心血瘀阻证心肌血管新生及其养心通脉有效部位方干预效应的研究
摘要
第一部分心血瘀阻证血管新生的中医理论研究
目的:研究中医络病学及血管新生的相关性,从络病学理论角度阐述心血瘀阻证的病理基础。
方法:运用文献研究,主要参考CNKI数据库、VIP数据库中收录的与络病理论相关文献、血管新生相关文献。
结果:
1.通过研究表明中医的络病理论在运用于冠心病时与血管新生具有相关性,主要体现在络脉系统与现代的血管神经、神经-内分泌-免疫网络、血管内皮损伤具有推论上的相关性。
2.心血瘀阻证的络病学基础为主要表现为心络瘀阻、心络绌急和络虚不荣三个方面。
第二部分抗心血瘀阻证的有效成分部位方的研究
实验1:养心通脉方起主要作用有效成分部位抗心肌缺血的研究
目的:寻找养心通脉方中起主要作用的有效部位。
方法:取wistat雄性大鼠120只,随机分为12组,每组10只,包括人参皂苷组、人参多糖组、丹参酮ⅡA组、丹参菲醌组、复方苷元组、复方苷类、复方蛋白组、总多糖组、总生物碱组、总挥发油组、空白模型组和健康对照组。其中10个有效部位组均在喂饲标准饲料同时,灌服相应的有效部位口服液,每次4毫升;健康对照组给于灌服等量的生理盐水。每天1次,连续10天,于第11天开始试验。每例大鼠在麻醉后均作Ⅱ导联心电图1次,随后按上述方法造模,记录观察注射垂体后叶素后15s、30s、120s、300s、600s的心电图;颈动脉插管取血做血液流变学指标。
结果:
(1)大鼠心电图J点位移变化:
①造模前各组之间心电图J点位移无差别(P＞0.05)。
②造模后J点的变化,15s、30s、2min、5min、10min时间段,人参皂苷组与模型组比较(P＜0.05);丹参酮ⅡA组与模型组比较(P＜0.05或P＜0.01);总生物碱组与模型组比较(P＜0.01)、丹参菲醌组与模型组比较(P＜0.05或P＜0.01)、人参多糖组与模型组(P＜0.01)、复方多糖组与模型组比较(P＜0.05,或P＜0.01)、总挥发油组与模型组比较(P＜0.01)有显著的统计学意义。
③复方苷类、复方苷元组、复方蛋白组与模型组比较无统计学意义(P＞0.05)。
(2)大鼠血液流变学的变化
①总生物碱、人参多糖、总挥发油组模型组比较具有极显著的统计学差异(P＜0.01)。
②复方苷元、复方苷类则明显加重大鼠血液流变学指标与模型组比较复方苷元组具有显著的统计学差异(P＜0.01),而复方苷类组与模型组则无显著性差异。血浆黏度,复方苷类组、复方苷元组与模型组均无显著性差异(P＞0.05)。
③丹参菲醌与模型组比较高切时(P＜0.01或P＜0.05);血浆黏度与模型组比较无显著差异(P＞0.05)。
④复方多糖则在中切时有加重指标的作用(与模型组比较P＜0.05)。血浆黏度与模型组比较无显著差异(P＞0.05)。
⑤复方蛋白则与模型组无显著差异(P＞0.05)。
结论:养心通脉方中提取分离出10种有效部位群,其中人参皂苷、丹参酮ⅡA、总生物碱、人参多糖、总挥发油,5种成分具有显著的抗心肌缺血作用,故作为养心通脉方起主要作用的有效成分部位,而将复方多糖与丹参菲醌作为次要有效成分部位。复方苷类、复方苷元、复方蛋白3种成分部位因其没有抗心肌缺血(心血瘀阻证)的作用,且对血流变学也无改善作用,故将其列为养心通脉方无效成分剔出。
实验2:养心通脉方主要与次要有效成分部位交互作用抗心肌缺血研究
目的:明确5个主要成分部位与2个次要成分之间是否有交互作用
方法:按L4(2~3)正交设计安排实验,将人参皂苷、丹参酮ⅡA、总生物碱、人参多糖、总挥发油做为基础因子,复方多糖与丹参菲醌作为考察因子。将wistar雄性大鼠40只,随机分为5组,每组8只,包括处方1组、处方2组、处方3、处方4组,模型组。各组均在喂饲标准饲料同时,灌服相应的有效部位口服液,每次4毫升;每天1次,连续10天,于第11天开始试验。每列大鼠在麻醉后均作Ⅱ导联心电图1次,随后按上述方法造模,记录观察注射垂体后叶素后15s、30s、120s、300s、600s的心电图;颈动脉插管取血做血液流变学指标。
结果:
(1)心电图J点位移变化
①造模后第15s、30s、120s、300s、600s,处方5(空白模型组)与其余四组比较,均具有显著性差异(P＜0.05)
②水平1、水平2差异均无统计学意义(P＞0.05)。
(2)血液流变学的变化
①处方1、2、3、4与处方5有显著的统计学意义((P＜0.05)
②水平1、水平2差异均无统计学意义(P＞0.05)。
结论:养心通脉方主要与次要有效成分部位无交互作用。
实验3:养心通脉方各有效成分部位的有效剂量配伍抗心血瘀阻证研究
目的:探讨养心通脉方有效部位配伍的最佳剂量
方法:取wistar雄性大鼠72只,随机分为9组,每组8只,按L9(3~4)正交表设计安排试验,每个因子取3个水平。9组均在喂饲标准饲料同时,灌服相应的有效部位口服液,每次4毫升;每天1次,连续10天,于第11天开始试验。每例大鼠在麻醉后均作Ⅱ导联心电图1次,随后按上述方法造模,记录观察注射垂体后叶素后15s、30s、120s、300s、600s的心电图。
结果及结论:采用直观分析法分析结果,5种有效部位的最佳配伍为:人参皂苷34.33g生药/kgw,丹参酮ⅡA 1.27g生药/kgw、人参多糖4.77g生药/kgw、总生物碱取0.67g生药/kgw、总挥发油62.2ml生药/kgw。
第三部分养心通脉有效部位方促心血瘀阻证心肌血管新生的研究
实验1:养心通脉有效部位方对心血瘀阻证大鼠血管生长因子VEGF及bFGF影响的研究
目的:探讨养心通脉有效部位方治疗心血瘀阻证的机理
方法:将结扎大鼠冠状动脉左前降支复制心血瘀阻证大鼠模型成功后的24只大鼠随机分为模型组、YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组,再与6只假手术组、6只正常组,一共组成6组;各组均在喂饲标准饲料同时,灌服相应处方口服液,每次4毫升,健康对照组、模型组灌服等量的生理盐水。每天1次,连续2周,于第15天,处死动物取材。用免疫组织化学法检测CD34、VEGF、bFGF表达。
