延胡索碱及延胡索复方抗冠心病室性心律失常的实验与临床研究
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摘要
研究背景
当今，冠心病已成为人类三大死亡原因之一，我国冠心病的发病率正逐年上升。冠心病的基本病理生理就是心肌缺血，要挽救缺血心肌就必须及时、有效地恢复缺血心肌的再灌注。但是缺血心肌在恢复血流灌注后，往往引起缺血再灌注损伤(ischemia reperfusion iniury，IRI)。如何防治心肌缺血再灌注损伤已成为心脏病学基础应用研究中的一个重要领域。
1986年Murry等发现缺血预处理可减轻IRI，但由于缺血预处理本身是一种损伤性因素，很难在临床推广应用，因此寻找安全有效的药物作为药物预处理手段防治IRI具有重要的现实意义。1988年，美国著名的CAST试验结果表明：抗心律失常药物有潜在致心律失常作用的危险性。这种危险性给发展中药预处理防治IRI，特别是抗再灌注心律失常带来了机遇和挑战。
近来在心血管疾病的防治研究中，特别是在治疗缺血性心脏病和抗心律失常方面，许多复方都选用了延胡索。延胡索是一种活血化瘀中药，现代药理研究表明，其具有增加冠脉流量、扩张血管、改善心肌营养性血流量及抗心律失常等作用。但是应用延胡索碱预处理抗心肌缺血再灌注损伤的实验研究及运用延胡索复方桃仁红花煎治疗冠心病室性心律失常的临床研究却未见报道。本课题即打算在此领域作些有益的探索。
实验研究
【目的】
通过动物实验，比较药物预处理与缺血预处理对心肌缺血再灌注损伤的作用效果，评价延胡索碱预处理对大鼠心肌缺血再灌注损伤的保护作用及其药理作用机制。
【方法与内容】
采用SD大鼠，随机分为6组：假手术组、模型组、缺血预处理组、延胡索碱低、中、高剂量组。建立大鼠心肌缺血再灌注模型，运用膜片钳技术、流式细胞仪技术、免疫组化、电镜酶细胞化学和分子生物学等方法，从整体、细胞乃至分子基因水平探讨延胡索碱预处理对大鼠心肌缺血再灌注损伤的保护作用及其药理作用机制。实验共分为六个部分。实验一：观察延胡索碱预处理对大鼠心肌缺血再灌注心律失常的影响。实验二：观察延胡索碱预处理对缺血再灌注心肌细胞凋亡的影响。实验三：观察延胡索碱预处理对缺血再灌注心肌Ca~(2+)-ATPase及Na~+-K~+-ATPase活性的影响。实验四：观察延胡索碱预处理对单个心肌细胞膜上L-型钙通道动力学的影响。实验五：观察延胡索碱预处理对缺血再灌注心肌细胞内游离Ca~(2+)浓度的影响。实验六：观察延胡索碱预处理对缺血再灌注心肌梗死范围的影响。
【结果】
1．室性心律失常发生率比较：延胡索碱中、高剂量组的室速(VT)和室颤(VF)的发生率显著降低，与模型组比较差异有统计学意义(P＜0.05，P＜0.01)，延胡索碱低剂量组上述指标变化无统计学意义(P＞0.05)；与缺血预处理组比较，延胡索碱中、高剂量组的VT和VF的发生率变化无统计学意义(P＞0.05)。各组对室性早博(VPB)发生率的影响，差异无统计学意义(P＞0.05)。
2．心律失常发生时间比较：延胡索碱低、中、高剂量组的心律失常出现时间明显推迟、持续时间明显缩短，与模型组比较差异有显著性(P＜0.01)。与缺血预处理组比较，延胡索碱预处理虽也能推迟心律失常出现时间、缩短心律失常持续时间，但作用较之减弱(P＜0.01)。
3．ST段抬高程度比较：在心肌缺血30min，再灌注20min和60min时间点时，假手术组ST段抬高程度无明显改变，模型组ST段则明显抬高；与模型组比较，缺血预处理组和延胡索碱预处理各剂量组ST段抬高幅度虽有所降低，但差异无显著性(P＞0.05)。心率变化比较：与模型组比较，延胡索碱低、中、高剂量组，以及缺血预处理组均能明显减慢心率，差异有显著性(P＜0.01)；与缺血预处理组比较，延胡索低、中剂量组减慢心率的作用较之减弱(P＜0.01)，延胡索碱高剂量组则较之增强(P＜0.05)。
4．原位末端标记法(TUNEL)检测大鼠心肌细胞凋亡结果：假手术组心肌仅偶见细胞凋亡发生，模型组可见大量胞核呈深浅不一棕褐色的凋亡心肌细胞，心肌细胞凋亡指数明显高于假手术组(P＜0.01)；缺血预处理组和延胡索碱高、中、低剂量组凋亡心肌细胞和心肌细胞凋亡指数均较模型组明显减少(P＜0.01)；而缺血预处理组和延胡索碱高剂量组间差异无显著性(P＞0.05)。
5．心肌细胞bcl-2基因蛋白表达变化：与假手术组比较，抑凋亡基因bcl-2在缺血再灌注后表达明显减少，心肌细胞bcl-2蛋白阳性表达指数(PEI)明显低于假手术组(P＜0.01)；缺血预处理及用药后bcl-2表达增高，缺血预处理组和延胡索碱高、中、低剂量组bcl-2蛋白阳性表达指数(PEI)均较模型组组明显增高(P＜0.05)。而缺血预处理组和延胡索碱高剂量组比较，差异无显著性(P＞0.05)。
6．心肌细胞Fas基因蛋白表达变化：假手术组极少数心肌细胞Fas基因蛋白表达阳性；与假手术组比较，缺血再灌注后Fas基因蛋白表达明显加强，心肌细胞Fas蛋白阳性表达指数(PEI)明显高于假手术组(P＜0.01)；缺血预处理组和延胡索碱高、中、低剂量组Fas蛋白阳性表达指数(PEI)均较模型组明显减少(P＜0.05)；而缺血预处理组和延胡索碱高剂量组比较，差异无显著性(P＞0.05)。
7．心肌细胞Na~+，K~+-ATP酶活力分析：与假手术组比较，心肌缺血再灌注损伤后，心肌细胞Na~+，K~+-ATP酶活力显著下降(P＜0.01)。与模型组比较，除低剂量组(P＞0.05)外，缺血预处理组和延胡索碱中、高剂量组的心肌细胞Na~+-K~+-ATP酶活力都明显升高，差异有统计学意义(P＜0.01)；与缺血预处理组比较，延胡索碱中、高剂量组心肌细胞Na~+-K~+-ATP酶活力差异无显著性(P＞0.05)。
8．心肌细胞Ca~(2+)-ATP酶活力分析：与假手术组比较，心肌缺血再灌注损伤后，心肌细胞Ca~(2+)-ATP酶活力显著下降(P＜0.01)。与模型组比较，除低、中剂量组(P＞0.05)外，缺血预处理组和延胡索碱高剂量组的心肌细胞Ca~(2+)-ATP酶活力都明显升高，差异有统计学意义(P＜0.05)；与缺血预处理组比较，延胡索碱高剂量组心肌细胞Ca~(2+)-ATP酶活力差异无显著性(P＞0.05)。
9．单个心肌细胞膜上L-型钙通道动力学变化
(1)L-型钙离子通道平均开放概率比较：
与假手术组比较，模型组L-型钙离子通道平均开放概率明显提高(P＜0.01)；与模型组比较，缺血预处理组和延胡索碱高、中、低剂量组心肌细胞的L-型钙离子通道平均开放概率明显降低(P＜0.01)；而且缺血预处理组与延胡索碱高、中、低剂量组比较，无统计学差异(P＜0.05)。
(2)L-型钙离子通道平均开放时间比较：
与假手术组比较，模型组心肌细胞L-型钙离子通道平均开放时间明显缩短(P＜0.05)；与模型组比较，缺血预处理组和延胡索碱高、中、低剂量组平均开放时间无显著性差异(P＞0.05)。
(3)L-型钙离子通道平均电流幅值比较：
与假手术组比较，模型组平均电流幅值明显增高(P＜0.05)；与模型组比较，延胡索碱低、中剂量组可减弱L-型钙通道平均电流幅度值(P＜0.05)，但缺血预处理组和延胡索碱高剂量组反而增强L-型钙通道电流幅度值(P＜0.05)。
