三七总皂甙、川芎嗪抑制病毒性心肌炎小鼠钙超载的机制研究
摘要
病毒性心肌炎(Viral myocarditis VMC)是儿科临床常见的心血管疾病之一。二十世纪七十年代以来，VMC发病日趋增多，相继报道了很多有关该病的临床资料和病毒学诊断，但其发病机制仍未完全阐明，其后各国主要关注于发病机制的研究。近年来，随着分子生物学的快速发展，对本病的研究有很大的突破，但尚无特效的治疗方法。仍以对症治疗为主。随着对该病研究的深入，中西医结合治疗取得了明显的效果，显示出对VMC的良好前景。
通过柯萨奇病毒B型(Coxsackievirus B CVB)感染小鼠急性心肌炎实验研究，至少有两种与病毒感染有关的心肌损伤机理已经明确。一种为病毒的直接损伤作用，另一种为机体的免疫反应对心肌细胞的杀伤作用。有研究表明，病毒的直接作用和免疫损伤均可引起心肌细胞钙超载，钙超载亦是VMC心肌损害的发病机制之一。并认为钙超载是病毒引起心肌细胞损伤和坏死的共同通路之一，心肌细胞肌浆网(sarcoplasmic reteculum SR)的生理功能主要是通过调节心肌细胞内钙离子浓度来控制心肌细胞的收缩和舒张。研究发现，收缩期心肌细胞内游离钙离子浓度升高的90％由SR释放，而舒张期胞浆钙离子浓度的下降，70％—75％是由肌浆网钙泵摄取并储存于SR腔内。如果SR的结构和功能发生异常，引起钙离子代谢障碍，则易导致心肌舒缩
浙江大掌协士学位论文
功能不全，直至心功能衰竭。
三七总皂试为我国常用的传统中药，是三七的主要活性成分，以
Rbl和Rgl为主，Rbl和Rgl对钙离子转运都有抑制作用，Rbl的作用
在于阻止外源性钙离子流入，而Rg；的作用则为抑制胞内钙离子的释
放，由于 Rb和 Rg；分别作用于钙转运的不同环节，故二者在作用上
表现协同。大量的药理研究证实，三七总皂贰具有抑制血小板聚集、
抗血栓、增加冠脉血流、降低血压和心肌负性变频及负性变力作用’，
从而纠正了心肌的能量缺乏。有研究表明三七总皂成通过上述多种药
理作用提高心肌细胞膜上钙泵的活性，使心肌细胞内钙超载明显减轻。
川穹嗓是中药川芍的有效成分，从川答中提取而得，是一种生物
碱，川穹嗓的主要作用是活血化瘀，随着研究的增多，逐步发现川芍
嗓的许多药理特性，临床应用范围亦逐步扩大。目前川穹喷己成为临
床心脑血管疾病的一种常用的比较安全的药物。较多的研究证实川芍
唉具有类似钙通道阻滞剂维拉帕米的作用，中科院基础医学研究所发
现，川苇嗓不但能抑制高血压动物血管平滑肌细胞钙离子内流，而H
能提高钙泵的活性。有报道川穹嗓佐治VMC 取得良好的疗效，但木
见作用机理的研究报道。
本课题通过腹腔内注射CVB3m制成VMC模型，以中成药二七总皂
贰和川苇嚷注射液加以干预，探讨VMC的形态学（光镜和电镇），血
清心肌酶谱、心肌细胞内游离钙离子浓度、肌浆网钙泵活性和肌浆网
钙转运蛋白（肌浆网钙泵、钙离子释放通道和磷酸受纳蛋白）基因表
达水平的变化，并在此基础上，探讨三七总皂贰和川草唉注射液对以
上因素的影响。本研究旨在寻找VMC 新的治疗药物，并进一步探讨
其可能的作用机制。
第一部分 三七总皂妖和川穹嚎注射液对病毒性
心肌炎小鼠心肌损害的干预作用研究
用亲心肌的C。XB 3m病毒（TCID”为10七）0．4thl 腹腔注射至
2
浙江大学博士学位论文
BALB儿小鼠（雄性，4—6周），制作VMC模型。同时以不含病毒的
培养液0．4ml注射于同年龄的同批实验小鼠作为对照组。腹腔注射病
毒和不含病毒的培养液后约半小时，VMC模型组和对照组分别腹腔注
生理盐水 0．2 ml 7天，三七总皂贰组和川穹噎组分别将三七总皂贰
（40mg／kg）和川穹嗓（40mg／kg）注射液稀释至 0．Zml腹腔注射于
己感染病毒的小鼠，连用7天。实验第8天摘眼球取血后处死各组实
验鼠。血清离心后集中测心肌酶谱，同时称心脏净重量，并留左．室心
肌作病理形态学检查（光镜和电镜）。
结果1．实验动物心脏重量（HW）和体重（BW）的比较：实验
第8 天，模型组BW明显低于对照组（P＜0．01），三七总皂成组和J；【穹
喷组与模型组比较，BW分别增加了 22％和 18％，均具有显著性差异
（P＜0．05），但两干预组的BW与对照组相比亦有明显降低（P＜0．05）。
模型组 HW／BW明显高于对照组（P＜0．01），三七总皂贰组和川穹喷组
的 HW／BW 与模型组比较有显著性差异（P＜0．of），和对照组比较无
显著性差异（P＞0．05）。说明VMC可使动物BW下降，HW／BW增加，
三七总皂贰和川穹嚎干预后可使VMC引起的BW下降和HW／BW增
加得到明显改善。
2．实验动物血清心肌酶谱的变化：模型组血清心肌酶谱的CK－MB、
CK、AST、LDH、HBDH与对照组比较均有显著增高（P＜0．01），应用
三七总皂戍和川穹嗓干预后，血清心肌酶谱各项值均有明显降低
（P＜0．05），但与对照组之间仍有显著性差异（P＜0．05），说明三七总皂
术和川穹咦组均可
Viral myocarditis(VMC) is one of the common cardiovascular diseases in pediatrics. Since the 1970's, the occurrence of viral myocarditis has become more and more, and there have been many reports on the clinical data and virological diagnosis of it. However, its pathogenesis has not clarificated completely, thus, later on, the focus of research of all countries shifted to its pathogenesis. In recent years, along with the rapid development of molecular biology, the research on this disease has had some great breakthroughs, but no therapy with obvious effect has been found out yet. The way to deal with it is still mainly the specific treatment of specific symptoms. Along with the deep going of the research on the disease, the integrated traditional Chinese and western medicine has produced obvious effects, showing a good prospect of the treatment of viral myocarditis.