结果:
(1)新生血管数:YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组与模型组比较,具有显著的统计学意义(P＜0.05)。YTⅠ治疗组与SXBXW治疗组比较,无显著的统计学意义。
(2) VEGF的表达:YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组与模型组比较,具有显著的统计学意义(P＜0.05)。YTⅠ治疗组与SXBXW治疗组比较,无显著的统计学意义。
(3) bFGF的表达:YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组与模型组比较,具有显著的统计学意义(P＜0.05)。YTⅠ治疗组与SXBXW治疗组比较,无显著的统计学意义。
结论:促进VEGFmRNA、bFGFmRNA上调,使VEGF、bFGF的合成分泌增加,引起缺血区血管新生,从而侧支循环的良好建立可能是养心通脉有效成分部位方治疗心血瘀阻证的重要机制。
实验2:养心通脉有效部位方对心血瘀阻证大鼠血管生长因子基因表达量影响的研究
目的:探讨养心通脉有效部位方治疗心血瘀阻证的机理
方法:将结扎大鼠冠状动脉左前降支复制心血瘀阻证大鼠模型成功后的24只大鼠随机分为模型组、YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组,再与6只假手术组、6只正常组,一共组成6组;各组均在喂饲标准饲料同时,灌服相应处方口服液,每次4毫升,健康对照组、模型组灌服等量的生理盐水。每天1次,连续2周,于第15天,处死动物取材。用免疫组织化学法检测CD34、VEGF、bFGF表达;
结果:
(1) VEGFmRNA的表达:YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组与模型组比较,具有显著的统计学意义(P＜0.05)。YTⅠ治疗组与SXBXW治疗组比较,无显著的统计学意义。
(2) bFGFmRNA的表达:YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组与模型组比较,具有显著的统计学意义(P＜0.05)。YTⅠ治疗组与SXBXW治疗组比较,无显著的统计学意义。
结论:促进VEGFmRNA、bFGFmRNA上调,促进VEGF、bFGF的合成分泌增加,引起缺血区血管新生,从而侧支循环的良好建立可能是养心通脉有效成分部位方治疗心血瘀阻证的重要机制。
实验3:养心通脉有效部位方对心血瘀阻证大鼠冠状微循环及相关因子影响的研究
目的:探讨养心通脉有效部位方治疗心血瘀阻证的机理
方法:取上述wistar雄性大鼠128只,随机分为4组:养心通脉有效部位方组(养通Ⅱ组)、复方丹参注射液组(丹参组)、空白模型组(模型组)、假手术组。结扎大鼠冠状动脉左前降支复制心血瘀阻证大鼠模型10分钟后经颈外静脉注入给药,养心通脉有效部位方组按0.5ml/100g体重给予YTⅡ注射液、复方丹参注射液组按0.5ml/100g体重给予复方丹参注射液,空白模型组按0.5ml/100g体重给予生理盐水,假手术组按0.5ml/100g体重给予生理盐水。用药15分钟后,采用墨汁灌注法进行冠状微循环形态观察,采用荧光造影法进行冠状微循环活体观察,采颈动脉血用生化检测法,按不同试剂盒操作要求分别检测心肌组织丙二醛(MDA)含量、心肌及血清酶学指标、血管内皮功能指标。
结果:
(1)大鼠心肌毛细血管墨汁灌流数:未缺血区右室壁4组之间无明显差别(均p＞0.05)。与假手术组比较,模型组心肌的其他4个部位毛细血管灌流数均明显减少;但模型组的左室前壁外层灌流相对较好,与左前室壁中内层比较有明显差异(p＜0.01)。两用药组与模型组比较,原缺血部位心肌毛细血管墨汁灌流数有明显增加,除左室前壁外层之外,其他部位均有显著性差异(均p＜0.01)。较之复方丹参组,养心通脉Ⅱ组的左室前壁中内层及室间隔部位毛细血管灌流数明显增加(p＜0.01)。
(2)大鼠冠状微循环荧光变化时间比较:模型组心脏表面荧光出现时间(AT)、密布时间(FT)和饱和时间(ST)均较假手术组延长(p＜0.01)与模型组比较,两用药组的ST均明显缩短,而FT差异不显。养通Ⅱ组的AT比模型组明显缩短(p＜0.05),而复方丹参组的AT和ST均较假手术组明显延长(均p＜0.01)。
(3)大鼠心肌和血液生化免疫指标比较:假手术组→养通Ⅱ组→丹参组→模型组,MDA、TXB_2和CK的测值呈递增趋势,而NO、6-K-PGF_(1α)、Na~+-K~+-ATPase和Ca~(2+)-ATPase的测值则呈递减的趋势(p＜0.05或＜0.01)。与模型组比较,两治疗组心肌组织MDA含量明显降低,NO含量增高;血浆6-K-PGF_(1α)含量升高,而TXB_2含量显著降低;Na~+-K~+-ATPase和Ca~(2+)-ATPase活性均增高,而血清CK水平降低。两治疗组比较,养通Ⅱ组的各项指标测值均优于复方通脉组,其中心肌组织MDA和血清CK的含量比较都具有显著意义(p＜0.05或＜0.01)。
结论:养心通脉有效部位方注射液促进心血瘀阻部位的血管新生,改善冠状微循环与抗氧自由基生成、减轻钙超载和调整血管内皮细胞功能等多种机制有关。
PartⅠtheoretical research
Objective:To research the relevance between the theory of collateral disease and angiogenesis, probe the basic pathological basis of HBSS from perspective of theory of collateral disease.