10．心肌细胞内钙离子浓度比较：与假手术组比较，模型组心肌细胞内平均钙离子荧光强度明显增强(P＜0.01)；与模型组比较，缺血预处理组与延胡索碱高、中、低剂量组平均钙离子荧光强度减弱，差异有统计学意义(P＜0.01)；缺血预处理与延胡索碱高剂量组比较，差异无统计学意义(P＞0.05)。
11．心肌缺血、梗死面积比较
(1)心肌缺血面积比较：与模型组比较，除低剂量组(P＞0.05)外，其余各组心肌缺血面积均有减少(P＜0.01或P＜0.05)；与缺血预处理组比较，除低剂量组(P＜0.05)外，延胡索碱高、中剂量组心肌缺血面积与其相当，差异无显著性(P＞0.05)。
(2)心肌梗死面积比较：与模型组比较，缺血预处理组和延胡索碱高、中、低剂量组梗死面积均缩小(P＜0.05)；与缺血预处理组比较，除低剂量组(P＜0.01)外，延胡索碱高、中剂量组心肌梗死面积与其相当，差异无显著性(P＞0.05)。
【结论】
1．对大鼠心肌缺血再灌注室性心律失常而言，延胡索碱预处理不仅可推迟其出现时间，缩短其持续时间，而且还可降低室速(VT)和室颤(VF)的发生率，减慢大鼠心肌缺血再灌注损伤后心率的增快。说明延胡索碱预处理具有抗大鼠心肌缺血再灌注室性心律失常的作用。
2．延胡索碱预处理可通过上调缺血再灌注心肌抑凋亡基因bcl-2的蛋白表达和下调促凋亡基因Fas的蛋白表达，从而抑制心肌细胞凋亡的发生，保护心肌细胞免受缺血及缺血再灌注的损伤，从而保护心脏功能，具有类似于缺血预处理的内源性抗凋亡保护机制。
3．延胡索碱预处理能显著提高心肌细胞Na~+-K~+-ATPase、Ca~(2+)-ATPase活性，通过肌浆网Ca~(2+)-ATP酶(肌浆网钙泵)、Na~+-Ca~(2+)交换体系、肌膜Ca~(2+)-ATPas等途径将细胞内Ca~(2+)运出细胞外，从而减轻心肌细胞内钙离子浓度和钙超载，起到保护心肌细胞的作用。
4．延胡索碱预处理可降低心肌细胞膜上L-型钙通道平均开放概率，并显著减弱心肌细胞膜上L-型钙通道平均电流幅度值，从而阻断心肌细胞膜L-型钙通道开放，减少“外钙内流”、“内钙释放”，降低心肌细胞内游离钙离子的浓度，避免了细胞内钙离子超载，发挥保护心肌细胞的作用。
5．延胡索碱预处理与经典缺血预处理一样，可显著缩小大鼠心肌缺血再灌注的心肌梗死面积，对缺血再灌注心肌损伤有保护作用。
临床研究
【目的】
观察延胡索复方桃仁红花煎对冠心病频发室性早博患者的临床疗效。
【方法与内容】
采用前瞻性试验性设计方案。遵循随机、对照、单盲原则进行研究。将60例冠心病频发室性早博患者按为1∶1随机分为试验组与对照组。试验组采用冠心病西医基础治疗加上延胡索复方桃仁红花煎治疗，对照组仅采用单纯西医基础治疗，不用中医中药治疗。通过观察治疗前后室性早博次数的变化以及中医证候、症状的改变，比较试验组与对照组二者间的临床疗效。
【结果】
1．治疗后两组患者室性早搏疗效比较：试验组总有效率85％，对照组75％，P＞0.05，差异无统计学意义，说明两组患者的疗效相当。
2．两组患者治疗前后24h室性早博次数的比较：试验组和对照组治疗前后自身比较，P＜0.01，差异有显著统计学意义。两组患者治疗前后24h室性早博次数差值比较，P＞0.05，差异无统计学意义。
3．两组患者中医证候疗效比较：试验组总有效率90％，对照组70％，经X~2检验P＜0.05，差异有统计学意义。
4．两组患者中医症状积分比较：治疗前后自身比较，差异有统计学意义(P＜0.05)。试验组患者治疗前后症状积分差值明显高于对照组，差异有统计学意义(P＜0.05)。
5．两组患者中医症状疗效比较：试验组心悸中医症状总有效率为89.7％，对照组为66.7％，两组差异有统计学意义(P＜0.05)；试验组胸闷中医症状总有效率为76.9％％，对照组为45.8％，两组差异有统计学意义(P＜0.05)；余各中医症状疗效差异无统计学意义(P＞0.05)。
【结论】
通过临床小样本观察，我们发现西医基础治疗结合中药延胡索复方(桃仁红花煎)治疗，在减少冠心病频发室性早搏次数方面与单纯西药治疗疗效相当；但是在改善冠心病频发室性早搏的中医证候及中医症状特别是心悸、胸闷等方面疗效优于单纯西药治疗，而且副作用少，没发现有任何致心律失常作用，值得在临床上推广应用。
结语
1．延胡索碱预处理不仅可推迟大鼠心肌缺血再灌注室性心律失出现时间，缩短其持续时间，而且还可降低室速(VT)和室颤(VF)的发生率，减慢大鼠再灌注损伤后心率的增快。说明延胡索碱预处理有抗大鼠心肌缺血再灌注室性心律失常的作用。
2．延胡索碱预处理可通过上调缺血再灌注心肌抑凋亡基因bcl-2的蛋白表达和下调促凋亡基因Fas的蛋白表达，从而抑制心肌细胞凋亡的发生，保护心肌细胞免受缺血及缺血再灌注的损伤，具有类似于缺血预处理的内源性抗凋亡保护机制。
3．延胡索碱预处理能显著提高心肌细胞Na~+-K~(+-)ATPase、Ca~(2+)-ATPase活性，通过肌浆网Ca~(2+)-ATP酶(肌浆网钙泵)、Na~+-Ca~(2+)交换体系、肌膜Ca~(2+)-ATPas等途径将细胞内Ca~(2+)运出细胞外，从而减轻心肌细胞内钙浓度和钙超载，起到保护心肌细胞的作用。
4．延胡索碱预处理可降低心肌细胞膜上L-型钙通道平均开放概率和平均电流幅值，从而阻断心肌细胞膜L-型钙通道，减少“外钙内流”、“内钙释放”，降低心肌细胞内钙离子的浓度，避免了细胞内钙离子超载，起到保护心肌细胞的作用。
5．延胡索碱预处理与经典缺血预处理一样，可显著缩小心肌缺血再灌注损伤大鼠的心肌梗死面积，对缺血再灌注损伤心肌有保护作用。
6．通过临床观察，我们发现西医基础治疗结合延胡索复方(桃仁红花煎)治疗，在减少冠心病频发室性早搏次数、抗冠心病心律失常方面与单纯西药治疗疗效相当；但是在改善冠心病频发室性早搏的中医证候及中医症状特别是心悸、胸闷等方面疗效优于单纯西药治疗，而且副作用少，没发现有任何致心律失常作用，值得在临床上推广应用。
Today, coronary heart disease (CHD) has become one of the three cause of human death. The morbidity of CHD has increased year after year. Because the basic pathophysiology of CHD is myocardial ischemia, if we are going to save ischemic myocardium, we must resume the myocardial ischemic-reperfuse timely and efficiently. But the reperfusing of myocardium often causing ischemia reperfusion injury (IRI). How to control the ischemic reperfusion injury of myocardium has become an important field in basic and applying research of cardiology.
