抗凝护心Ⅱ号对急性心肌梗死后大鼠MMPS与CGRP的影响
摘要
为探求AMI后，KNHX-Ⅱ扩张冠状动脉及抑制明胶酶的机理和疗效，建立了大鼠AMI模型，通过观察实验动物梗死区心肌的染色及MMP9含量的变化，并测定血浆中CGRP含量的变化来说明这一机制。结扎大鼠LAD，造模成功术后2小时，颈总动脉取血，制备血浆，采用放免法检测降钙素基因相关肽。处死大鼠后取梗死区心肌进行HE染色及免疫组化法测定金属基质蛋白酶的含量(定性分析)。通过光镜观察MI的程度。
实验证明，KNHX-Ⅱ能明显提高血浆中CGRP的含量，降低MMPs活性，并随着剂量的增加与治疗作用成正相关。
KNHX-Ⅱ防治MI机制可能是良性调节血浆中CGRP和梗死心肌内的MMP9的含量。众所周知，心脏持续射血满足全身各组织脏器供血的能力与心肌损伤的程度直接相关，AMI后常常同时伴随着冠状动脉痉挛的发生，KNHX-Ⅱ通过增加血浆中CGRP含量，舒张血管平滑肌，扩张痉挛的冠状动脉，降低心脏的负荷，保护缺血的心肌，并改善心功能。AMI后MMP9被激活，表现为梗死区心肌MMP9含量明显增加，而MMP9会导致纤维类胶原的分解破坏，左心室的扩张和心室重塑。KNHX-Ⅱ不仅能抑制MMP9的活性，也能抑制它的合成，减少ECM的降解，从而防止心室重构，保护缺血心肌和改善心功能。
In order to study the mechanism and curative effectiveness of the KangNingHuXin(KNHX-II) on the AMI.we established on rats the acute myocardial infarction models to study the change of the activity of MMP9 in the necrosis zone and the levels of CGRP in the plasma of AMI rats . adult wistar rats were ligated the left descinding coronary artery, then being devided randomly into six groups: sham-operation; saline; aspirin-Kaptopril; low-dosage, normal-dosage,high-dosage group.The quantity of each group is ten. After the operation was finished,Two hours later, taking the blood in the artery to measure the CGRP. The contents of CGRP in the plasma of rats (50 AMI and 10 sham-operaton rats )were masured by the methods of radioimmunoassay. Parts of the necrosis zone in rats heart were selected for HE and immunohistochemical staining .Some of the specimens in necrosis zone of AMI rats were stained with HE to identify the ischemic or necrosis degree. Immunohistochemical method was used to measure the secretion of MMP9
.
we learned the results by measuring the contents of CGRP and MMP9.The results demonstrated that normal-dosage of KNHX-II,high-dosage of KNHX-II can increase the contents of CGRPand decrease the concentration of MMP9,singnificantly,the effects were enhanced with the increasing of the drugs' concentration.
The favourable regulation of plasma CGRP and MMP9 in necrosis zone is possibly one of mechanisms for KNHX-II preventing and treating AMI. As is well known to all .the ability of the heart to continue functioning as a pump relates directly to
the extent of myocardial damage. AMI is usually accompanied with coronary spasm .The mechanism of therapeutic actions of KNHX-II may be explained by its ability to increase the contents of CGRP .CGRP can relax vascular smooth muscle and cause coronary arterial dilatation, consequently ,reduce cardial preload and afterload ,reduce the work of the heart.
The activity of MMP9 in the necrosis zone showed an obvious increase . The latent MMP9 were activated after infarction ,which resulted in the damage of the fibrillar network and dalitation of the left ventricle and ventricle remodeling . KNHX-II not only attenuates the activity of MMP9 but also prevents collagen synthesis, decreases the total collagon in the necrosis zone at the stage after infarction .Thus regressing the progress dysfunction of the infarction heart and protecting the ischemic myocardium.
Conclusions : the KNHX-II can alleviate coronaryspasm and prevent ventricle remodeling and avoid the occurance of re-infarction after AMI. .
