天给药后一小时的分别于兔耳部中心动脉取血由ACL-200(美国贝克曼)型智能血液凝集仪检测测量PT、APTT；于第7天取血由血液流变分析仪器LG-R-80（北京世帝科学仪器有限公司）完成全血粘度、血浆粘度、红细胞聚集指数、红细胞变形能力检测；对纤溶活性的影响（优秀球蛋白溶解时间ELT）取家兔随18只随机分成3组，设空白对照组，丹芎抑凝饮根据服用中药剂量不同设高低两个剂量组，每组6只。各组按公斤体重灌胃给药给，每日一次，连续给药7天后，取血，加钙法测定ELT；同样方式，7天后取血应用比浊法测定5分钟内血小板最大聚集率，并计算对血小板的抑制率。
结果：服用丹芎抑凝饮中药组的家兔，PT、APTT逐渐延长，于第3天时取血化验PT、APTT丹芎抑凝饮低高剂量组与空白组间比较无统计学差异(P>0.05)，而服用华法林组的家兔与其他三组相比较PT、APTT显著延长(P<0.05)。服药后第5天丹芎抑凝饮低高剂量组、华法林组与空白组间比较PT、APTT 均显著延长(P<0.05)。丹芎抑凝饮低高剂量组与华法林组无统计学差异(P>.05)。服药后第7天丹芎抑凝饮低高剂量组、华法林组与空白组间比较PT、APTT 均显著延长(P<0.01)。丹芎抑凝饮低高剂量组与华法林组无统计学差异(P>.05)。于第7天取血检测血液流变学的各项指标：华法林组虽然也可以降低血液粘度但在红细胞变形能力上与空白组对照，无统计学差别。丹芎抑凝饮低高剂量组则显示在改善血液流变学各项指标中优于华法林组(P<0.05)。主要表现在降低全血粘度、血浆粘度同时降低红细胞的聚集性，增强了红细胞的变形能力。对于血小板聚集率的比较：结果丹芎抑凝饮低高剂量组对家兔的血小板最大聚集率分别为33.29±4.72%，25.57±3.27 %与空白组比较67.32±5.21%显示明显的抑制血小板聚集的作用(P<0.01)。丹芎抑凝饮对优球蛋白溶解时间低高剂量组118.7±12.6min，109.4±9.8min与空白组145.5±13.9min做对照显著降低(P<0.01)。
结论：实验证明中药组方丹芎抑凝饮可以使PT、APTT显著延长，对凝血过程中存在的内源性和外源性两条途径都存在干预作用。丹芎抑凝饮可显著改善血液流变学各项指标全血粘度、血浆粘度、红细胞聚集指数、红细胞变形指数，并能够显著抑制血小板的聚集。说明其有调节血液的流变性，改善血液的“浓、粘、凝、聚”的倾向等作用，这与祖
国医学所记载的破血逐瘀的理论相一致。丹芎抑凝饮对优球蛋白溶解时间与空白组作对照显著缩短(P<0.01)，其抗凝作用还与增强纤溶酶的活性有关。在丹芎抑凝饮中还包含了多种补益心气的中药党参、黄芪、白术、甘草、当归、白芍等，补气药虽对凝血及纤溶活性无直接影响；但能对活血药起到协同或增强作用。总之丹芎抑凝饮能够显著延长PT、APTT与华法林相当，在改善血液流变学全血粘度、血浆粘度、红细胞聚集指数、红细胞变形指数方面优于华法
Objective: The task to prevent embolism after heart valve repalcement is always paid more attention all the while.Thrombus is induced by boring normal mechanism of blood coagalation and making some blood cell and protein actived.At last the thrombus of platelet-fibrin is formed.It is an complex proedss concluding so many kind of cell and metabolic channel and it has very close realation with hemorrheology. The drug of anti-vitaminK and anti-platele such as warfarin and asprin are applied in clinic.But they all have some side effects,for example, haemorrhage was easily brought on by warfarin. It is disputed if warfarin induces oaf at gestation. Furthermore the platele which is the main component of thrombus is not restrained by warfarin. Asprin results in a series of side effects of alimentary canal such as hemorrhage, canker,etc .