The experimental study on the mouse acute VMC induced with Coxsackie virus B(CVB) has shown that there are at least two kinds of mechanism of myocardial damage related to virus infection. One is the direct damaging action of the virus, and the other is the damaging effect of the immunoreaction of the body on the myocardial cells. Research has shown that, both the direct action of the virus and the immunologic injury can lead to the overload of the myocardial intracellular Ca2+ and the calcium overload is also a pathogenesis for the myocardial damage of VMC. Another conclusion is that calcium overload is one of the common way for the damage and necrosis of myocardial cells. The chief physiological function of the sarcoplasmic reticulum (SR) of the myocardial cell is to adjust the concentration of calcium ions in the myocardial cell so as to control the contraction and diastole of the cardiac muscle. Research has found out that, 90% of the increase of the concentration of free calcium ions in the myocardial ce
ll is a result of the release
from the SR, while the 70% - 75% of the decrease of the concentration of free calcium ions during the phase of relaxation is a result of the fact that the SERCA2a has taken them in and stored them in the sarcoplasmic reticulum. If the structure and function of SR have become abnormal , abnomal metabolism of calcium ions will be caused, which will easily result in insufficiency of diastole and contraction of cardiac muscles, even causing the heart failure.
Total Saponins of Panax Notoginseng (TSPNS) is a commonly used traditional Chinese medicine. It is composed of the major active ingredients of panax notoginseng, chiefly being Rb1 and Rg1. Both Rb1 and Rg1 have an inhibiting action on the motion of calcium ions: the function of Rb1 is to prevent the calcium ions entering cell from outside while that of Rg1 is to inhibit the release of intracellular calcium ions. As Rb1 and Rg1 function in different steps of the motion of the calcium, the two may have a synergetic function together. A lot of research on pharmacology has shown that, TSPNS is able to inhibit platelet aggregation, resist thrombosis, increase coronary flow, lower blood pressure and produce the negative inotropic action of the cardiac muscles, thus, it can serve as a remedy for the energy deficiency of the cardiac muscle. Research results have proved that, through the above- mentioned many pharmacological actions, TSPNS has enhanced the activity of the calcium pump on the myocardial cell membrane, greatly relieving the overload of the myocardial intrallular Ca2+.