Murry found that ischemic preconditioning can relieve ischemia reperfusion injury in 1986. But it has difficult application and extension in clinic because of the injury of ischemicpreconditioning. So it is of great practical significance to find safe and effective drugs for preconditioning. In 1988, the results from CAST trail suggest that: antiarrhythmic drugs have the potential danger of causing arrhythmia. This bring opportunities and challenges for traditional Chinese drugs preconditioning to control ischemia reperfusion injury, specially in antiarrhythmic induced by myocardial ischemia and reperfusion injury.
Corydalis yanhusuo W. T. Wang has been used in much TCM composite prescriptions in research on preventing and curing cardiovascular disease recently, specially in ischemic heart disease and antiarrhythmic. Corydalis yanhusuo W. T. Wang, as a kind of promoting blood circulation and removing blood stasis drug, has the effect of increasing the flow of coronary, dilating vessel, improving nutritional flow in myocardium, antiarrhythmic, the modern pharmacodynamics study showed. Up to now, the experiment study of using Corydalis yanhusuo W. T. Wang preconditioning on myocardial ischemia reperfusion injury and the clinical study of using the composite prescriptions containing Corydalis yanhusuo W. T. Wang (raoren Honghua Decoction) in the treatment of ventricular arrhythmia in CHD have not been reported. This study was a beneficial evaluation in this field.
OBJECTIVE: To compare the action between ischemic preconditioning and drug preconditioning on myocardial ischemia reperfusion injury by using the experimental model of rats. To evaluate the protective action of Corydalis yanhusuo W. T. Wang preconditioning on myocardial ischemia reperfusion injury in rats and the pharmacodynamics mechanism.
METHODS: SD rats were randomized into six groups: sham-operation group, model group, ischemia preconditioning group, dcordaline large, moderate and low dose group. To establish rats model with myocardial ischemic-reperfuse, with the methods such as the patch clamp technique, flow cytometry, immunohistochemical technique, electron microscopic cytochemistry of enzyme, molecular biologic technique, to evaluate the protective action of dcordaline preconditioning on myocardial ischemia reperfusion injury in rats and the pharmacodynamics mechanism. This study includes 6 parts. Part 1: observation on the effect of dcordaline preconditioning on rats myocardial ischemic-reperfuse arrhythmic. Part 2: observation on the effect ofdcordaline preconditioning on myocardial ischemic-reperfuse cell apoptosis. Part 3: observation on the effect of dcordaline preconditioning on activities of Ca~(2+)-ATPase and Na~+-K~+-ArPase in ischemic-reperfuse myocardium. Part 4: observation on the effect of dcordaline preconditioning on gating dynamics of L-type calcium currents(I_(Ca-L)) in single myocardial cell. Part 5: observation on the effect of dcordaline preconditioning on the concentration of free Ca~(2+) in ischemic-reperfuse myocardium. Part 6: observation on the effect of dcordaline preconditioning on the infarct size in ischemic-reperfuse myocardium.
RESULTS:
1. Comparion of the accident rate of ventricular arrhythmia: in dcordaline large and moderate dose groups, ventricular tachycardia (VT) and ventricular fibrillation (VF) rate were markedly reduced, there were significant differences between the tow groups and model group(P＜0.05, P＜0.01). while there were no significant differences in dcordaline low dose group(P＞0.05). There were no significant differences of the VT and VF rate between the large, moderate dose groups and model group(P＞0.05). There were no significant differences of the ventricularpremature beat (PVBs) rate among the groups(P＞0.05).
2. Comparion of the occuring time of arrhythmic: in dcordaline large, moderate and low dose groups, the occuring time of arrhythmic was obviously postponed and the duration was obviously shortend, there were significant differences between these groups and model group(P＜0.01). these effect of dcordaline preconditioning were weaker than ischemic preconditioning(P＜0.01).
3. Comparion of ST segment elevation level: There were no significant differences between ischemia preconditioning group, dcordaline preconditioning groups and model group(P＜0.01). Comparion of heart rate: ischemia preconditioning and dcordaline preconditioning could obviously decrease heart rate. There were significant differences between these groups and model group(P＜0.01). The effect of slowing heart rate in dcordaline Imoderate and low dose groups was weaker than that in ischemia preconditioning group(P＜0.01), while that in large dose group was stranger (P＜0.05).
4. The apoptosis cells in the rats myocardial cells was counted by employing in situ end labeling technique. The results showed: the apoptosis status in the model group was higher than that in the sham-operation group (P＜0.01); the apoptosis myocardial cells and the apoptosis status in the ischemia preconditioning group and the three dcordaline preconditioning groups markedly decreased to the model group (P＜0.01); while there were not significant differences between the ischemia preconditioning group and dcordaline large dose group(P＞0.05).
5. Expression of Bcl-2 proteins in myocardial cells: after ischemic-reperfuse, the expression of bcl-2 gene markedly decreased to the sham-operation group. The positive expression index was markedly lower than that in the sham-operation group (P＜0.01). After ischemia preconditioning and dcordaline preconditioning, the expression of bcl-2 markedly increased. The positive expression index in the ischemia preconditioning group and the three dcordaline preconditioning groups markedly increased to the model group (P＜0.01); while there were not significant differences between the ischemia preconditioning group and dcordaline large dose group(P＞0.05).
6. Expression of Fas proteins in myocardial cells: after ischemic-reperfuse, the expression of Fas gene markedly increased to the sham-operation group. The positive expression index was markedly higher than that in the sham-operation group (P＜0.01). After ischemia preconditioning and dcordaline preconditioning, the expression of Fas markedly decreased. The positive expression index in the ischemia preconditioning group and the three dcordaline preconditioning groups markedly decreased to the model group (P＜0.01). While there were not significant differences between the ischemia preconditioning group and dcordaline large dose group(P＞0.05).
7. Analyzing the activities of Na~+-K~+ATPase in myocardial cells: after ischemic-reperfuse, the activities of Na~+-K~+-ATPase in myocardial cells markedly decreased to the sham-operation group(P＜0.01). After ischemia preconditioning and dcordaline preconditioning, the activities of Na~+-K~+-ATPase in the ischemia preconditioning group and the dcordaline large, moderate dose groups markedly increased to the model group(P＜0.01). While there were not significant differences between the ischemia preconditioning group and dcordaline large, moderate dose groups(P＞0.05).
8. Analyzing the activities of Ca~(2+)-ATPase in myocardial cells: after ischemic-reperfuse, the activities of Ca~(2+)-ATPase in myocardial cells markedly decreased to the sham-operation group(P＜0.01). After ischemia preconditioning and dcordaline preconditioning, the activities of Ca~(2+)-ATPase in the ischemia preconditioning group and the dcordaline large dose group markedly increased to the model group(P＜0.01). While there were not significant differences between the ischemia preconditioning group and dcordaline large dose group(P＞0.05).
9. Gating dynamics of L-type calcium currents(ICa-L) in single myocardial cell:
(1) Open-state probability (NPo): NPO in the model group markedly increased to the sham-operation group (P＜0.01). NPO in the ischemia preconditioning group and the three dcordaline preconditioning groups markedly decreased to the model group (P＜0.01); while there were not significant differences between the ischemia preconditioning group and dcordaline large dose group(P＞0.05).
(2) Open time: open time in the model group markedly decreased to the sham-operation group (P＜0.01). there were not significant differences between the ischemia preconditioning group, the three dcordaline preconditioning groups and the model group(P＞0.05).
(3) Amplitude: amplitude in the model group markedly increased to the sham-operation group (P＜0.01). Amplitude in the dcordaline moderate and low dose groups decreased to the model group (P＜0.05), while that in the dcordaline large group and ischemia preconditioning group increased (P＜0.05).