Methods:using literature research,documents from the CNKI database and VIP database which relevant with theory of collateral disease and angiogenesis.
Conclusion:
1、Through research that when theory of collateral disease applied to coronary heart disease, there has highly relevance with angiogenesis.Mainly reflected in the theory of collateral disease have the inference relevance with blood vessels and nerves,neural-endocrine-immune network and vascular endothelial injury in modern medicine.
2、The basic theory of collateral disease of HSBB is xinluobizu,xinluochuji and luoxuburong.
PartⅡResearch Prescription
Experiment 1:Experimental study of Yang Xin Tong Mai Recipe effective component parts anti-Acute myocardial ischemia
Objective:to determinate Yang Xin Tong Mai Recipe main effective component
Methods:Randomly divided Wistar rat into 10 groups Blank model group,normal comparison group,total alkaloid group,compound prescription glycosides group,compound prescription aglycone group, the compound prescription protein group,the salvia miltiorrhiza phenanthrenequinone group, the ginseng polysaccharide group,the compound prescription polysaccharide group and the total volatile oil group.All groups except normal comparison group were established with Pit inject via caudal vein.Every rat was examined15s,30s,2min,5min,10min electrocardiogram ECG after they were in narcosis,then take Carotid artery blood to examine Whole blood viscosity and Plasma viscosity.
Result:
(1) Electrocardiogram change degree:
①The Ginsenoside,tanshinoneⅡA,The ginseng polysaccharide,the compound prescription polysaccharide,the total alkaloid,the total volatile oil,the salvia miltiorrhiza phenanthrenequinone 7 groups' J point displacement have Significant statistical significance, Compared with the model group(P＜0.05 or P＜0.01).
②The compound prescription protein,the compound prescription aglycone and the compound prescription glycosides groups' J point displacement have non Significant statistical significance Compared with the model groups(P＞0.05);
(2) Whole blood viscosity and Plasma viscosity change:
①The Ginsenoside,the tanshinoneⅡA,the total alkaloid,the ginseng polysaccharide,the total volatile oil can obviously improve the rat's blood rheology indicators,compares with the model group has the extremely remarkable statistics difference(P＜0.01);
②Compound prescription aglycone,compound prescription glycosides then the obviously increase blood hemorheology indicators(Whole blood shear rate),compares compound prescription aglycone group with the model group to have the remarkable statistics difference (P＜0.01).
③Compound prescription glycosides group,compound prescription aglycone and the model group no significant difference in the Plasma viscosity(P＞0.05);
Conclusion:The Ginsenoside,tanshinoneⅡA,ginseng polysaccharide,the compound prescription polysaccharide,the total alkaloid,the total volatile oil,the salvia miltiorrhiza phenan threnequinone 7 component parts have the anti-acute myocardial ischemia initiated by Pit,however the compound prescription protein,the compound prescription aglycone,the compound prescription glycosides does not have the anti-acute myocardial ischemia function. So,we take The Ginsenoside,tanshinoneⅡA,ginseng polysaccharide,the compound prescription polysaccharide,the total alkaloid,the total volatile oil 5 components as the main effective components and exclude the compound prescription protein,the compound prescription aglycone,the compound prescription glycosides 3 No Role component parts.
Experiment 2:Experimental study of Yang Xin Tong Mai Recipe effective component and the Secondary effective components parts orthogonal interaction on anti-Acute myocardial ischemia.
Objective:to clear if there have interaction between five major components parts and two minor components parts
Methods:take The Ginsenoside,tanshinoneⅡA,ginseng polysaccharide,the total alkaloid, the total volatile oil as the basic factor,the compound prescription polysaccharide,the salvia miltiorrhiza phenan threnequinone as Investigation factors.According L4(2~3) orthogonal design and arrange the experiments.Randomly divided 40 Wistar rats into 5 groups:Blank model group,1 prescription group,2 prescription group,3 prescription and 4 prescription group.All groups were established with Pit inject via caudal vein.Every rat was examined15s,30s,2min,5min, 10min electrocardiogram ECG after they were in narcosis,then take Carotid artery blood to examine whole blood viscosity and plasma viscosity.
Result:
(1) Electrocardiogram change degree:
①Here have significant statistical significance 1 prescription group,2 prescription group,3 prescription and 4 prescription group compared with the model groups in 15s,30s,120s,300s, 600s after module established(P＜0.05).
②differences of level 1,level 2 were not statistically significant(P＞0.05).
(2) Whole blood viscosity and Plasma viscosity change:
①Here have significant statistical significance 1 prescription group,2 prescription group,3 prescription and 4 prescription group Compared with the model groups(P＜0.05).
②differences of level 1,level 2 were not statistically significant(P＞0.05).
Conclusion:there have no interaction between five major components parts and two minor components parts.