Lately along with the study of salvia milliorhiza and ligusticum wallichii franch in-depth evidence for they do good to cardiovascular system become more and more.It can prevent thormbus through restraining platelet assembling. It is said that thrombus has relation with fettle of platelet assembling by
Chinese iatrology.And that huoxuehuayu could restain platelet assembling, improve blood circulation and restrain platelet assembling. We supprose to select some Cinese medical herbs which has the effect of anticoafalation and cardioqi-nourishing technique. That we could make Danxiong Yiningyin (DX).Through the animal experiment choose some parameter which could reflect the anticoagalation and hemorrheology.We observe the effect of Danxiong Yiningyin in comparsion with warfarin in order to provide experimental data for the development and application of the two drugs in clinic .
Methods:Choose pure bred twenty-four rabbits (2.2± 0.5kg).Divide them into four groups at radom. Every group has six rabbit.The four group include Danxiong Yiningyin low high group warfarin group and control group. The Chinese medical herbs of the root of red rooted salvia, chuanxiong, honghua,etc, provided by Hebei medical material company. Then make it into hydromel.Warfarin was made into power and mixed pured water into solution.Accroding to the weighth each rabbit take the drugs every day. Take the blood and then examine the PT,APTT at third, fifth, seventh day by appartus ACL-200(America backman).Examine the hemorrheologic at the seventh day by appartus LG-R-80 automatic blood analyzer（Beijing shidi company）.Examine the rate of platelet assembling max and ELT at the seventh day too. All data was tested with spss10.0 software. Numberical variable data were wxpressed mean( stand deviation.P value<0.05 was considered
statistically signifiant difference.
Result: Results showed that Dxiong Yiningyin could significantly prolong PT,APTT in rabbit which take it.The third day the PT,APTT of Dxiong Yiningyin low and high group were simliar with control group.No significantly different- ce(P>0.05)showed.but That compared with warfarin group, has significantly difference(P<0.05).At fifth day the Dxiong Yiningyin low and high group.No significant difference has found in two Chinese medical herbs(P>0.05). Compared with control group It has significant difference(P<0.05).Compare with warfarin group no significant difference was observed(P>0.05).At the seventh day no significant difference has found in two Chinese medical herbs(P>0.05).Compared with control group It has significant difference(P<0.05). Compare with warfarin group, no significant difference was observed(P>0.05).Take blood to examine the hemorrheologic parameters. Whole blood viscosity, plasm viscosity and erythrocyte deformed index lowered obviously as compared with warfarin group(P<0.05). The platele Amax in the DX group was 33.29±4.72%, 25.57±3.27 % and that Compare with control group significant difference was observed(P<0.05) in ELT.