10. Concentration of free Ca~(2+) in myocardial cells: Ca~(2+) fluorescence density in the model group markedly increased to the sham-operation group (P＜0.01).Ca~(2+) fluorescence density in the ischemia preconditioning group and the three dcordaline preconditioning groups markedly decreased to the model group (P＜0.01); while there were not significant differences between theischemia preconditioning group and dcordaline large dose group(P＞0.05).
11. Ischemic, infarct size in myocardium:
(1) Ischemic size in myocardium: Except in the dcordaline low dose group(P＞0.05), the ischemic size in myocardium in the other groups decreased to that in the model group (P＜0.01 or P＜0.05). Except in the dcordaline low dose group(P＜0.05), the ischemic size in myocardium in the dcordaline large, moderate dose groups were the same as that in the ischemia preconditioning group(P＞0.05).
(2) Infarct size in myocardium: the infarct size in myocardium in ischemia preconditioning group, the three dcordaline preconditioning groups decreased to that in the model group (P＜0.05). Except in the dcordaline low dose group(P＜0.05), the infarct size in myocardium in the dcordaline large, moderate dose groups were the same as that in the ischemia preconditioning group(P＞0.05).
CONCLUSION:
1. To ischemia reperfusion ventricular arrhythmic in rats myocardium, dcordaline preconditioning can not only postpone the occuring time of arrhythmic, shorten the duration, but also reduce ventricular tachycardia (VT) and ventricular fibrillation (VF) rate. We conclude that dcordaline preconditioning has antiarrhythmic effect against ischemia and reperfusion in rats myocardium.
2. Dcordaline preconditioning can inhibite apoptosis of myocardial cells and protect myocardial cells from ischemia and ischemia reperfusion injury by up-regulation of the expression of bcl-2 proteins and down-regulation of the expression of Fas proteins. We conclude that dcordaline preconditioning has heart protected effect by the mechanism that similar to endogenous anti-apoptosis of ischemia preconditioning.
3. Dcordaline preconditioning can markedly increase the activities of Na~+-K~+-ATPase and Ca~(2+)-ATPase in myocardial cells, which can carry Ca~(2+) out from intercellular to extracellular through the pathway as follows: Ca~(2+)-ATPase in sarcoplasmic reticulum, Na+-Ca~(2+) exchange system, Ca(2+)-ATPase sarcolemma. So as to decrease the concentration of free Ca2+ and calcium overload in myocardium to protect myocardial cells.
4. Dcordaline preconditioning can decrease the open-state probability and the amplitude of L-type calcium currents(ICa-L) in myocardial cell so as to block the L-type calcium currents opening, to decrease the concentration of free Ca~(2+) and calcium overload in myocardium to protect myocardial cells.
5. Dcordaline preconditioning can markedly decrease infarct size in rats myocardium induced by myocardial ischemia and reperfusion injury, same as ischemia preconditioning.
OBJECTIVE: To observe the clinic effect of the composite prescriptions containing Corydalis yanhusuo W. T. Wang(Taoren Honghua Decoction) to frequent ventricular premature complexes(VPC) in patients with coronary heart disease(CHD).
METHODS: A prospective study was done of frequent ventricular premature complexes in 60 patients with CHD under the randomized, controlled and single-blind rules. These patients were randomized into control and experimental groups in 1:1 proportion. The patients in experimental group received basic western medical therapy for CHD combined with Taoren Honghua Decoction; while the patients in control group received only basic western medical therapy. To compare the clinic efficacy to the patients in between control and experimental groups by observing the change of ventricular premature rate and the change of traditional Chinese medicine syndrome and symptom before and after treatment.
RESULTS:
1. Compare of the efficacy to ventricular premature after treatment: the results of therapy were assessed as follows: the general effective rate being 85% in experimental group, while 75% in control group. There was not significant differences between the two groups(P＞0.05). It is illustrate that the two groups has same effect.
2. Compare of the 24h ventricular premature beats pre-treatment and post-treatment: A design of oneself comparison according to pre-treatment and post-treatment was performed in both groups. There was significant differences in each group(P＜0.01). The value between pre-treatment and post-treatment in experimental group had no difference to that in control group(P＞0.05).
3. Compare of the efficacy to traditional Chinese medicine syndrome between control and experimental group: the general effective rate being 90% in experimental group, while 70% in control group. There were significant differences between the two groups(P＜0.05).
4. Compare of the scores of traditional Chinese clinical symptoms between control and experimental group: A design of oneself comparison according to pre-treatment and post-treatment was performed in both groups. There were significant differences between pre-treatment and post-treatment in each group(P＜0.05). The value between pre-treatment and post-treatment in experimental group had significant difference to that in control group(P＜0.05).
5. Compare of the traditional Chinese medicine symptom between control and experimental group: the general effective rate to palpitation being 89.7% in experimental group, while 66.7% in control group. There were significant differences between the two groups(P＜0.05). The general effective rate to chest stifling being 76.7% in experimental group, while 45.8% in control group. There were significant differences between the two groups(P＜0.05). There were not significant differences of other symptom between the two groups(P＜0.05)
CONCLUSION:
Though the observation of treatment of the composite prescriptions containing Corydalis yanhusuo W. T. Wang(Taoren Honghua Decoction) for frequent ventricular premature complexes in 30 patients with coronary heart disease(CHD), we found that the basic western medical therapy for CHD combined with Taoren Honghua Decoction has the same efficacy as single western medical therapy in decreasing frequent ventricular premature complexes and antiarrhythmic in patients with coronary heart disease. But the improvement of traditional Chinese medicine syndrome and symptom, specially palpitation and chest stifling, is significantly increased in experimental group than in contro group, we also found that the basic western medical therapy combined with Taoren Honghua Decoction has lower side effect, little causing arrhythmia.
CONCLUDING:
1. To ischemia reperfusion ventricular arrhythmic in rats myocardium, dcordaline preconditioning can not only postpone the occuring time of ventricular arrhythmic, shorten the duration, but also reduce ventricular tachycardia (VT) and ventricular fibrillation (VF) rate. The results show that dcordaline preconditioning has antiarrhythmic effect against ischemia and reperfusion in rats myocardium
2. Dcordaline preconditioning can inhibite apoptosis of myocardial cells and protect myocardial cells from ischemia and ischemia reperfusion injury by up-regulation of the expression of bcl-2 proteins and down-regulation of the expression of Fas proteins. The results show that dcordaline preconditioning has heart protected effect by the mechanism that similar to endogenous anti-apoptosis of ischemia preconditioning.
3. Dcordaline preconditioning can markedly increase the activities of Na+-K+-ATPase and Ca~(2+)-ATPase in myocardial cells, which can carry Ca~(2+) out from intercellular to extracellular through the pathway as follows: Ca~(2+)-ATPase in sarcoplasmic reticulum, Na+-Ca~(2+) exchange system, Ca~(2+)-ATPase sarcolemma. So as to decrease the concentration of free Ca2+ and calcium overload in myocardium to protect myocardial cells.
4. Dcordaline preconditioning can decrease the open-state probability and the amplitude of L-type calcium currents(ICa-L) in myocardial cell so as to block the L-type calcium currents opening, to decrease the concentration of free Ca~(2+) and calcium overload in myocardium to protect myocardial cells.
5. Dcordaline preconditioning can markedly decrease infarct size in rats myocardium induced by myocardial ischemia and reperfusion injury, same as ischemia preconditioning.