Ligustrazine is the effective ingredient of the Chinese traditional medicine, chuanxiong rhizome, extracted from the latter. It is an alkaloid, whose major function is promoting blood circulation and removing blood stasis. In the earlier time, it was mostly studied and used from the function of promoting blood circulation and removing blood stasis. But with the deep going of the research, we have found many more functions of it, thus, its scope of clinical application is gradually expanding as well. At present, ligustrazine has become a commonly used and safe medicine for clinical treat
通过柯萨奇病毒B型(Coxsackievirus B CVB)感染小鼠急性心肌炎实验研究，至少有两种与病毒感染有关的心肌损伤机理已经明确。一种为病毒的直接损伤作用，另一种为机体的免疫反应对心肌细胞的杀伤作用。有研究表明，病毒的直接作用和免疫损伤均可引起心肌细胞钙超载，钙超载亦是VMC心肌损害的发病机制之一。并认为钙超载是病毒引起心肌细胞损伤和坏死的共同通路之一，心肌细胞肌浆网(sarcoplasmic reteculum SR)的生理功能主要是通过调节心肌细胞内钙离子浓度来控制心肌细胞的收缩和舒张。研究发现，收缩期心肌细胞内游离钙离子浓度升高的90％由SR释放，而舒张期胞浆钙离子浓度的下降，70％—75％是由肌浆网钙泵摄取并储存于SR腔内。如果SR的结构和功能发生异常，引起钙离子代谢障碍，则易导致心肌舒缩
浙江大掌协士学位论文
功能不全，直至心功能衰竭。
三七总皂试为我国常用的传统中药，是三七的主要活性成分，以
Rbl和Rgl为主，Rbl和Rgl对钙离子转运都有抑制作用，Rbl的作用
在于阻止外源性钙离子流入，而Rg；的作用则为抑制胞内钙离子的释
放，由于 Rb和 Rg；分别作用于钙转运的不同环节，故二者在作用上
表现协同。大量的药理研究证实，三七总皂贰具有抑制血小板聚集、
抗血栓、增加冠脉血流、降低血压和心肌负性变频及负性变力作用’，
从而纠正了心肌的能量缺乏。有研究表明三七总皂成通过上述多种药
理作用提高心肌细胞膜上钙泵的活性，使心肌细胞内钙超载明显减轻。
川穹嗓是中药川芍的有效成分，从川答中提取而得，是一种生物
碱，川穹嗓的主要作用是活血化瘀，随着研究的增多，逐步发现川芍
嗓的许多药理特性，临床应用范围亦逐步扩大。目前川穹喷己成为临
床心脑血管疾病的一种常用的比较安全的药物。较多的研究证实川芍
唉具有类似钙通道阻滞剂维拉帕米的作用，中科院基础医学研究所发
现，川苇嗓不但能抑制高血压动物血管平滑肌细胞钙离子内流，而H
能提高钙泵的活性。有报道川穹嗓佐治VMC 取得良好的疗效，但木
见作用机理的研究报道。
本课题通过腹腔内注射CVB3m制成VMC模型，以中成药二七总皂
贰和川苇嚷注射液加以干预，探讨VMC的形态学（光镜和电镇），血
清心肌酶谱、心肌细胞内游离钙离子浓度、肌浆网钙泵活性和肌浆网
钙转运蛋白（肌浆网钙泵、钙离子释放通道和磷酸受纳蛋白）基因表
达水平的变化，并在此基础上，探讨三七总皂贰和川草唉注射液对以
上因素的影响。本研究旨在寻找VMC 新的治疗药物，并进一步探讨
其可能的作用机制。
第一部分 三七总皂妖和川穹嚎注射液对病毒性
心肌炎小鼠心肌损害的干预作用研究
用亲心肌的C。XB 3m病毒（TCID”为10七）0．4thl 腹腔注射至
2
浙江大学博士学位论文
BALB儿小鼠（雄性，4—6周），制作VMC模型。同时以不含病毒的
培养液0．4ml注射于同年龄的同批实验小鼠作为对照组。腹腔注射病
毒和不含病毒的培养液后约半小时，VMC模型组和对照组分别腹腔注
生理盐水 0．2 ml 7天，三七总皂贰组和川穹噎组分别将三七总皂贰
（40mg／kg）和川穹嗓（40mg／kg）注射液稀释至 0．Zml腹腔注射于
己感染病毒的小鼠，连用7天。实验第8天摘眼球取血后处死各组实
验鼠。血清离心后集中测心肌酶谱，同时称心脏净重量，并留左．室心
肌作病理形态学检查（光镜和电镜）。
结果1．实验动物心脏重量（HW）和体重（BW）的比较：实验
第8 天，模型组BW明显低于对照组（P＜0．01），三七总皂成组和J；【穹
喷组与模型组比较，BW分别增加了 22％和 18％，均具有显著性差异
（P＜0．05），但两干预组的BW与对照组相比亦有明显降低（P＜0．05）。
模型组 HW／BW明显高于对照组（P＜0．01），三七总皂贰组和川穹喷组
的 HW／BW 与模型组比较有显著性差异（P＜0．of），和对照组比较无
显著性差异（P＞0．05）。说明VMC可使动物BW下降，HW／BW增加，
三七总皂贰和川穹嚎干预后可使VMC引起的BW下降和HW／BW增
加得到明显改善。
2．实验动物血清心肌酶谱的变化：模型组血清心肌酶谱的CK－MB、
CK、AST、LDH、HBDH与对照组比较均有显著增高（P＜0．01），应用
三七总皂戍和川穹嗓干预后，血清心肌酶谱各项值均有明显降低
（P＜0．05），但与对照组之间仍有显著性差异（P＜0．05），说明三七总皂
术和川穹咦组均可
Viral myocarditis(VMC) is one of the common cardiovascular diseases in pediatrics. Since the 1970's, the occurrence of viral myocarditis has become more and more, and there have been many reports on the clinical data and virological diagnosis of it. However, its pathogenesis has not clarificated completely, thus, later on, the focus of research of all countries shifted to its pathogenesis. In recent years, along with the rapid development of molecular biology, the research on this disease has had some great breakthroughs, but no therapy with obvious effect has been found out yet. The way to deal with it is still mainly the specific treatment of specific symptoms. Along with the deep going of the research on the disease, the integrated traditional Chinese and western medicine has produced obvious effects, showing a good prospect of the treatment of viral myocarditis.