Experiment 3:Experimental study of Yang Xin Tong Mai Recipe effective component effective dose combinations anti-Acute myocardial ischemia.
Objective:to Explore best dosage of Yang Xin Tong Mai effective component effective Recipe.
Methods:Randomly divided 72 Wistar rats into 9 groups,According L4(3~4).orthogonal design and arrange the experiments.Every factor take 3 different level.All groups were established with Pit inject via caudal vein.Every rat was examined15s,30s,2min,5min,10min electrocardiogram ECG after they were in narcosis,then take Carotid artery blood to examine Whole blood viscosity and Plasma viscosity.
Result and Conclusion:select Intuitive statistical analysis method to analysis the result,5 effective component effective dose should like follows,The Ginsenoside:34.33g/kgbw, tanshinoneⅡA:1.27g/kgbw,ginseng polysaccharide:4.77g/kgbw,the total alkaloid: 0.67g/kgbw,the total volatile oil:62.2ml/kgbw.
PartⅢExperimental study of Yang Xin Tong Mai effective component Recipe promote angiogenesis of HSBB
Experiment 1:Experimental study the VEGF,bFGF expression of HSBB rats treated by Yang Xin Tong Mai effective component Recipe
Objective:to explore the mechanism of Yang Xin Tong Mai effective component Recipe effective component recipe anti-HBSS.
Methods:Randomly divided 24 Wistar rats Successful model established by Ligation of the left anterior descending coronary artery into 4 groups:model group,YTⅠtherapy group, YTⅡtherapy group,SXBXW therapy group and add the sham group,health group,all is 6groups.Every group feed Standard feed and gavages corresponding recipe 4ml/qd for 2weeks. To the 15th day,animals were sacrificed and myocardial tissue samples were frozen in liquid nitrogen.Immunohistochemistry used to detect the expression of CD34,VEGF,bFGF in myocardial tissue.
Result:
①MVC:YTⅠtherapy group,YTⅡtherapy group,SXBXW therapy group compared with the model groups have significant statistical significance(P＜0.05).
②VEGF expression:YTⅠtherapy group,YTⅡtherapy group,SXBXW therapy group compared with the model groups have significant statistical significance(P＜0.05).
③bFGF expression:YTⅠtherapy group,YTⅡtherapy group,SXBXW therapy group compared with the model groups have significant statistical significance(P＜0.05).
Conclusion:Promote VEGF,bFGF increase in the synthesis and secretion caused ischemic angiogenesis,thereby establishing a good collateral circulation maybe the important mechanisms of Yang Xin Tong Mai effective component Recipe to treat HBSS.
Experiment 2:Experimental study the VEGFmRNA,bFGFmRNA expression of HSBB rats treated by Yang Xin Tong Mai effective component recipe
Objective:to explore the mechanism of Yang Xin Tong Mai effective component Recipe effective component recipe anti-HBSS.
Methods:Randomly divided 24 Wistar rats Successful model established by Ligation of the left anterior descending coronary artery into 4 groups:model group,YTⅠtherapy group, YTⅡtherapy group,SXBXW therapy group and add the sham group,health group,all is 6groups.Every group feed Standard feed and gavages corresponding recipe 4ml/qd for 2weeks. To the 15th day,animals were sacrificed and myocardial tissue samples were frozen in liquid nitrogen.RT-PCR and agarose gel electrophoresis used to detect the expression of VEGFmRNA,bFGFmRNA.
Result:
①VEGFmRNA expression:YTⅠtherapy group,YTⅡtherapy group,SXBXW therapy group compared with the model groups have significant statistical significance(P＜0.05).
②bFGFmRNA expression:YTⅠtherapy group,YTⅡtherapy group,SXBXW therapy group compared with the model groups have significant statistical significance(P＜0.05).
Conclusion:Promote VEGFmRNA,bFGFmRNA up to VEGF,bFGF increase in the synthesis and secretion caused ischemic angiogenesis,thereby establishing a good collateral circulation maybe the important mechanisms of Yang Xin Tong Mai effective component Recipe to treat HBSS.
Experiment 3:Experimental study the impact of Coronary microcirculation and Factors expression of HSBB rats treated by Yang Xin Tong Mai effective component Recipe
Objective:to explore the mechanism of Yang Xin Tong Mai effective component Recipe effective component recipe anti-HBSS by research on Coronary microcirculation and related factors expression.
Methods:Randomly divided 128 Wistar rats Successful model established by Ligation of the left anterior descending coronary artery into 4 groups:model group,YTⅡinjection group, Fufang Danshen injection group and add the sham group.After 10mins since modeling inject the corresponding injection by external jugular vein,then ink perfusion,fluorescence Methods were used to observe coronary microcirculation;Carotid artery blood be used to test the MDA, Na~+-K~+-ATPase,Ca2~+-ATPase,TXB2,6-K-PGF1α,NO.
Result:
①Capillary perfusion of ink:YTⅡinjection therapy group compared with model group、 Fufang Danshen injection therapy group、the sham group has significant statistical significance (P＜0.05 or P＜0.01).
②AT、FT、ST:YTⅡinjection group、model group、Fufang Danshen injection group、compared with the sham group is more slowly(P＜0.01);The AT of YTⅡinjection therapy group is shorter than model group;the AT and ST of Fufang Danshen injection group are longer than he sham group's(p＜0.01).
③MDA,Na~+-K~+-ATPase,Ca~(2+)-ATPase,TXB_2,6-K-PGF1α,NO:YTⅡinjection therapy group compared with other 3 groups has significant statistical significance(P＜0.05 or P＜0.01).
Conclusion:Yang Xin Tong Mai effective component promote angiogenesis maybe have relation with anti-free radicals,reducing calcium overload,Adjustment of endothelial function.