6. Though the clinic observation we conclude that the basic western medical therapy for CHD combined with Taoren Honghua Decoction has the same efficacy as single western medical therapy in decreasing frequent ventricular premature complexes and antiarrhythmic in patients with coronary heart disease. But the improvement of traditional Chinese medicine syndrome and symptom, specially palpitation and chest stifling, is significantly increased in experimental group than in contro group. The combined therapy has lower side effect, little causing arrhythmia, so as to has a good prospect of application and extension
当今，冠心病已成为人类三大死亡原因之一，我国冠心病的发病率正逐年上升。冠心病的基本病理生理就是心肌缺血，要挽救缺血心肌就必须及时、有效地恢复缺血心肌的再灌注。但是缺血心肌在恢复血流灌注后，往往引起缺血再灌注损伤(ischemia reperfusion iniury，IRI)。如何防治心肌缺血再灌注损伤已成为心脏病学基础应用研究中的一个重要领域。
1986年Murry等发现缺血预处理可减轻IRI，但由于缺血预处理本身是一种损伤性因素，很难在临床推广应用，因此寻找安全有效的药物作为药物预处理手段防治IRI具有重要的现实意义。1988年，美国著名的CAST试验结果表明：抗心律失常药物有潜在致心律失常作用的危险性。这种危险性给发展中药预处理防治IRI，特别是抗再灌注心律失常带来了机遇和挑战。
近来在心血管疾病的防治研究中，特别是在治疗缺血性心脏病和抗心律失常方面，许多复方都选用了延胡索。延胡索是一种活血化瘀中药，现代药理研究表明，其具有增加冠脉流量、扩张血管、改善心肌营养性血流量及抗心律失常等作用。但是应用延胡索碱预处理抗心肌缺血再灌注损伤的实验研究及运用延胡索复方桃仁红花煎治疗冠心病室性心律失常的临床研究却未见报道。本课题即打算在此领域作些有益的探索。
实验研究
【目的】
通过动物实验，比较药物预处理与缺血预处理对心肌缺血再灌注损伤的作用效果，评价延胡索碱预处理对大鼠心肌缺血再灌注损伤的保护作用及其药理作用机制。
【方法与内容】
采用SD大鼠，随机分为6组：假手术组、模型组、缺血预处理组、延胡索碱低、中、高剂量组。建立大鼠心肌缺血再灌注模型，运用膜片钳技术、流式细胞仪技术、免疫组化、电镜酶细胞化学和分子生物学等方法，从整体、细胞乃至分子基因水平探讨延胡索碱预处理对大鼠心肌缺血再灌注损伤的保护作用及其药理作用机制。实验共分为六个部分。实验一：观察延胡索碱预处理对大鼠心肌缺血再灌注心律失常的影响。实验二：观察延胡索碱预处理对缺血再灌注心肌细胞凋亡的影响。实验三：观察延胡索碱预处理对缺血再灌注心肌Ca~(2+)-ATPase及Na~+-K~+-ATPase活性的影响。实验四：观察延胡索碱预处理对单个心肌细胞膜上L-型钙通道动力学的影响。实验五：观察延胡索碱预处理对缺血再灌注心肌细胞内游离Ca~(2+)浓度的影响。实验六：观察延胡索碱预处理对缺血再灌注心肌梗死范围的影响。
【结果】
1．室性心律失常发生率比较：延胡索碱中、高剂量组的室速(VT)和室颤(VF)的发生率显著降低，与模型组比较差异有统计学意义(P＜0.05，P＜0.01)，延胡索碱低剂量组上述指标变化无统计学意义(P＞0.05)；与缺血预处理组比较，延胡索碱中、高剂量组的VT和VF的发生率变化无统计学意义(P＞0.05)。各组对室性早博(VPB)发生率的影响，差异无统计学意义(P＞0.05)。
2．心律失常发生时间比较：延胡索碱低、中、高剂量组的心律失常出现时间明显推迟、持续时间明显缩短，与模型组比较差异有显著性(P＜0.01)。与缺血预处理组比较，延胡索碱预处理虽也能推迟心律失常出现时间、缩短心律失常持续时间，但作用较之减弱(P＜0.01)。
3．ST段抬高程度比较：在心肌缺血30min，再灌注20min和60min时间点时，假手术组ST段抬高程度无明显改变，模型组ST段则明显抬高；与模型组比较，缺血预处理组和延胡索碱预处理各剂量组ST段抬高幅度虽有所降低，但差异无显著性(P＞0.05)。心率变化比较：与模型组比较，延胡索碱低、中、高剂量组，以及缺血预处理组均能明显减慢心率，差异有显著性(P＜0.01)；与缺血预处理组比较，延胡索低、中剂量组减慢心率的作用较之减弱(P＜0.01)，延胡索碱高剂量组则较之增强(P＜0.05)。
4．原位末端标记法(TUNEL)检测大鼠心肌细胞凋亡结果：假手术组心肌仅偶见细胞凋亡发生，模型组可见大量胞核呈深浅不一棕褐色的凋亡心肌细胞，心肌细胞凋亡指数明显高于假手术组(P＜0.01)；缺血预处理组和延胡索碱高、中、低剂量组凋亡心肌细胞和心肌细胞凋亡指数均较模型组明显减少(P＜0.01)；而缺血预处理组和延胡索碱高剂量组间差异无显著性(P＞0.05)。
5．心肌细胞bcl-2基因蛋白表达变化：与假手术组比较，抑凋亡基因bcl-2在缺血再灌注后表达明显减少，心肌细胞bcl-2蛋白阳性表达指数(PEI)明显低于假手术组(P＜0.01)；缺血预处理及用药后bcl-2表达增高，缺血预处理组和延胡索碱高、中、低剂量组bcl-2蛋白阳性表达指数(PEI)均较模型组组明显增高(P＜0.05)。而缺血预处理组和延胡索碱高剂量组比较，差异无显著性(P＞0.05)。
6．心肌细胞Fas基因蛋白表达变化：假手术组极少数心肌细胞Fas基因蛋白表达阳性；与假手术组比较，缺血再灌注后Fas基因蛋白表达明显加强，心肌细胞Fas蛋白阳性表达指数(PEI)明显高于假手术组(P＜0.01)；缺血预处理组和延胡索碱高、中、低剂量组Fas蛋白阳性表达指数(PEI)均较模型组明显减少(P＜0.05)；而缺血预处理组和延胡索碱高剂量组比较，差异无显著性(P＞0.05)。
7．心肌细胞Na~+，K~+-ATP酶活力分析：与假手术组比较，心肌缺血再灌注损伤后，心肌细胞Na~+，K~+-ATP酶活力显著下降(P＜0.01)。与模型组比较，除低剂量组(P＞0.05)外，缺血预处理组和延胡索碱中、高剂量组的心肌细胞Na~+-K~+-ATP酶活力都明显升高，差异有统计学意义(P＜0.01)；与缺血预处理组比较，延胡索碱中、高剂量组心肌细胞Na~+-K~+-ATP酶活力差异无显著性(P＞0.05)。
8．心肌细胞Ca~(2+)-ATP酶活力分析：与假手术组比较，心肌缺血再灌注损伤后，心肌细胞Ca~(2+)-ATP酶活力显著下降(P＜0.01)。与模型组比较，除低、中剂量组(P＞0.05)外，缺血预处理组和延胡索碱高剂量组的心肌细胞Ca~(2+)-ATP酶活力都明显升高，差异有统计学意义(P＜0.05)；与缺血预处理组比较，延胡索碱高剂量组心肌细胞Ca~(2+)-ATP酶活力差异无显著性(P＞0.05)。
9．单个心肌细胞膜上L-型钙通道动力学变化
(1)L-型钙离子通道平均开放概率比较：
与假手术组比较，模型组L-型钙离子通道平均开放概率明显提高(P＜0.01)；与模型组比较，缺血预处理组和延胡索碱高、中、低剂量组心肌细胞的L-型钙离子通道平均开放概率明显降低(P＜0.01)；而且缺血预处理组与延胡索碱高、中、低剂量组比较，无统计学差异(P＜0.05)。