The experimental study on the mouse acute VMC induced with Coxsackie virus B(CVB) has shown that there are at least two kinds of mechanism of myocardial damage related to virus infection. One is the direct damaging action of the virus, and the other is the damaging effect of the immunoreaction of the body on the myocardial cells. Research has shown that, both the direct action of the virus and the immunologic injury can lead to the overload of the myocardial intracellular Ca2+ and the calcium overload is also a pathogenesis for the myocardial damage of VMC. Another conclusion is that calcium overload is one of the common way for the damage and necrosis of myocardial cells. The chief physiological function of the sarcoplasmic reticulum (SR) of the myocardial cell is to adjust the concentration of calcium ions in the myocardial cell so as to control the contraction and diastole of the cardiac muscle. Research has found out that, 90% of the increase of the concentration of free calcium ions in the myocardial ce
ll is a result of the release
from the SR, while the 70% - 75% of the decrease of the concentration of free calcium ions during the phase of relaxation is a result of the fact that the SERCA2a has taken them in and stored them in the sarcoplasmic reticulum. If the structure and function of SR have become abnormal , abnomal metabolism of calcium ions will be caused, which will easily result in insufficiency of diastole and contraction of cardiac muscles, even causing the heart failure.
Total Saponins of Panax Notoginseng (TSPNS) is a commonly used traditional Chinese medicine. It is composed of the major active ingredients of panax notoginseng, chiefly being Rb1 and Rg1. Both Rb1 and Rg1 have an inhibiting action on the motion of calcium ions: the function of Rb1 is to prevent the calcium ions entering cell from outside while that of Rg1 is to inhibit the release of intracellular calcium ions. As Rb1 and Rg1 function in different steps of the motion of the calcium, the two may have a synergetic function together. A lot of research on pharmacology has shown that, TSPNS is able to inhibit platelet aggregation, resist thrombosis, increase coronary flow, lower blood pressure and produce the negative inotropic action of the cardiac muscles, thus, it can serve as a remedy for the energy deficiency of the cardiac muscle. Research results have proved that, through the above- mentioned many pharmacological actions, TSPNS has enhanced the activity of the calcium pump on the myocardial cell membrane, greatly relieving the overload of the myocardial intrallular Ca2+.