目的:研究中医络病学及血管新生的相关性,从络病学理论角度阐述心血瘀阻证的病理基础。
方法:运用文献研究,主要参考CNKI数据库、VIP数据库中收录的与络病理论相关文献、血管新生相关文献。
结果:
1.通过研究表明中医的络病理论在运用于冠心病时与血管新生具有相关性,主要体现在络脉系统与现代的血管神经、神经-内分泌-免疫网络、血管内皮损伤具有推论上的相关性。
2.心血瘀阻证的络病学基础为主要表现为心络瘀阻、心络绌急和络虚不荣三个方面。
第二部分抗心血瘀阻证的有效成分部位方的研究
实验1:养心通脉方起主要作用有效成分部位抗心肌缺血的研究
目的:寻找养心通脉方中起主要作用的有效部位。
方法:取wistat雄性大鼠120只,随机分为12组,每组10只,包括人参皂苷组、人参多糖组、丹参酮ⅡA组、丹参菲醌组、复方苷元组、复方苷类、复方蛋白组、总多糖组、总生物碱组、总挥发油组、空白模型组和健康对照组。其中10个有效部位组均在喂饲标准饲料同时,灌服相应的有效部位口服液,每次4毫升;健康对照组给于灌服等量的生理盐水。每天1次,连续10天,于第11天开始试验。每例大鼠在麻醉后均作Ⅱ导联心电图1次,随后按上述方法造模,记录观察注射垂体后叶素后15s、30s、120s、300s、600s的心电图;颈动脉插管取血做血液流变学指标。
结果:
(1)大鼠心电图J点位移变化:
①造模前各组之间心电图J点位移无差别(P＞0.05)。
②造模后J点的变化,15s、30s、2min、5min、10min时间段,人参皂苷组与模型组比较(P＜0.05);丹参酮ⅡA组与模型组比较(P＜0.05或P＜0.01);总生物碱组与模型组比较(P＜0.01)、丹参菲醌组与模型组比较(P＜0.05或P＜0.01)、人参多糖组与模型组(P＜0.01)、复方多糖组与模型组比较(P＜0.05,或P＜0.01)、总挥发油组与模型组比较(P＜0.01)有显著的统计学意义。
③复方苷类、复方苷元组、复方蛋白组与模型组比较无统计学意义(P＞0.05)。
(2)大鼠血液流变学的变化
①总生物碱、人参多糖、总挥发油组模型组比较具有极显著的统计学差异(P＜0.01)。
②复方苷元、复方苷类则明显加重大鼠血液流变学指标与模型组比较复方苷元组具有显著的统计学差异(P＜0.01),而复方苷类组与模型组则无显著性差异。血浆黏度,复方苷类组、复方苷元组与模型组均无显著性差异(P＞0.05)。
③丹参菲醌与模型组比较高切时(P＜0.01或P＜0.05);血浆黏度与模型组比较无显著差异(P＞0.05)。
④复方多糖则在中切时有加重指标的作用(与模型组比较P＜0.05)。血浆黏度与模型组比较无显著差异(P＞0.05)。
⑤复方蛋白则与模型组无显著差异(P＞0.05)。
结论:养心通脉方中提取分离出10种有效部位群,其中人参皂苷、丹参酮ⅡA、总生物碱、人参多糖、总挥发油,5种成分具有显著的抗心肌缺血作用,故作为养心通脉方起主要作用的有效成分部位,而将复方多糖与丹参菲醌作为次要有效成分部位。复方苷类、复方苷元、复方蛋白3种成分部位因其没有抗心肌缺血(心血瘀阻证)的作用,且对血流变学也无改善作用,故将其列为养心通脉方无效成分剔出。
实验2:养心通脉方主要与次要有效成分部位交互作用抗心肌缺血研究
目的:明确5个主要成分部位与2个次要成分之间是否有交互作用
方法:按L4(2~3)正交设计安排实验,将人参皂苷、丹参酮ⅡA、总生物碱、人参多糖、总挥发油做为基础因子,复方多糖与丹参菲醌作为考察因子。将wistar雄性大鼠40只,随机分为5组,每组8只,包括处方1组、处方2组、处方3、处方4组,模型组。各组均在喂饲标准饲料同时,灌服相应的有效部位口服液,每次4毫升;每天1次,连续10天,于第11天开始试验。每列大鼠在麻醉后均作Ⅱ导联心电图1次,随后按上述方法造模,记录观察注射垂体后叶素后15s、30s、120s、300s、600s的心电图;颈动脉插管取血做血液流变学指标。
结果:
(1)心电图J点位移变化
①造模后第15s、30s、120s、300s、600s,处方5(空白模型组)与其余四组比较,均具有显著性差异(P＜0.05)
②水平1、水平2差异均无统计学意义(P＞0.05)。
(2)血液流变学的变化
①处方1、2、3、4与处方5有显著的统计学意义((P＜0.05)
②水平1、水平2差异均无统计学意义(P＞0.05)。
结论:养心通脉方主要与次要有效成分部位无交互作用。
实验3:养心通脉方各有效成分部位的有效剂量配伍抗心血瘀阻证研究
目的:探讨养心通脉方有效部位配伍的最佳剂量
方法:取wistar雄性大鼠72只,随机分为9组,每组8只,按L9(3~4)正交表设计安排试验,每个因子取3个水平。9组均在喂饲标准饲料同时,灌服相应的有效部位口服液,每次4毫升;每天1次,连续10天,于第11天开始试验。每例大鼠在麻醉后均作Ⅱ导联心电图1次,随后按上述方法造模,记录观察注射垂体后叶素后15s、30s、120s、300s、600s的心电图。
结果及结论:采用直观分析法分析结果,5种有效部位的最佳配伍为:人参皂苷34.33g生药/kgw,丹参酮ⅡA 1.27g生药/kgw、人参多糖4.77g生药/kgw、总生物碱取0.67g生药/kgw、总挥发油62.2ml生药/kgw。
第三部分养心通脉有效部位方促心血瘀阻证心肌血管新生的研究
实验1:养心通脉有效部位方对心血瘀阻证大鼠血管生长因子VEGF及bFGF影响的研究
目的:探讨养心通脉有效部位方治疗心血瘀阻证的机理
方法:将结扎大鼠冠状动脉左前降支复制心血瘀阻证大鼠模型成功后的24只大鼠随机分为模型组、YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组,再与6只假手术组、6只正常组,一共组成6组;各组均在喂饲标准饲料同时,灌服相应处方口服液,每次4毫升,健康对照组、模型组灌服等量的生理盐水。每天1次,连续2周,于第15天,处死动物取材。用免疫组织化学法检测CD34、VEGF、bFGF表达。