(2)L-型钙离子通道平均开放时间比较：
与假手术组比较，模型组心肌细胞L-型钙离子通道平均开放时间明显缩短(P＜0.05)；与模型组比较，缺血预处理组和延胡索碱高、中、低剂量组平均开放时间无显著性差异(P＞0.05)。
(3)L-型钙离子通道平均电流幅值比较：
与假手术组比较，模型组平均电流幅值明显增高(P＜0.05)；与模型组比较，延胡索碱低、中剂量组可减弱L-型钙通道平均电流幅度值(P＜0.05)，但缺血预处理组和延胡索碱高剂量组反而增强L-型钙通道电流幅度值(P＜0.05)。
10．心肌细胞内钙离子浓度比较：与假手术组比较，模型组心肌细胞内平均钙离子荧光强度明显增强(P＜0.01)；与模型组比较，缺血预处理组与延胡索碱高、中、低剂量组平均钙离子荧光强度减弱，差异有统计学意义(P＜0.01)；缺血预处理与延胡索碱高剂量组比较，差异无统计学意义(P＞0.05)。
11．心肌缺血、梗死面积比较
(1)心肌缺血面积比较：与模型组比较，除低剂量组(P＞0.05)外，其余各组心肌缺血面积均有减少(P＜0.01或P＜0.05)；与缺血预处理组比较，除低剂量组(P＜0.05)外，延胡索碱高、中剂量组心肌缺血面积与其相当，差异无显著性(P＞0.05)。
(2)心肌梗死面积比较：与模型组比较，缺血预处理组和延胡索碱高、中、低剂量组梗死面积均缩小(P＜0.05)；与缺血预处理组比较，除低剂量组(P＜0.01)外，延胡索碱高、中剂量组心肌梗死面积与其相当，差异无显著性(P＞0.05)。
【结论】
1．对大鼠心肌缺血再灌注室性心律失常而言，延胡索碱预处理不仅可推迟其出现时间，缩短其持续时间，而且还可降低室速(VT)和室颤(VF)的发生率，减慢大鼠心肌缺血再灌注损伤后心率的增快。说明延胡索碱预处理具有抗大鼠心肌缺血再灌注室性心律失常的作用。
2．延胡索碱预处理可通过上调缺血再灌注心肌抑凋亡基因bcl-2的蛋白表达和下调促凋亡基因Fas的蛋白表达，从而抑制心肌细胞凋亡的发生，保护心肌细胞免受缺血及缺血再灌注的损伤，从而保护心脏功能，具有类似于缺血预处理的内源性抗凋亡保护机制。
3．延胡索碱预处理能显著提高心肌细胞Na~+-K~+-ATPase、Ca~(2+)-ATPase活性，通过肌浆网Ca~(2+)-ATP酶(肌浆网钙泵)、Na~+-Ca~(2+)交换体系、肌膜Ca~(2+)-ATPas等途径将细胞内Ca~(2+)运出细胞外，从而减轻心肌细胞内钙离子浓度和钙超载，起到保护心肌细胞的作用。
4．延胡索碱预处理可降低心肌细胞膜上L-型钙通道平均开放概率，并显著减弱心肌细胞膜上L-型钙通道平均电流幅度值，从而阻断心肌细胞膜L-型钙通道开放，减少“外钙内流”、“内钙释放”，降低心肌细胞内游离钙离子的浓度，避免了细胞内钙离子超载，发挥保护心肌细胞的作用。
5．延胡索碱预处理与经典缺血预处理一样，可显著缩小大鼠心肌缺血再灌注的心肌梗死面积，对缺血再灌注心肌损伤有保护作用。
临床研究
【目的】
观察延胡索复方桃仁红花煎对冠心病频发室性早博患者的临床疗效。
【方法与内容】
采用前瞻性试验性设计方案。遵循随机、对照、单盲原则进行研究。将60例冠心病频发室性早博患者按为1∶1随机分为试验组与对照组。试验组采用冠心病西医基础治疗加上延胡索复方桃仁红花煎治疗，对照组仅采用单纯西医基础治疗，不用中医中药治疗。通过观察治疗前后室性早博次数的变化以及中医证候、症状的改变，比较试验组与对照组二者间的临床疗效。
【结果】
1．治疗后两组患者室性早搏疗效比较：试验组总有效率85％，对照组75％，P＞0.05，差异无统计学意义，说明两组患者的疗效相当。
2．两组患者治疗前后24h室性早博次数的比较：试验组和对照组治疗前后自身比较，P＜0.01，差异有显著统计学意义。两组患者治疗前后24h室性早博次数差值比较，P＞0.05，差异无统计学意义。
3．两组患者中医证候疗效比较：试验组总有效率90％，对照组70％，经X~2检验P＜0.05，差异有统计学意义。
4．两组患者中医症状积分比较：治疗前后自身比较，差异有统计学意义(P＜0.05)。试验组患者治疗前后症状积分差值明显高于对照组，差异有统计学意义(P＜0.05)。
5．两组患者中医症状疗效比较：试验组心悸中医症状总有效率为89.7％，对照组为66.7％，两组差异有统计学意义(P＜0.05)；试验组胸闷中医症状总有效率为76.9％％，对照组为45.8％，两组差异有统计学意义(P＜0.05)；余各中医症状疗效差异无统计学意义(P＞0.05)。
【结论】
通过临床小样本观察，我们发现西医基础治疗结合中药延胡索复方(桃仁红花煎)治疗，在减少冠心病频发室性早搏次数方面与单纯西药治疗疗效相当；但是在改善冠心病频发室性早搏的中医证候及中医症状特别是心悸、胸闷等方面疗效优于单纯西药治疗，而且副作用少，没发现有任何致心律失常作用，值得在临床上推广应用。
结语
1．延胡索碱预处理不仅可推迟大鼠心肌缺血再灌注室性心律失出现时间，缩短其持续时间，而且还可降低室速(VT)和室颤(VF)的发生率，减慢大鼠再灌注损伤后心率的增快。说明延胡索碱预处理有抗大鼠心肌缺血再灌注室性心律失常的作用。
2．延胡索碱预处理可通过上调缺血再灌注心肌抑凋亡基因bcl-2的蛋白表达和下调促凋亡基因Fas的蛋白表达，从而抑制心肌细胞凋亡的发生，保护心肌细胞免受缺血及缺血再灌注的损伤，具有类似于缺血预处理的内源性抗凋亡保护机制。
3．延胡索碱预处理能显著提高心肌细胞Na~+-K~(+-)ATPase、Ca~(2+)-ATPase活性，通过肌浆网Ca~(2+)-ATP酶(肌浆网钙泵)、Na~+-Ca~(2+)交换体系、肌膜Ca~(2+)-ATPas等途径将细胞内Ca~(2+)运出细胞外，从而减轻心肌细胞内钙浓度和钙超载，起到保护心肌细胞的作用。
4．延胡索碱预处理可降低心肌细胞膜上L-型钙通道平均开放概率和平均电流幅值，从而阻断心肌细胞膜L-型钙通道，减少“外钙内流”、“内钙释放”，降低心肌细胞内钙离子的浓度，避免了细胞内钙离子超载，起到保护心肌细胞的作用。
5．延胡索碱预处理与经典缺血预处理一样，可显著缩小心肌缺血再灌注损伤大鼠的心肌梗死面积，对缺血再灌注损伤心肌有保护作用。
6．通过临床观察，我们发现西医基础治疗结合延胡索复方(桃仁红花煎)治疗，在减少冠心病频发室性早搏次数、抗冠心病心律失常方面与单纯西药治疗疗效相当；但是在改善冠心病频发室性早搏的中医证候及中医症状特别是心悸、胸闷等方面疗效优于单纯西药治疗，而且副作用少，没发现有任何致心律失常作用，值得在临床上推广应用。
Today, coronary heart disease (CHD) has become one of the three cause of human death. The morbidity of CHD has increased year after year. Because the basic pathophysiology of CHD is myocardial ischemia, if we are going to save ischemic myocardium, we must resume the myocardial ischemic-reperfuse timely and efficiently. But the reperfusing of myocardium often causing ischemia reperfusion injury (IRI). How to control the ischemic reperfusion injury of myocardium has become an important field in basic and applying research of cardiology.