Ligustrazine is the effective ingredient of the Chinese traditional medicine, chuanxiong rhizome, extracted from the latter. It is an alkaloid, whose major function is promoting blood circulation and removing blood stasis. In the earlier time, it was mostly studied and used from the function of promoting blood circulation and removing blood stasis. But with the deep going of the research, we have found many more functions of it, thus, its scope of clinical application is gradually expanding as well. At present, ligustrazine has become a commonly used and safe medicine for clinical treat
引文
1．九省市小儿心肌炎协作组．九省(市)小儿VMC调查，中华儿科杂志，1982；20(1)：23—27．
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17. Dong RP, Liu L, Wee L, et al. Verapamil ameliorates the clinical and Pathological course of murine myocarditis. J Clin Invest, 1992; 90(5):2022-2030.
18. Felzen B, Shilkut M, Less H, et al. Fas(CDS/Apo-1)-mediated damage to ventricular myocytes induced by cytotoxic T lymphocytes from perforin-deficient mice. Cir Res, 1998; 82: 438-450.
19．陆曙，张寄南，杨笛，等．黄芪总皂甙对病毒性心肌炎小鼠心肌损伤及肌浆网钙泵的影响，中国中西医结合杂志，1999；19(11)：672-674．
20．冯培芳，蒋惠芳．三七总皂甙对SHR心肌细胞内Ca~(2+)及其肌浆网膜上钙泵活性的影响．中国中药杂志，1998；23(3)：173—175．
21．王玉良，巴彦坤．川芎嗪对心血管组织的药理和电生理作用：
一种新的钙离子拮抗剂．中西医结合杂志，1985：5(2)：291—294．
22．夏腊梅，伍杰雄．川芎嗪对心肌细胞核钙转运功能异常的保护．中国临床药理学与治疗学，2002；7(2)：124—126．
23．范占东．川芎嗪注射液佐治急性 VMC，黑龙江医药，1997；10(4)：243—244．
24. Hamm CW, Katus HA. New biochemical markers for myocardial cell injury. Curr Opin Cardiol. 1995; 10(2):355—360.
25. Rezkalla S, Kloner RA, Khatib G, et al. Beneficial effects of captopril in acute coxsackievirus B3 murine myocarditis. Circulation, 1990;81(3):1039—1046.
26. Zaidi SH, Hui CC, Cheah AY, et al. Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis. J Clin Invest, 1999, 103(8): 1211-1219.
27. Lewis DA, Dhala A. Syncope in the pediatricpatient. The cardiologist's perspective. Pediatr Clin North Am, 1999; 46(2): 205-219.
28．蒋岩，崔小岱，吴莎，等．红芪提取物抗亲心柯萨奇病毒感染的实验研究．中国中西医结合杂志，1995，49—51．
29．崔小岱，孙国贤，马连华，等．VitC保护病毒感染小鼠心肌细胞的机理探讨．中华临床及病毒学杂志，1993，7(4)：401—404．
30．杨英珍．VMC进展(二)．中国中西医结合杂志，1995，15(9)：557—561．
31. Alida LP, Caforio,William J.MeKenna. Recognetion and optimum of myocardits. Drugs, 1996,52(4):515-525.
32．陈新民．小儿心肌病与VMC的诊断．中国实用儿科杂志，1996，11(5)：266—268．
33．谢志华．广西田七总皂甙扶正固本作用的实验研究．中药药理与临床．1991，7(2)：27．
34．王甲东．三七总皂甙对心脏血液动力学的作用．中国药理学报．
1984，5(3)：181-185．
35．郝朝庆．三七总皂甙的抗炎作用．中国药理学报．1986，7(3)：252—255．
36．张宝恒．三七总皂甙的抗炎作用及其作用机制．中国药理学通报．1990，6(4)：236-239．
37．黄聪，顾天香，关永源，等．三七总皂甙对清醒兔心肌缺血再灌注损伤的保护作用．中国药理学通报．1991，7(3)：190—193．
38．苗明三主编．法定中药药理与临床．第一版．西安：世界图书出版西安公司．1998：47—54．
39. Kwan CY. Plant-derived drugs acting on cellular Ca~(2+) mobilization in vascular smooth muscle: tetramethylpyrazine and tetrandrine. Stem Cell, 1994; 12(1): 64-67.