结果:
(1)新生血管数:YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组与模型组比较,具有显著的统计学意义(P＜0.05)。YTⅠ治疗组与SXBXW治疗组比较,无显著的统计学意义。
(2) VEGF的表达:YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组与模型组比较,具有显著的统计学意义(P＜0.05)。YTⅠ治疗组与SXBXW治疗组比较,无显著的统计学意义。
(3) bFGF的表达:YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组与模型组比较,具有显著的统计学意义(P＜0.05)。YTⅠ治疗组与SXBXW治疗组比较,无显著的统计学意义。
结论:促进VEGFmRNA、bFGFmRNA上调,使VEGF、bFGF的合成分泌增加,引起缺血区血管新生,从而侧支循环的良好建立可能是养心通脉有效成分部位方治疗心血瘀阻证的重要机制。
实验2:养心通脉有效部位方对心血瘀阻证大鼠血管生长因子基因表达量影响的研究
目的:探讨养心通脉有效部位方治疗心血瘀阻证的机理
方法:将结扎大鼠冠状动脉左前降支复制心血瘀阻证大鼠模型成功后的24只大鼠随机分为模型组、YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组,再与6只假手术组、6只正常组,一共组成6组;各组均在喂饲标准饲料同时,灌服相应处方口服液,每次4毫升,健康对照组、模型组灌服等量的生理盐水。每天1次,连续2周,于第15天,处死动物取材。用免疫组织化学法检测CD34、VEGF、bFGF表达;
结果:
(1) VEGFmRNA的表达:YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组与模型组比较,具有显著的统计学意义(P＜0.05)。YTⅠ治疗组与SXBXW治疗组比较,无显著的统计学意义。
(2) bFGFmRNA的表达:YTⅠ治疗组、YTⅡ治疗组,SXBXW治疗组与模型组比较,具有显著的统计学意义(P＜0.05)。YTⅠ治疗组与SXBXW治疗组比较,无显著的统计学意义。
结论:促进VEGFmRNA、bFGFmRNA上调,促进VEGF、bFGF的合成分泌增加,引起缺血区血管新生,从而侧支循环的良好建立可能是养心通脉有效成分部位方治疗心血瘀阻证的重要机制。
实验3:养心通脉有效部位方对心血瘀阻证大鼠冠状微循环及相关因子影响的研究
目的:探讨养心通脉有效部位方治疗心血瘀阻证的机理
方法:取上述wistar雄性大鼠128只,随机分为4组:养心通脉有效部位方组(养通Ⅱ组)、复方丹参注射液组(丹参组)、空白模型组(模型组)、假手术组。结扎大鼠冠状动脉左前降支复制心血瘀阻证大鼠模型10分钟后经颈外静脉注入给药,养心通脉有效部位方组按0.5ml/100g体重给予YTⅡ注射液、复方丹参注射液组按0.5ml/100g体重给予复方丹参注射液,空白模型组按0.5ml/100g体重给予生理盐水,假手术组按0.5ml/100g体重给予生理盐水。用药15分钟后,采用墨汁灌注法进行冠状微循环形态观察,采用荧光造影法进行冠状微循环活体观察,采颈动脉血用生化检测法,按不同试剂盒操作要求分别检测心肌组织丙二醛(MDA)含量、心肌及血清酶学指标、血管内皮功能指标。
结果:
(1)大鼠心肌毛细血管墨汁灌流数:未缺血区右室壁4组之间无明显差别(均p＞0.05)。与假手术组比较,模型组心肌的其他4个部位毛细血管灌流数均明显减少;但模型组的左室前壁外层灌流相对较好,与左前室壁中内层比较有明显差异(p＜0.01)。两用药组与模型组比较,原缺血部位心肌毛细血管墨汁灌流数有明显增加,除左室前壁外层之外,其他部位均有显著性差异(均p＜0.01)。较之复方丹参组,养心通脉Ⅱ组的左室前壁中内层及室间隔部位毛细血管灌流数明显增加(p＜0.01)。
(2)大鼠冠状微循环荧光变化时间比较:模型组心脏表面荧光出现时间(AT)、密布时间(FT)和饱和时间(ST)均较假手术组延长(p＜0.01)与模型组比较,两用药组的ST均明显缩短,而FT差异不显。养通Ⅱ组的AT比模型组明显缩短(p＜0.05),而复方丹参组的AT和ST均较假手术组明显延长(均p＜0.01)。
(3)大鼠心肌和血液生化免疫指标比较:假手术组→养通Ⅱ组→丹参组→模型组,MDA、TXB_2和CK的测值呈递增趋势,而NO、6-K-PGF_(1α)、Na~+-K~+-ATPase和Ca~(2+)-ATPase的测值则呈递减的趋势(p＜0.05或＜0.01)。与模型组比较,两治疗组心肌组织MDA含量明显降低,NO含量增高;血浆6-K-PGF_(1α)含量升高,而TXB_2含量显著降低;Na~+-K~+-ATPase和Ca~(2+)-ATPase活性均增高,而血清CK水平降低。两治疗组比较,养通Ⅱ组的各项指标测值均优于复方通脉组,其中心肌组织MDA和血清CK的含量比较都具有显著意义(p＜0.05或＜0.01)。
结论:养心通脉有效部位方注射液促进心血瘀阻部位的血管新生,改善冠状微循环与抗氧自由基生成、减轻钙超载和调整血管内皮细胞功能等多种机制有关。
PartⅠtheoretical research
Objective:To research the relevance between the theory of collateral disease and angiogenesis, probe the basic pathological basis of HBSS from perspective of theory of collateral disease.