Murry found that ischemic preconditioning can relieve ischemia reperfusion injury in 1986. But it has difficult application and extension in clinic because of the injury of ischemicpreconditioning. So it is of great practical significance to find safe and effective drugs for preconditioning. In 1988, the results from CAST trail suggest that: antiarrhythmic drugs have the potential danger of causing arrhythmia. This bring opportunities and challenges for traditional Chinese drugs preconditioning to control ischemia reperfusion injury, specially in antiarrhythmic induced by myocardial ischemia and reperfusion injury.
Corydalis yanhusuo W. T. Wang has been used in much TCM composite prescriptions in research on preventing and curing cardiovascular disease recently, specially in ischemic heart disease and antiarrhythmic. Corydalis yanhusuo W. T. Wang, as a kind of promoting blood circulation and removing blood stasis drug, has the effect of increasing the flow of coronary, dilating vessel, improving nutritional flow in myocardium, antiarrhythmic, the modern pharmacodynamics study showed. Up to now, the experiment study of using Corydalis yanhusuo W. T. Wang preconditioning on myocardial ischemia reperfusion injury and the clinical study of using the composite prescriptions containing Corydalis yanhusuo W. T. Wang (raoren Honghua Decoction) in the treatment of ventricular arrhythmia in CHD have not been reported. This study was a beneficial evaluation in this field.
OBJECTIVE: To compare the action between ischemic preconditioning and drug preconditioning on myocardial ischemia reperfusion injury by using the experimental model of rats. To evaluate the protective action of Corydalis yanhusuo W. T. Wang preconditioning on myocardial ischemia reperfusion injury in rats and the pharmacodynamics mechanism.
METHODS: SD rats were randomized into six groups: sham-operation group, model group, ischemia preconditioning group, dcordaline large, moderate and low dose group. To establish rats model with myocardial ischemic-reperfuse, with the methods such as the patch clamp technique, flow cytometry, immunohistochemical technique, electron microscopic cytochemistry of enzyme, molecular biologic technique, to evaluate the protective action of dcordaline preconditioning on myocardial ischemia reperfusion injury in rats and the pharmacodynamics mechanism. This study includes 6 parts. Part 1: observation on the effect of dcordaline preconditioning on rats myocardial ischemic-reperfuse arrhythmic. Part 2: observation on the effect ofdcordaline preconditioning on myocardial ischemic-reperfuse cell apoptosis. Part 3: observation on the effect of dcordaline preconditioning on activities of Ca~(2+)-ATPase and Na~+-K~+-ArPase in ischemic-reperfuse myocardium. Part 4: observation on the effect of dcordaline preconditioning on gating dynamics of L-type calcium currents(I_(Ca-L)) in single myocardial cell. Part 5: observation on the effect of dcordaline preconditioning on the concentration of free Ca~(2+) in ischemic-reperfuse myocardium. Part 6: observation on the effect of dcordaline preconditioning on the infarct size in ischemic-reperfuse myocardium.
RESULTS:
1. Comparion of the accident rate of ventricular arrhythmia: in dcordaline large and moderate dose groups, ventricular tachycardia (VT) and ventricular fibrillation (VF) rate were markedly reduced, there were significant differences between the tow groups and model group(P＜0.05, P＜0.01). while there were no significant differences in dcordaline low dose group(P＞0.05). There were no significant differences of the VT and VF rate between the large, moderate dose groups and model group(P＞0.05). There were no significant differences of the ventricularpremature beat (PVBs) rate among the groups(P＞0.05).
2. Comparion of the occuring time of arrhythmic: in dcordaline large, moderate and low dose groups, the occuring time of arrhythmic was obviously postponed and the duration was obviously shortend, there were significant differences between these groups and model group(P＜0.01). these effect of dcordaline preconditioning were weaker than ischemic preconditioning(P＜0.01).
3. Comparion of ST segment elevation level: There were no significant differences between ischemia preconditioning group, dcordaline preconditioning groups and model group(P＜0.01). Comparion of heart rate: ischemia preconditioning and dcordaline preconditioning could obviously decrease heart rate. There were significant differences between these groups and model group(P＜0.01). The effect of slowing heart rate in dcordaline Imoderate and low dose groups was weaker than that in ischemia preconditioning group(P＜0.01), while that in large dose group was stranger (P＜0.05).
4. The apoptosis cells in the rats myocardial cells was counted by employing in situ end labeling technique. The results showed: the apoptosis status in the model group was higher than that in the sham-operation group (P＜0.01); the apoptosis myocardial cells and the apoptosis status in the ischemia preconditioning group and the three dcordaline preconditioning groups markedly decreased to the model group (P＜0.01); while there were not significant differences between the ischemia preconditioning group and dcordaline large dose group(P＞0.05).
5. Expression of Bcl-2 proteins in myocardial cells: after ischemic-reperfuse, the expression of bcl-2 gene markedly decreased to the sham-operation group. The positive expression index was markedly lower than that in the sham-operation group (P＜0.01). After ischemia preconditioning and dcordaline preconditioning, the expression of bcl-2 markedly increased. The positive expression index in the ischemia preconditioning group and the three dcordaline preconditioning groups markedly increased to the model group (P＜0.01); while there were not significant differences between the ischemia preconditioning group and dcordaline large dose group(P＞0.05).
6. Expression of Fas proteins in myocardial cells: after ischemic-reperfuse, the expression of Fas gene markedly increased to the sham-operation group. The positive expression index was markedly higher than that in the sham-operation group (P＜0.01). After ischemia preconditioning and dcordaline preconditioning, the expression of Fas markedly decreased. The positive expression index in the ischemia preconditioning group and the three dcordaline preconditioning groups markedly decreased to the model group (P＜0.01). While there were not significant differences between the ischemia preconditioning group and dcordaline large dose group(P＞0.05).
7. Analyzing the activities of Na~+-K~+ATPase in myocardial cells: after ischemic-reperfuse, the activities of Na~+-K~+-ATPase in myocardial cells markedly decreased to the sham-operation group(P＜0.01). After ischemia preconditioning and dcordaline preconditioning, the activities of Na~+-K~+-ATPase in the ischemia preconditioning group and the dcordaline large, moderate dose groups markedly increased to the model group(P＜0.01). While there were not significant differences between the ischemia preconditioning group and dcordaline large, moderate dose groups(P＞0.05).
8. Analyzing the activities of Ca~(2+)-ATPase in myocardial cells: after ischemic-reperfuse, the activities of Ca~(2+)-ATPase in myocardial cells markedly decreased to the sham-operation group(P＜0.01). After ischemia preconditioning and dcordaline preconditioning, the activities of Ca~(2+)-ATPase in the ischemia preconditioning group and the dcordaline large dose group markedly increased to the model group(P＜0.01). While there were not significant differences between the ischemia preconditioning group and dcordaline large dose group(P＞0.05).
9. Gating dynamics of L-type calcium currents(ICa-L) in single myocardial cell:
(1) Open-state probability (NPo): NPO in the model group markedly increased to the sham-operation group (P＜0.01). NPO in the ischemia preconditioning group and the three dcordaline preconditioning groups markedly decreased to the model group (P＜0.01); while there were not significant differences between the ischemia preconditioning group and dcordaline large dose group(P＞0.05).
(2) Open time: open time in the model group markedly decreased to the sham-operation group (P＜0.01). there were not significant differences between the ischemia preconditioning group, the three dcordaline preconditioning groups and the model group(P＞0.05).
(3) Amplitude: amplitude in the model group markedly increased to the sham-operation group (P＜0.01). Amplitude in the dcordaline moderate and low dose groups decreased to the model group (P＜0.05), while that in the dcordaline large group and ischemia preconditioning group increased (P＜0.05).