实验证明，KNHX-Ⅱ能明显提高血浆中CGRP的含量，降低MMPs活性，并随着剂量的增加与治疗作用成正相关。
KNHX-Ⅱ防治MI机制可能是良性调节血浆中CGRP和梗死心肌内的MMP9的含量。众所周知，心脏持续射血满足全身各组织脏器供血的能力与心肌损伤的程度直接相关，AMI后常常同时伴随着冠状动脉痉挛的发生，KNHX-Ⅱ通过增加血浆中CGRP含量，舒张血管平滑肌，扩张痉挛的冠状动脉，降低心脏的负荷，保护缺血的心肌，并改善心功能。AMI后MMP9被激活，表现为梗死区心肌MMP9含量明显增加，而MMP9会导致纤维类胶原的分解破坏，左心室的扩张和心室重塑。KNHX-Ⅱ不仅能抑制MMP9的活性，也能抑制它的合成，减少ECM的降解，从而防止心室重构，保护缺血心肌和改善心功能。
In order to study the mechanism and curative effectiveness of the KangNingHuXin(KNHX-II) on the AMI.we established on rats the acute myocardial infarction models to study the change of the activity of MMP9 in the necrosis zone and the levels of CGRP in the plasma of AMI rats . adult wistar rats were ligated the left descinding coronary artery, then being devided randomly into six groups: sham-operation; saline; aspirin-Kaptopril; low-dosage, normal-dosage,high-dosage group.The quantity of each group is ten. After the operation was finished,Two hours later, taking the blood in the artery to measure the CGRP. The contents of CGRP in the plasma of rats (50 AMI and 10 sham-operaton rats )were masured by the methods of radioimmunoassay. Parts of the necrosis zone in rats heart were selected for HE and immunohistochemical staining .Some of the specimens in necrosis zone of AMI rats were stained with HE to identify the ischemic or necrosis degree. Immunohistochemical method was used to measure the secretion of MMP9
.
we learned the results by measuring the contents of CGRP and MMP9.The results demonstrated that normal-dosage of KNHX-II,high-dosage of KNHX-II can increase the contents of CGRPand decrease the concentration of MMP9,singnificantly,the effects were enhanced with the increasing of the drugs' concentration.
The favourable regulation of plasma CGRP and MMP9 in necrosis zone is possibly one of mechanisms for KNHX-II preventing and treating AMI. As is well known to all .the ability of the heart to continue functioning as a pump relates directly to
the extent of myocardial damage. AMI is usually accompanied with coronary spasm .The mechanism of therapeutic actions of KNHX-II may be explained by its ability to increase the contents of CGRP .CGRP can relax vascular smooth muscle and cause coronary arterial dilatation, consequently ,reduce cardial preload and afterload ,reduce the work of the heart.
The activity of MMP9 in the necrosis zone showed an obvious increase . The latent MMP9 were activated after infarction ,which resulted in the damage of the fibrillar network and dalitation of the left ventricle and ventricle remodeling . KNHX-II not only attenuates the activity of MMP9 but also prevents collagen synthesis, decreases the total collagon in the necrosis zone at the stage after infarction .Thus regressing the progress dysfunction of the infarction heart and protecting the ischemic myocardium.
Conclusions : the KNHX-II can alleviate coronaryspasm and prevent ventricle remodeling and avoid the occurance of re-infarction after AMI. .
引文
[1] Brown ZG, Zhao XQ,Sacco DE,et al .Lipid lowering and plague regression:new insights into prevention of plaque disruption and clinicaleventsin coronary disease. Circulation. 1993,87:1781-1791.
[2] Vos J, Roygrok PN,de Feyter PJ Progression and regression of coronary atherosclerosis:a review of trials by quantitative angioplasty. In: Fuster V. Syndromes of atherosclerosis:correlations of clinical imaging and pathology. ArmonkNY:Futura Publishing. 1996,437-453.
[3] Casscells W, NaghaviM,WillersonJT, Vulnerableatherosclerosisplague:amultifocal disease. Circulation.2003,107:2072-2075.
[4] LibbyP, Molecularbases of the acute coronary Sydroms. Circulation. 1995, 91:2844-2850.
[5] FalkE, ShahPK, Fuster V, Coronaryplaque disrupion. Circulation.1996,92:657-671.
[6] Qiao JH, Fishbein MC, The severity of coronary atherosclerosis at sites of plaque rupture with occlusive thrombosis.J Am Coll Cardiol, 1991,17:1139-1142.
[7] Buffor A,Biasucci LM, Liuzzo G, et al .Widespread coronary inflammation in unstable angina. N Engl J Med, 2002,347:5-12.