Methods:using literature research,documents from the CNKI database and VIP database which relevant with theory of collateral disease and angiogenesis.
Conclusion:
1、Through research that when theory of collateral disease applied to coronary heart disease, there has highly relevance with angiogenesis.Mainly reflected in the theory of collateral disease have the inference relevance with blood vessels and nerves,neural-endocrine-immune network and vascular endothelial injury in modern medicine.
2、The basic theory of collateral disease of HSBB is xinluobizu,xinluochuji and luoxuburong.
PartⅡResearch Prescription
Experiment 1:Experimental study of Yang Xin Tong Mai Recipe effective component parts anti-Acute myocardial ischemia
Objective:to determinate Yang Xin Tong Mai Recipe main effective component
Methods:Randomly divided Wistar rat into 10 groups Blank model group,normal comparison group,total alkaloid group,compound prescription glycosides group,compound prescription aglycone group, the compound prescription protein group,the salvia miltiorrhiza phenanthrenequinone group, the ginseng polysaccharide group,the compound prescription polysaccharide group and the total volatile oil group.All groups except normal comparison group were established with Pit inject via caudal vein.Every rat was examined15s,30s,2min,5min,10min electrocardiogram ECG after they were in narcosis,then take Carotid artery blood to examine Whole blood viscosity and Plasma viscosity.
Result:
(1) Electrocardiogram change degree:
①The Ginsenoside,tanshinoneⅡA,The ginseng polysaccharide,the compound prescription polysaccharide,the total alkaloid,the total volatile oil,the salvia miltiorrhiza phenanthrenequinone 7 groups' J point displacement have Significant statistical significance, Compared with the model group(P＜0.05 or P＜0.01).
②The compound prescription protein,the compound prescription aglycone and the compound prescription glycosides groups' J point displacement have non Significant statistical significance Compared with the model groups(P＞0.05);
(2) Whole blood viscosity and Plasma viscosity change:
①The Ginsenoside,the tanshinoneⅡA,the total alkaloid,the ginseng polysaccharide,the total volatile oil can obviously improve the rat's blood rheology indicators,compares with the model group has the extremely remarkable statistics difference(P＜0.01);
②Compound prescription aglycone,compound prescription glycosides then the obviously increase blood hemorheology indicators(Whole blood shear rate),compares compound prescription aglycone group with the model group to have the remarkable statistics difference (P＜0.01).
③Compound prescription glycosides group,compound prescription aglycone and the model group no significant difference in the Plasma viscosity(P＞0.05);
Conclusion:The Ginsenoside,tanshinoneⅡA,ginseng polysaccharide,the compound prescription polysaccharide,the total alkaloid,the total volatile oil,the salvia miltiorrhiza phenan threnequinone 7 component parts have the anti-acute myocardial ischemia initiated by Pit,however the compound prescription protein,the compound prescription aglycone,the compound prescription glycosides does not have the anti-acute myocardial ischemia function. So,we take The Ginsenoside,tanshinoneⅡA,ginseng polysaccharide,the compound prescription polysaccharide,the total alkaloid,the total volatile oil 5 components as the main effective components and exclude the compound prescription protein,the compound prescription aglycone,the compound prescription glycosides 3 No Role component parts.
Experiment 2:Experimental study of Yang Xin Tong Mai Recipe effective component and the Secondary effective components parts orthogonal interaction on anti-Acute myocardial ischemia.
Objective:to clear if there have interaction between five major components parts and two minor components parts
Methods:take The Ginsenoside,tanshinoneⅡA,ginseng polysaccharide,the total alkaloid, the total volatile oil as the basic factor,the compound prescription polysaccharide,the salvia miltiorrhiza phenan threnequinone as Investigation factors.According L4(2~3) orthogonal design and arrange the experiments.Randomly divided 40 Wistar rats into 5 groups:Blank model group,1 prescription group,2 prescription group,3 prescription and 4 prescription group.All groups were established with Pit inject via caudal vein.Every rat was examined15s,30s,2min,5min, 10min electrocardiogram ECG after they were in narcosis,then take Carotid artery blood to examine whole blood viscosity and plasma viscosity.
Result:
(1) Electrocardiogram change degree:
①Here have significant statistical significance 1 prescription group,2 prescription group,3 prescription and 4 prescription group compared with the model groups in 15s,30s,120s,300s, 600s after module established(P＜0.05).
②differences of level 1,level 2 were not statistically significant(P＞0.05).
(2) Whole blood viscosity and Plasma viscosity change:
①Here have significant statistical significance 1 prescription group,2 prescription group,3 prescription and 4 prescription group Compared with the model groups(P＜0.05).
②differences of level 1,level 2 were not statistically significant(P＞0.05).
Conclusion:there have no interaction between five major components parts and two minor components parts.