10. Concentration of free Ca~(2+) in myocardial cells: Ca~(2+) fluorescence density in the model group markedly increased to the sham-operation group (P＜0.01).Ca~(2+) fluorescence density in the ischemia preconditioning group and the three dcordaline preconditioning groups markedly decreased to the model group (P＜0.01); while there were not significant differences between theischemia preconditioning group and dcordaline large dose group(P＞0.05).
11. Ischemic, infarct size in myocardium:
(1) Ischemic size in myocardium: Except in the dcordaline low dose group(P＞0.05), the ischemic size in myocardium in the other groups decreased to that in the model group (P＜0.01 or P＜0.05). Except in the dcordaline low dose group(P＜0.05), the ischemic size in myocardium in the dcordaline large, moderate dose groups were the same as that in the ischemia preconditioning group(P＞0.05).
(2) Infarct size in myocardium: the infarct size in myocardium in ischemia preconditioning group, the three dcordaline preconditioning groups decreased to that in the model group (P＜0.05). Except in the dcordaline low dose group(P＜0.05), the infarct size in myocardium in the dcordaline large, moderate dose groups were the same as that in the ischemia preconditioning group(P＞0.05).
CONCLUSION:
1. To ischemia reperfusion ventricular arrhythmic in rats myocardium, dcordaline preconditioning can not only postpone the occuring time of arrhythmic, shorten the duration, but also reduce ventricular tachycardia (VT) and ventricular fibrillation (VF) rate. We conclude that dcordaline preconditioning has antiarrhythmic effect against ischemia and reperfusion in rats myocardium.
2. Dcordaline preconditioning can inhibite apoptosis of myocardial cells and protect myocardial cells from ischemia and ischemia reperfusion injury by up-regulation of the expression of bcl-2 proteins and down-regulation of the expression of Fas proteins. We conclude that dcordaline preconditioning has heart protected effect by the mechanism that similar to endogenous anti-apoptosis of ischemia preconditioning.
3. Dcordaline preconditioning can markedly increase the activities of Na~+-K~+-ATPase and Ca~(2+)-ATPase in myocardial cells, which can carry Ca~(2+) out from intercellular to extracellular through the pathway as follows: Ca~(2+)-ATPase in sarcoplasmic reticulum, Na+-Ca~(2+) exchange system, Ca(2+)-ATPase sarcolemma. So as to decrease the concentration of free Ca2+ and calcium overload in myocardium to protect myocardial cells.
4. Dcordaline preconditioning can decrease the open-state probability and the amplitude of L-type calcium currents(ICa-L) in myocardial cell so as to block the L-type calcium currents opening, to decrease the concentration of free Ca~(2+) and calcium overload in myocardium to protect myocardial cells.
5. Dcordaline preconditioning can markedly decrease infarct size in rats myocardium induced by myocardial ischemia and reperfusion injury, same as ischemia preconditioning.
OBJECTIVE: To observe the clinic effect of the composite prescriptions containing Corydalis yanhusuo W. T. Wang(Taoren Honghua Decoction) to frequent ventricular premature complexes(VPC) in patients with coronary heart disease(CHD).
METHODS: A prospective study was done of frequent ventricular premature complexes in 60 patients with CHD under the randomized, controlled and single-blind rules. These patients were randomized into control and experimental groups in 1:1 proportion. The patients in experimental group received basic western medical therapy for CHD combined with Taoren Honghua Decoction; while the patients in control group received only basic western medical therapy. To compare the clinic efficacy to the patients in between control and experimental groups by observing the change of ventricular premature rate and the change of traditional Chinese medicine syndrome and symptom before and after treatment.
RESULTS:
1. Compare of the efficacy to ventricular premature after treatment: the results of therapy were assessed as follows: the general effective rate being 85% in experimental group, while 75% in control group. There was not significant differences between the two groups(P＞0.05). It is illustrate that the two groups has same effect.
2. Compare of the 24h ventricular premature beats pre-treatment and post-treatment: A design of oneself comparison according to pre-treatment and post-treatment was performed in both groups. There was significant differences in each group(P＜0.01). The value between pre-treatment and post-treatment in experimental group had no difference to that in control group(P＞0.05).
3. Compare of the efficacy to traditional Chinese medicine syndrome between control and experimental group: the general effective rate being 90% in experimental group, while 70% in control group. There were significant differences between the two groups(P＜0.05).
4. Compare of the scores of traditional Chinese clinical symptoms between control and experimental group: A design of oneself comparison according to pre-treatment and post-treatment was performed in both groups. There were significant differences between pre-treatment and post-treatment in each group(P＜0.05). The value between pre-treatment and post-treatment in experimental group had significant difference to that in control group(P＜0.05).
5. Compare of the traditional Chinese medicine symptom between control and experimental group: the general effective rate to palpitation being 89.7% in experimental group, while 66.7% in control group. There were significant differences between the two groups(P＜0.05). The general effective rate to chest stifling being 76.7% in experimental group, while 45.8% in control group. There were significant differences between the two groups(P＜0.05). There were not significant differences of other symptom between the two groups(P＜0.05)
CONCLUSION:
Though the observation of treatment of the composite prescriptions containing Corydalis yanhusuo W. T. Wang(Taoren Honghua Decoction) for frequent ventricular premature complexes in 30 patients with coronary heart disease(CHD), we found that the basic western medical therapy for CHD combined with Taoren Honghua Decoction has the same efficacy as single western medical therapy in decreasing frequent ventricular premature complexes and antiarrhythmic in patients with coronary heart disease. But the improvement of traditional Chinese medicine syndrome and symptom, specially palpitation and chest stifling, is significantly increased in experimental group than in contro group, we also found that the basic western medical therapy combined with Taoren Honghua Decoction has lower side effect, little causing arrhythmia.
CONCLUDING:
1. To ischemia reperfusion ventricular arrhythmic in rats myocardium, dcordaline preconditioning can not only postpone the occuring time of ventricular arrhythmic, shorten the duration, but also reduce ventricular tachycardia (VT) and ventricular fibrillation (VF) rate. The results show that dcordaline preconditioning has antiarrhythmic effect against ischemia and reperfusion in rats myocardium
2. Dcordaline preconditioning can inhibite apoptosis of myocardial cells and protect myocardial cells from ischemia and ischemia reperfusion injury by up-regulation of the expression of bcl-2 proteins and down-regulation of the expression of Fas proteins. The results show that dcordaline preconditioning has heart protected effect by the mechanism that similar to endogenous anti-apoptosis of ischemia preconditioning.
3. Dcordaline preconditioning can markedly increase the activities of Na+-K+-ATPase and Ca~(2+)-ATPase in myocardial cells, which can carry Ca~(2+) out from intercellular to extracellular through the pathway as follows: Ca~(2+)-ATPase in sarcoplasmic reticulum, Na+-Ca~(2+) exchange system, Ca~(2+)-ATPase sarcolemma. So as to decrease the concentration of free Ca2+ and calcium overload in myocardium to protect myocardial cells.
4. Dcordaline preconditioning can decrease the open-state probability and the amplitude of L-type calcium currents(ICa-L) in myocardial cell so as to block the L-type calcium currents opening, to decrease the concentration of free Ca~(2+) and calcium overload in myocardium to protect myocardial cells.
5. Dcordaline preconditioning can markedly decrease infarct size in rats myocardium induced by myocardial ischemia and reperfusion injury, same as ischemia preconditioning.
6. Though the clinic observation we conclude that the basic western medical therapy for CHD combined with Taoren Honghua Decoction has the same efficacy as single western medical therapy in decreasing frequent ventricular premature complexes and antiarrhythmic in patients with coronary heart disease. But the improvement of traditional Chinese medicine syndrome and symptom, specially palpitation and chest stifling, is significantly increased in experimental group than in contro group. The combined therapy has lower side effect, little causing arrhythmia, so as to has a good prospect of application and extension
引文
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