[8] Lendon, Davis MJ, Born GV, et al. Atherosclerotic plaque caps are locally weakened when macrophage density is increased. Atherosis,1991,87:87-90.
[9] 白江涛 基质金属蛋白酶与心血管疾病心血管病学进展2003(24)1
[10] Etoht, Joffsc, Deschamps AI, etal. Myocardial andinterstitial matrix metal loprote einase acitvity after acute myocardial infarction inpigs.[J].Am J Physiol Heart Circ Physiol,2001,281 (3)987～994.
[11] Okaday,Narak,Kawamurak.Localization of matrix metal loproteinase9(92Kdage latinase/type Ⅳ collagenase=gelatinaseB) inosteoclasts: implications for bone resorption[J].Lab Invest, 1995,72:311 322.
[12] Aimes RT, Quigley JP. Matrix talloproteinase2 is an insterstitial collagenase: inhibitor free enzymecatalyze the cleavagc of collagen fibrils and soluble native
type Ⅰ collagen generating the special 3/4 and 1/4 length fragments.[J].J Biol Chem, 1995,270:5872 5876.
[13] Kahari VM, Saarial ho KereU.Matrix metalloproteinase in skin[J]. exp Dermatol, 1997,6:199 213.
[14] Malik N,Green field BW, WahlAF, etal.Activation of human monocytes through CD40 induces matrix metalloproteinase[J].J Immunol,1996,156:3952 3960.
[15] Schonbeck U, Mach F, Sukhova G K,etal.Regulation of matrix metalloproteinase expression in human vascular smooth muscle cell sby T lymphocytes. [J]. Circres,-1997, 81:448 454.
[16] TyagiSC, Matsubara L, Weber KT, etal.Direct extraction and estimation of collagenases activity byzymography in micro quantities of rat myocardium and uterus.[J]Clin Biochem ,1993,26:191 198.
[17] Cleut jens JPM, K and ala JC, Guarda E, etal.Regulation of collagen degradation in the rat myocardium after infarction[J] J Mol Cell Cardiol,1994,27:1281 1292.
[18] Coker MS, Thomas CV, Doscher MA.Matrixmetalloproteinase expression and activity in adult ventricular myocytes: influence of baser men membrane adhension[J](Abstract).Circulatoin, 1997,96: 689.
[19] WeismanHF, B bush DE,Mannisi JA,etal.Cellular mechanisms of myocardial expension. [J]. Circulation, 1988,78:186 201.
[20] PfefferMA, Braun WaldE.Ventricular remodellin gafter myocardial infarction: experimental observations and clinical implication. [J]. Circulation, 1990, 81: 1161-1172.
[21] Loftus IM.Naylor AR,Good all S,et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques: a potential role in acute plaque disruption. Stroke, 2000,31:40-47.
[22] Heymans S.Luttun A,Nuyens D,etaI.Inhibition of plasm inogen activators or matrix metalloproteinase prevent cardia crupture but impairs the rape uicangio genesis and causes cardiac failure.[J].Nat Med,1999,10:1135 1142.
[23] Ducharme A, Frantz S, Aikawa M, etal. Targeted delection of matrix
metalloproteinase 9 atteunates left ventricular enlargement and collagen accumulation after, experimental myocardial infarction.[J].J Clin Invest. 2000, 106: 55 62.
[24] Amara SG, Jonas V, Rosenfeld MG, etal.Alternative RNA process in gincalcitonin gene expression gene rates mRNA sencoding different polypeptide products. Nature, 1982, 298:240
[25] 张明 急性心肌梗死诊断和治疗新概念 心血管康复医学杂志 2002(4)2：102～109
[26] 迟东升，吾柏铭，洪小苏，等．急性心肌梗死患者血浆降钙素基因相关肽含量变化及尿激酶溶栓治疗对其影响的观察[J]．中国危重病急救医学，2000，12(3)：169．
[27] 黄振平，林莲初，鲍正毅，等．冠心病血浆神经肽Y，降钙素基因相关肽、P物质、脑腓吠及神经降压肽水平的研究[J]．中国老年学杂志，1998，18(1)：16．
[28] 樊贵，牛春雨，韩敏，等．降钙素基因相关肽对大鼠肠系膜微循环的作用[J]．微循环学杂志，1998，8(1)：13-15．
[29] 迟学栋．急性心肌梗塞患者血浆内皮素及降钙素基因相关肽的动态变化及其意义．北京医科大学学报，1993，5：371
[30] 李兆萍，范新民，唐朝枢，等．降钙素基因相关肽对缺血心肌细胞的保护作用．北京医科大学学报，1988，20：320
[31] 黄振平，鲍正毅，丁世忠，等．冠心病患者血浆降钙素基因相关肽水平的临床观察[J]．中国老年学杂志，1998，18(5)：278．
[32] The joint European Society of Cardiology/American College of Cardiology Committee. Myocardial Infarction Redefined-A Consensus Document of The Joint European Society of Cardiology/American College of Cardiology committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol, 2000,36(3): 959-969.