Experiment 3:Experimental study of Yang Xin Tong Mai Recipe effective component effective dose combinations anti-Acute myocardial ischemia.
Objective:to Explore best dosage of Yang Xin Tong Mai effective component effective Recipe.
Methods:Randomly divided 72 Wistar rats into 9 groups,According L4(3~4).orthogonal design and arrange the experiments.Every factor take 3 different level.All groups were established with Pit inject via caudal vein.Every rat was examined15s,30s,2min,5min,10min electrocardiogram ECG after they were in narcosis,then take Carotid artery blood to examine Whole blood viscosity and Plasma viscosity.
Result and Conclusion:select Intuitive statistical analysis method to analysis the result,5 effective component effective dose should like follows,The Ginsenoside:34.33g/kgbw, tanshinoneⅡA:1.27g/kgbw,ginseng polysaccharide:4.77g/kgbw,the total alkaloid: 0.67g/kgbw,the total volatile oil:62.2ml/kgbw.
PartⅢExperimental study of Yang Xin Tong Mai effective component Recipe promote angiogenesis of HSBB
Experiment 1:Experimental study the VEGF,bFGF expression of HSBB rats treated by Yang Xin Tong Mai effective component Recipe
Objective:to explore the mechanism of Yang Xin Tong Mai effective component Recipe effective component recipe anti-HBSS.
Methods:Randomly divided 24 Wistar rats Successful model established by Ligation of the left anterior descending coronary artery into 4 groups:model group,YTⅠtherapy group, YTⅡtherapy group,SXBXW therapy group and add the sham group,health group,all is 6groups.Every group feed Standard feed and gavages corresponding recipe 4ml/qd for 2weeks. To the 15th day,animals were sacrificed and myocardial tissue samples were frozen in liquid nitrogen.Immunohistochemistry used to detect the expression of CD34,VEGF,bFGF in myocardial tissue.
Result:
①MVC:YTⅠtherapy group,YTⅡtherapy group,SXBXW therapy group compared with the model groups have significant statistical significance(P＜0.05).
②VEGF expression:YTⅠtherapy group,YTⅡtherapy group,SXBXW therapy group compared with the model groups have significant statistical significance(P＜0.05).
③bFGF expression:YTⅠtherapy group,YTⅡtherapy group,SXBXW therapy group compared with the model groups have significant statistical significance(P＜0.05).
Conclusion:Promote VEGF,bFGF increase in the synthesis and secretion caused ischemic angiogenesis,thereby establishing a good collateral circulation maybe the important mechanisms of Yang Xin Tong Mai effective component Recipe to treat HBSS.
Experiment 2:Experimental study the VEGFmRNA,bFGFmRNA expression of HSBB rats treated by Yang Xin Tong Mai effective component recipe
Objective:to explore the mechanism of Yang Xin Tong Mai effective component Recipe effective component recipe anti-HBSS.
Methods:Randomly divided 24 Wistar rats Successful model established by Ligation of the left anterior descending coronary artery into 4 groups:model group,YTⅠtherapy group, YTⅡtherapy group,SXBXW therapy group and add the sham group,health group,all is 6groups.Every group feed Standard feed and gavages corresponding recipe 4ml/qd for 2weeks. To the 15th day,animals were sacrificed and myocardial tissue samples were frozen in liquid nitrogen.RT-PCR and agarose gel electrophoresis used to detect the expression of VEGFmRNA,bFGFmRNA.
Result:
①VEGFmRNA expression:YTⅠtherapy group,YTⅡtherapy group,SXBXW therapy group compared with the model groups have significant statistical significance(P＜0.05).
②bFGFmRNA expression:YTⅠtherapy group,YTⅡtherapy group,SXBXW therapy group compared with the model groups have significant statistical significance(P＜0.05).
Conclusion:Promote VEGFmRNA,bFGFmRNA up to VEGF,bFGF increase in the synthesis and secretion caused ischemic angiogenesis,thereby establishing a good collateral circulation maybe the important mechanisms of Yang Xin Tong Mai effective component Recipe to treat HBSS.
Experiment 3:Experimental study the impact of Coronary microcirculation and Factors expression of HSBB rats treated by Yang Xin Tong Mai effective component Recipe
Objective:to explore the mechanism of Yang Xin Tong Mai effective component Recipe effective component recipe anti-HBSS by research on Coronary microcirculation and related factors expression.
Methods:Randomly divided 128 Wistar rats Successful model established by Ligation of the left anterior descending coronary artery into 4 groups:model group,YTⅡinjection group, Fufang Danshen injection group and add the sham group.After 10mins since modeling inject the corresponding injection by external jugular vein,then ink perfusion,fluorescence Methods were used to observe coronary microcirculation;Carotid artery blood be used to test the MDA, Na~+-K~+-ATPase,Ca2~+-ATPase,TXB2,6-K-PGF1α,NO.
Result:
①Capillary perfusion of ink:YTⅡinjection therapy group compared with model group、 Fufang Danshen injection therapy group、the sham group has significant statistical significance (P＜0.05 or P＜0.01).
②AT、FT、ST:YTⅡinjection group、model group、Fufang Danshen injection group、compared with the sham group is more slowly(P＜0.01);The AT of YTⅡinjection therapy group is shorter than model group;the AT and ST of Fufang Danshen injection group are longer than he sham group's(p＜0.01).
③MDA,Na~+-K~+-ATPase,Ca~(2+)-ATPase,TXB_2,6-K-PGF1α,NO:YTⅡinjection therapy group compared with other 3 groups has significant statistical significance(P＜0.05 or P＜0.01).
Conclusion:Yang Xin Tong Mai effective component promote angiogenesis maybe have relation with anti-free radicals,reducing calcium overload,Adjustment of endothelial function.
引文
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