40. Kwan CY, Daniel EE, Chen MC. Inhibition of vasoconstriction by tetramethylpyrazine: does it act by blocking the voltage -dependent Ca~(2+) channel. J Cardiovasc Pharmacol. 1990;15(1):157-162.
41. Feng J, Wu G, Tang S. The effects of tetramethylpyrazine on the incidence of arthythmias and the release of PGI_2 and TXA_2 in the ischemic rat heart. Plamta Med,1999;65(3):268-270.
42. Pang PK, Shan J J, Chiu KW. Tetramethylpyrazine, a calcium antagonist. Planta Med,1995;62(5):431-435.
43. Grisold M, Koppel H, Gasser R. First description of the effect of a non-sulfonylurea compound, tetramethylpyrazine, on coronary response to desoxyglucose-indueed ischemia. Acta Meal Austriaca, 1998;25(1): 16-20.
44. Sheu JR, Kan YC, Hung WC, et al. Mechanisms involved in the antiplatelet activity of tetramethylpyrazine in human platelets. Thromb Res, 1997; 88(3): 259-270.
45．韩玲，陈可冀．川芎嗪对缺血再灌注心肌保护作用的研究进展．解放军药学学报，2002；18(1)，41—43．
2. See DM and Tilles JG. Viral myocarditis. Rev Invect Dis. 1991;13(5):951—956.
3. Hingorani AD. Post infectious myocarditis. BMJ, 1992; 304 (6843): 1676—1678.
4. Remes J, Helin M,Vaino P, et al Clinical outcome and left ventricular function 23 years after acute coxsackie virus myopericarditis. Eur Heart J,1990;11(2):182—188.
5．杨英珍．病毒性心脏病．实验性VMC模型 上海科学技术出版社，2001；p348-p353．
6. Klingel K, Kandolf R. The role of enterovirus replication in the development of acute and chronic heart muscles disease in different immunocompetent mouse strain. Scan J infect Disease, 1993; 88(supple):79-85.
7. Mcmanus BM, Chow LH, Wilson JE, et al. Direct myocarditis injury by enterovirus: a central role in the evolution of murine myocarditis. Clin Immunol Immunopathol,1993; 68(2):159-169.
8. Sato S, Tsutsumi R, Burke A, et al. Persistent of replicating coxsackievirus B3 in the athymic murine heart is associated with development of myocarditic lesion. J Gen Virol, 1994; 75(pt 11):2911-2924.
9. Badorff C, Lee GH,Lamphear BJ,et al. Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nat Med.1999;5(3): 320-326.
10. Knowlton KU, Badorff C. The immune system in virus myocarditis: maintaining the balance.Cir Res, 1999;85(6): 559-561.
11. Gebhard IR, Perry CM, Harkins S, et al. Coxsackievirus B3-induced myocarditis: perforin exacerbates disease, but play no detectable role in virus clearance. Am J Pathol, 1998; 153 (2): 413-428.
12. Seko Y, Takahashi N, Azuma M, et al. Effects of in vivo administration of anti-B7-7/B7-2 monoclonal antibodies on murine acute myocarditis caused by coxsackievirus B3.Cir Res, 1998; 82(5):613-618.
13. Seko Y, Takahashi N, Azuma M, et al. Expression of costimulatory molecule CD40 in murine heart with acute myocarditis and reduction of inflammation by treatment with anti-CD40L/B7-1 monoclonal antibodies. Cir Res,1998;83(4):463-469.
14. Matsumori A, To ioka N,et al. Protective effect of recombinant alpha interfer on coxsackievirus B3 myocarditis in mice. Am Heart J,1998; 115(6):1229-1232.
15. Meldrum DR. Tumor necrosis factor in the heart. Am J physiol, 1998; 274(3 pt 2): R577-595.
16. Silver MA, Kowalezy K. Coronary microvascular narrowing in acute murine coxsacke B3 myocarditis. Am Heart J, 1989;118(1): 173-174.
17. Dong RP, Liu L, Wee L, et al. Verapamil ameliorates the clinical and Pathological course of murine myocarditis. J Clin Invest, 1992; 90(5):2022-2030.
18. Felzen B, Shilkut M, Less H, et al. Fas(CDS/Apo-1)-mediated damage to ventricular myocytes induced by cytotoxic T lymphocytes from perforin-deficient mice. Cir Res, 1998; 82: 438-450.