[33] Ryan TJ, Anderson JL, Antman EM, et al. Acc/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Force on Practice Guidclines(Committee on Managcment of Acute Myocardial Infarction)J Am Coll Cardial, 1996,28: 1328-1428.
[34] 马长生 2003年欧洲心脏病学会ST段抬高急性心肌梗死的处理指南 心脏病学实践2003年9月 人民卫生出版社
[35] The task Force on the Management of Acute Myocardial Infarction of the European of Cardiology. Management of acute Myocardial Infarction in patients presenting with ST-segment elvevation. European Heart J, 2003,24:28-66.
[36] 史旭波 急性心肌梗死溶栓治疗中的辅助抗栓治疗进展 中国医院用药评价与分析 2003(3)1；60-61
[37] Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N EnglJ M ed, 2000, 342: 145-153.
[38] Ryan TJ, Antman EM, et al. Acc/.AHA guidelines for the management of patients with acute myocardial infarction: 1999 uptate: a report of the American College of Cardiology/American Heart Association Force on Practice Guidelines(Committee on Management of Acute Myocardial Infarction). Available at www.acc.org.
[39] Fitzgerald PJ, Hayasse M, Yeung AC, et al: New approaches and conduits: In situ venous arterialization and coronary artery bypass. Currr Interv Cardial Rep 1999; 1: 127-137.
[40] Tweden KS, Eales F, Cameron JD, et al: Ventriculocoronary artery bypass(VCAB), a novel approach to myocardial revascularization. Heart Surg Forum2000; 3(1):47-55.
[41] Suehiro K, Shimizu J, Yi GH, et al: Direct coronary artey perfusion from the left ventricle. J Thorac Cardiovasc Surg 2001;121:307-315.
[42] Eckstein F, Bonilla L, Meyer B, et al: Sutureless mechanical anstamosis of a saphenous vein graft to a coronary artery with a new connector device. Lancet 2001; 357:931-932.
[43] Sousa JE, Costa MA, Sousa AG, et al .Twayear angiographic and ultrasound follow-up after implantation of sirolimus-eluting stants in human coronary arteries. Culation 2003,107;381-383.
[44] PARK S-J, shim WH, HoDs, et al. Paclitaxel-eluting stent for the prevention of coronary resternosis. N Engl J Med. 2003, 348:1537-1545.
[45] 乔树宾远端保护装置在介入治疗中的应用心脏病学实践 2003 人民卫生出版社
[46] Morishita R, Recent progress in gene therapy for cardiovascular disease. Circulation. 2002;66: 1077-1086.
[47] Vale PR, Losordo DW, Miliken CE, et al. Left ventricular electromechanical mapping to assess efficacy of ph VEGF165 gene transfer therapeutic angiogenesis in chronic myocardial ischemia. Circulation, 2000; 102:965-974.
[48] Jackson KA, Majka SM, et al. Kegeneration of ischemic cardiac muscle and vascular endothelium by adult stem cell. J Clin Invest, 2001;107(11):1395-1402.
[49] Kehat I, Kenyagin-Karsenti D, snir M. Human embryonic stem cell can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest, 2001, 108;407-414.
[50] 石刚 黄芪注射液对冠状动直接作用的研究[J]．中药新药与临床，1999，(1)：64 65．
[51] 杨立新 黄芪注射液在慢性心力衰竭治疗中的作用[J]．上海医药，1996，(2)：17 18．
[52] 曾治宇黄芪对大鼠心肌梗死后左室重构的影响急诊医学 1999年6月第8卷第3期
[53] 陆丰 西洋参叶20S-原人参二醇组皂苷对急性心肌梗死大鼠交感神经递质及肾素-血管紧张素系统的影响中草药2001年第32卷第7期
[54] 杨兴田，．实验动物复苏及缺氧时川芎嗪对心脑的作用[J]．中国急救医学，1997；17(1)：7．
[55] Feng J, Wug, Tang S.The effect soft extra methyl praline on the incidence of arrhythmias and the release of PGI_2 and TXA_2 in the ischemic rat heart [J].Plant a Med, 1999;65(3):268.