Conclousion: Through the animal experiment DX could significantly prolong PT,APTT in rabbit.It illuminates that DX interfere with endogenesis and exterior approach in cruor process. DX had a mor
引文
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Kfezel AM.Wagner G.SeymourUlmerJ.Structure of the RGD protein decorsin: conserved motif and distinct function In leech proteins that affect blood clotting Science, 1994; 2(64) :1944~1947
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唐刚华,姜国辉,王世真等.川芎哚的结构改造及生物活性研究 . [J]药学学报, 1999; 34(7):498~50 4
戈继业,张振岭.川芎嗪药理作用研究及临床应用进展.[J]中国中西医结合杂志1994;14(10) :638
徐正,王万铁 .川芎嗪对心肌缺血再灌注损伤时心脏血流动力学的影响. [J]温州医学院学报,1996; 26(3): 129~130
吴尧忠,倪正. 丹参活血化瘀作用及机理探讨[J].南京中医药大学学报,1995; 11(6)35~37
朱秉智,骆金华,秦建伟. 丹参对兔血液流变性?血小板及凝血功能影响的实验研究. [J]南京医科大学学报, 2001;8 (3): 170~171
吉中强 高晓昕等. 调脂中药抗血小板聚集和对红细胞流变性影响的实验研究[J].中医药研究, 1999;15 (5): 47~49
黄政德,蒋孟良,易延逵. 酒制丹参?大黄对大鼠血小板功能及抗凝血作用的研究. [J]中成药, 2001; 5 (23): 341~342
吕莉,李欣燕,韩国柱. 重组水蛭素体内抗凝活性的实验研究. [J]中草药2002; 6 (33): 520~522
杨锐,魏文宁,沈迪. 川芎嗪对凝血-纤溶系统酶活性的影响. [J] 同济医科大学学报, 1995; 24(5): 362
Haementeriaghilianii, et al. Seale L Finney S Sawyer RT Tridegin a novel peptidic inhibitor of factor XIIIa from the leech.Enhancesfibn-nolysts Thromb Haemort, 1997;77 (5): 959~ 963
Finney S Seale L Sawyer RTTridegin a new peptidic inhibitor offactor XIIIa.from the blood-sucking leech
Haementeria,1997; 3(24) :797~805
Kfezel AM.Wagner G.SeymourUlmerJ.Structure of the RGD protein decorsin: conserved motif and distinct function In leech proteins that affect blood clotting Science, 1994; 2(64) :1944~1947
Connolly TM, Jacobs JW, Condra C. An inhibitor of collagerrstimulated platelet activation from the salivary glands of the Haementeria offcinalis leech J Biol Chem,1992; 2(67): 6893~6898
Harsfalvi J, Stassen JM, Hoylaerts MF. Calm from Hirudo medicinalis.an inhbitor of von Willebrand hctor buding to collagen under static and flow conditions. Bood, 1995; 745(85): 705~711
周育,朱圣庚.水蛭中的抗凝血多肽与蛋白质. [J] 中华血液学杂志, 1998;(19): 9
毛腾敏.血瘀病理模四探索(二).衰老血瘀模型观察.[J]北京医科大学学报, 1991; 23(2): 100
戴稼禾.78例老年人体外血栓5年限踪监测报告.[J]实用老年医学, 1992; 6(3): 116
王振义,李家增,阮长耿,等.血栓与止血基础理论与临床[M]第2版,上海科学技术出版社,1996; 381,662～664
赵春亭,赵子文.临床血液流变学[M].人民卫生出版社,1997; 31～34,20～24
顾洪漳,赵春,施南萍. 中药红花煎剂对血小板聚集功能的影响. [J]中国血液流变学杂志, 1994;4(2): 56~58
刘志峰,李萍,李桂生. 红花提取物抗血小板聚集及抗血栓
作用的观察. [J]中药药理与临床2000;16(6):35~36
梁俊生,贺能树,吴胜勇. 川芎嗪对犬肾动脉成形术前后血小板聚集的影响.[J] 中国中西医结合外科杂志,1998,4(1) 20.
谷德祥,李德飞,张瑞祺.联用β七叶皂甙钠和复方丹参对急性脑梗塞患者脑血流量?血液流变学及血小板功能等的影响. [J] 中西医结合实用临床急救, 1998; 11 (4): 508~510
白玉莲,柯美玲,刘景德.红花对冠心病患者血液流变学和临床的影响.中医药研究1991; 7(5): 33
刘仁茂,丹参的药用化学成分及药理作用. [J]河南中医,1987; 6(12):34~36
黄力强. 川芎对心脑血管疾病活血化瘀药理作用的讨.[J] 2000; 27(10): 469
王凌燕,朱广谨,殷奎平,等 大鼠实验性心肌梗塞时血浆蛋白C?纤溶活性变化及人参皂甙作用的研究. 解剖报,1995; 26(3):309