19．陆曙，张寄南，杨笛，等．黄芪总皂甙对病毒性心肌炎小鼠心肌损伤及肌浆网钙泵的影响，中国中西医结合杂志，1999；19(11)：672-674．
20．冯培芳，蒋惠芳．三七总皂甙对SHR心肌细胞内Ca~(2+)及其肌浆网膜上钙泵活性的影响．中国中药杂志，1998；23(3)：173—175．
21．王玉良，巴彦坤．川芎嗪对心血管组织的药理和电生理作用：
一种新的钙离子拮抗剂．中西医结合杂志，1985：5(2)：291—294．
22．夏腊梅，伍杰雄．川芎嗪对心肌细胞核钙转运功能异常的保护．中国临床药理学与治疗学，2002；7(2)：124—126．
23．范占东．川芎嗪注射液佐治急性 VMC，黑龙江医药，1997；10(4)：243—244．
24. Hamm CW, Katus HA. New biochemical markers for myocardial cell injury. Curr Opin Cardiol. 1995; 10(2):355—360.
25. Rezkalla S, Kloner RA, Khatib G, et al. Beneficial effects of captopril in acute coxsackievirus B3 murine myocarditis. Circulation, 1990;81(3):1039—1046.
26. Zaidi SH, Hui CC, Cheah AY, et al. Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis. J Clin Invest, 1999, 103(8): 1211-1219.
27. Lewis DA, Dhala A. Syncope in the pediatricpatient. The cardiologist's perspective. Pediatr Clin North Am, 1999; 46(2): 205-219.
28．蒋岩，崔小岱，吴莎，等．红芪提取物抗亲心柯萨奇病毒感染的实验研究．中国中西医结合杂志，1995，49—51．
29．崔小岱，孙国贤，马连华，等．VitC保护病毒感染小鼠心肌细胞的机理探讨．中华临床及病毒学杂志，1993，7(4)：401—404．
30．杨英珍．VMC进展(二)．中国中西医结合杂志，1995，15(9)：557—561．
31. Alida LP, Caforio,William J.MeKenna. Recognetion and optimum of myocardits. Drugs, 1996,52(4):515-525.
32．陈新民．小儿心肌病与VMC的诊断．中国实用儿科杂志，1996，11(5)：266—268．
33．谢志华．广西田七总皂甙扶正固本作用的实验研究．中药药理与临床．1991，7(2)：27．
34．王甲东．三七总皂甙对心脏血液动力学的作用．中国药理学报．
1984，5(3)：181-185．
35．郝朝庆．三七总皂甙的抗炎作用．中国药理学报．1986，7(3)：252—255．
36．张宝恒．三七总皂甙的抗炎作用及其作用机制．中国药理学通报．1990，6(4)：236-239．
37．黄聪，顾天香，关永源，等．三七总皂甙对清醒兔心肌缺血再灌注损伤的保护作用．中国药理学通报．1991，7(3)：190—193．
38．苗明三主编．法定中药药理与临床．第一版．西安：世界图书出版西安公司．1998：47—54．
39. Kwan CY. Plant-derived drugs acting on cellular Ca~(2+) mobilization in vascular smooth muscle: tetramethylpyrazine and tetrandrine. Stem Cell, 1994; 12(1): 64-67.
40. Kwan CY, Daniel EE, Chen MC. Inhibition of vasoconstriction by tetramethylpyrazine: does it act by blocking the voltage -dependent Ca~(2+) channel. J Cardiovasc Pharmacol. 1990;15(1):157-162.
41. Feng J, Wu G, Tang S. The effects of tetramethylpyrazine on the incidence of arthythmias and the release of PGI_2 and TXA_2 in the ischemic rat heart. Plamta Med,1999;65(3):268-270.
42. Pang PK, Shan J J, Chiu KW. Tetramethylpyrazine, a calcium antagonist. Planta Med,1995;62(5):431-435.
43. Grisold M, Koppel H, Gasser R. First description of the effect of a non-sulfonylurea compound, tetramethylpyrazine, on coronary response to desoxyglucose-indueed ischemia. Acta Meal Austriaca, 1998;25(1): 16-20.
44. Sheu JR, Kan YC, Hung WC, et al. Mechanisms involved in the antiplatelet activity of tetramethylpyrazine in human platelets. Thromb Res, 1997; 88(3): 259-270.
45．韩玲，陈可冀．川芎嗪对缺血再灌注心肌保护作用的研究进展．解放军药学学报，2002；18(1)，41—43．
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