[56] Zeng Z,Zhu W, Zhou X, etal. Tetra ethyl pyridine, a chine drug, block coronary raccoons Lincoln beyond the inland decreases plasma end the line 1 levels in experimental animals.[J] J Cardiovascular Pharmacol. 1998: 31Supp
11:S313.
[57] 左保华．丹参制剂和川芎嗪对再灌注心律失常的作用[J]．中国药理与临床，1996；(1)：31．
[58] 王质良，关超然，陈孟勤．川芎嗪对心血管系统的作用[J]．生理科学进展，1992；23(4)：313．
[59] 朱晓琴 川芎嗪对急性心肌梗死大鼠血浆TXB_2、6Keto PGF1α的影响咸宁医学院学报2002年第16卷第3期
[60] 左晓莉 赤芍801治疗冠心病心绞痛的临床观察齐齐哈尔医学院学报2002(23)1
[61] 廖晖 红花注射液对急性心肌缺血大鼠的保护作用及机理探讨中国药房2003(14)5
[62] 王达理 红花水提物抗自由基保护心肌细胞的作用[J] 中国中医基础医学杂志，2001，7(2)：35
[63] 卢健棋 水蛭注射液溶栓治疗急性心肌梗死临床观察中国中西医结合急救杂志2000(5)73
[64] 阎农．栓体舒、尿激酶溶栓治疗急性心肌梗死80例疗效观察．中国中西医结合急救杂志，1998，5(8)：366367．
[65] 牛祝琴，丛月珠主编．水蛭的临床应用．第1版．北京：人民军医出版社，1994．630．
[66] 李红梅．蚯蚓的化学成分和药理作用研究[J]．1995，18：(9)．
[67] 卫泽华．地龙注射液治疗不稳定型心绞痛疗效观察．中医药研究2002(4)49
[68] 刘亚平 川参桃红汤治疗冠心病心绞痛60例 陕西中医2002(23)8
[69] 李建 复方丹参滴丸对急性心肌梗死左心室重构的影响天津药学2003．2(15)1．
[70] 幸志强等．丹参对冠心病患者血清脂质过氧化反应及超氧化物歧化酶的影响．中国中西医结合杂志，1996，16(5)：287
[71] 张恬．高血压左室肥厚及其药物逆转．国外医学．心血管分册，1999．26(5)：275
[72] 黄英 开搏通对心肌梗死大鼠胶原生化改建影响的研究中国病理生理杂志1996．12(4)：341～344。
[73] 刘子泉 高血压性心肌肥大逆转过程心肌胶原的变化．解放军预防医学杂志
2003年4月第21卷第2期105～108
[74] 唐震宇 阿司匹林对大鼠脑缺血再灌注损伤的影响广州医学院学报2002，9(3)9-11
[75] 吕雄文．卡托普利和低剂量阿司匹林相互作用对心衰大鼠左室重建的影响中国医院药学杂志 2002 11(1)656～658
[76] 徐淑云，卞如濂，陈修．药理实验方法学[M]．北京：人民卫生出版社，2002．1042-1058．
[77] 汤健，丁金凤，唐朝枢．心血管疾病基础与临床[M]．北京：北京医科大学、中国协和医科大学联合出版社，1990．166～190．
[78] Chert D, Krasinski K, Sylvester, et al. Down-regulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in VSMC by P27, an inhibitor of neointima formation in the rat cortid artery. J. Clin Invest 1997,99:2334-2341.
[79] Gallo R, Padurean A, Jayaramen T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999,99:2164～2170.
[80] Marx SO, jayaraman T, GOLO, Marks AR, Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ. Res. 1995, 76: 412-417.
[81] 胡大—心脏病学实践2003人民卫生出版社
[82] Morales PA, Heuser RR.Embolic protection devices. J Interven Cardiol. 2002,15:485～490.
[83] Marco J, Serruys P, Biamino G. The paris course on revascularization.2002,132～138.
[84] 陈鸣，王士雯．冠状动脉的内皮功能障碍[J]．国外医学老年医学分册，1996，17(5)：196-198．
[85] 曹润武，蔡俊坚，张凯伦．内皮素与心肌缺血再灌注损伤[J]．国外医学·生理、病理科学与临床分册，1998，18(2)：135-137．
[86] 张亚东，陈彤延，胡小琴．内皮细胞松驰因子的病理生理及有关治疗[J]．中国循环杂志，1996，11(2)：126—127．
[87] 唐巍 抗凝护心Ⅱ号对急性心肌梗死后大鼠的保护及治疗作用研究，天津药
学，2001．10(13)：5
[88] 闫晓霞硕士答辩论文抗凝护心Ⅱ号对大鼠急性心肌梗死保护作用研究 2001 4
[2] Vos J, Roygrok PN,de Feyter PJ Progression and regression of coronary atherosclerosis:a review of trials by quantitative angioplasty. In: Fuster V. Syndromes of atherosclerosis:correlations of clinical imaging and pathology. ArmonkNY:Futura Publishing. 1996,437-453.
[3] Casscells W, NaghaviM,WillersonJT, Vulnerableatherosclerosisplague:amultifocal disease. Circulation.2003,107:2072-2075.
[4] LibbyP, Molecularbases of the acute coronary Sydroms. Circulation. 1995, 91:2844-2850.
[5] FalkE, ShahPK, Fuster V, Coronaryplaque disrupion. Circulation.1996,92:657-671.
[6] Qiao JH, Fishbein MC, The severity of coronary atherosclerosis at sites of plaque rupture with occlusive thrombosis.J Am Coll Cardiol, 1991,17:1139-1142.
[7] Buffor A,Biasucci LM, Liuzzo G, et al .Widespread coronary inflammation in unstable angina. N Engl J Med, 2002,347:5-12.
[8] Lendon, Davis MJ, Born GV, et al. Atherosclerotic plaque caps are locally weakened when macrophage density is increased. Atherosis,1991,87:87-90.
[9] 白江涛 基质金属蛋白酶与心血管疾病心血管病学进展2003(24)1
[10] Etoht, Joffsc, Deschamps AI, etal. Myocardial andinterstitial matrix metal loprote einase acitvity after acute myocardial infarction inpigs.[J].Am J Physiol Heart Circ Physiol,2001,281 (3)987～994.
[11] Okaday,Narak,Kawamurak.Localization of matrix metal loproteinase9(92Kdage latinase/type Ⅳ collagenase=gelatinaseB) inosteoclasts: implications for bone resorption[J].Lab Invest, 1995,72:311 322.
[12] Aimes RT, Quigley JP. Matrix talloproteinase2 is an insterstitial collagenase: inhibitor free enzymecatalyze the cleavagc of collagen fibrils and soluble native
type Ⅰ collagen generating the special 3/4 and 1/4 length fragments.[J].J Biol Chem, 1995,270:5872 5876.
[13] Kahari VM, Saarial ho KereU.Matrix metalloproteinase in skin[J]. exp Dermatol, 1997,6:199 213.
[14] Malik N,Green field BW, WahlAF, etal.Activation of human monocytes through CD40 induces matrix metalloproteinase[J].J Immunol,1996,156:3952 3960.
[15] Schonbeck U, Mach F, Sukhova G K,etal.Regulation of matrix metalloproteinase expression in human vascular smooth muscle cell sby T lymphocytes. [J]. Circres,-1997, 81:448 454.
[16] TyagiSC, Matsubara L, Weber KT, etal.Direct extraction and estimation of collagenases activity byzymography in micro quantities of rat myocardium and uterus.[J]Clin Biochem ,1993,26:191 198.
[17] Cleut jens JPM, K and ala JC, Guarda E, etal.Regulation of collagen degradation in the rat myocardium after infarction[J] J Mol Cell Cardiol,1994,27:1281 1292.
[18] Coker MS, Thomas CV, Doscher MA.Matrixmetalloproteinase expression and activity in adult ventricular myocytes: influence of baser men membrane adhension[J](Abstract).Circulatoin, 1997,96: 689.
[19] WeismanHF, B bush DE,Mannisi JA,etal.Cellular mechanisms of myocardial expension. [J]. Circulation, 1988,78:186 201.
[20] PfefferMA, Braun WaldE.Ventricular remodellin gafter myocardial infarction: experimental observations and clinical implication. [J]. Circulation, 1990, 81: 1161-1172.
[21] Loftus IM.Naylor AR,Good all S,et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques: a potential role in acute plaque disruption. Stroke, 2000,31:40-47.
[22] Heymans S.Luttun A,Nuyens D,etaI.Inhibition of plasm inogen activators or matrix metalloproteinase prevent cardia crupture but impairs the rape uicangio genesis and causes cardiac failure.[J].Nat Med,1999,10:1135 1142.
[23] Ducharme A, Frantz S, Aikawa M, etal. Targeted delection of matrix
metalloproteinase 9 atteunates left ventricular enlargement and collagen accumulation after, experimental myocardial infarction.[J].J Clin Invest. 2000, 106: 55 62.
[24] Amara SG, Jonas V, Rosenfeld MG, etal.Alternative RNA process in gincalcitonin gene expression gene rates mRNA sencoding different polypeptide products. Nature, 1982, 298:240
[25] 张明 急性心肌梗死诊断和治疗新概念 心血管康复医学杂志 2002(4)2：102～109
[26] 迟东升，吾柏铭，洪小苏，等．急性心肌梗死患者血浆降钙素基因相关肽含量变化及尿激酶溶栓治疗对其影响的观察[J]．中国危重病急救医学，2000，12(3)：169．
[27] 黄振平，林莲初，鲍正毅，等．冠心病血浆神经肽Y，降钙素基因相关肽、P物质、脑腓吠及神经降压肽水平的研究[J]．中国老年学杂志，1998，18(1)：16．
[28] 樊贵，牛春雨，韩敏，等．降钙素基因相关肽对大鼠肠系膜微循环的作用[J]．微循环学杂志，1998，8(1)：13-15．
[29] 迟学栋．急性心肌梗塞患者血浆内皮素及降钙素基因相关肽的动态变化及其意义．北京医科大学学报，1993，5：371
[30] 李兆萍，范新民，唐朝枢，等．降钙素基因相关肽对缺血心肌细胞的保护作用．北京医科大学学报，1988，20：320
[31] 黄振平，鲍正毅，丁世忠，等．冠心病患者血浆降钙素基因相关肽水平的临床观察[J]．中国老年学杂志，1998，18(5)：278．
[32] The joint European Society of Cardiology/American College of Cardiology Committee. Myocardial Infarction Redefined-A Consensus Document of The Joint European Society of Cardiology/American College of Cardiology committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol, 2000,36(3): 959-969.
[33] Ryan TJ, Anderson JL, Antman EM, et al. Acc/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Force on Practice Guidclines(Committee on Managcment of Acute Myocardial Infarction)J Am Coll Cardial, 1996,28: 1328-1428.
[34] 马长生 2003年欧洲心脏病学会ST段抬高急性心肌梗死的处理指南 心脏病学实践2003年9月 人民卫生出版社
[35] The task Force on the Management of Acute Myocardial Infarction of the European of Cardiology. Management of acute Myocardial Infarction in patients presenting with ST-segment elvevation. European Heart J, 2003,24:28-66.
[36] 史旭波 急性心肌梗死溶栓治疗中的辅助抗栓治疗进展 中国医院用药评价与分析 2003(3)1；60-61
[37] Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N EnglJ M ed, 2000, 342: 145-153.
[38] Ryan TJ, Antman EM, et al. Acc/.AHA guidelines for the management of patients with acute myocardial infarction: 1999 uptate: a report of the American College of Cardiology/American Heart Association Force on Practice Guidelines(Committee on Management of Acute Myocardial Infarction). Available at www.acc.org.
[39] Fitzgerald PJ, Hayasse M, Yeung AC, et al: New approaches and conduits: In situ venous arterialization and coronary artery bypass. Currr Interv Cardial Rep 1999; 1: 127-137.
[40] Tweden KS, Eales F, Cameron JD, et al: Ventriculocoronary artery bypass(VCAB), a novel approach to myocardial revascularization. Heart Surg Forum2000; 3(1):47-55.
[41] Suehiro K, Shimizu J, Yi GH, et al: Direct coronary artey perfusion from the left ventricle. J Thorac Cardiovasc Surg 2001;121:307-315.
[42] Eckstein F, Bonilla L, Meyer B, et al: Sutureless mechanical anstamosis of a saphenous vein graft to a coronary artery with a new connector device. Lancet 2001; 357:931-932.
[43] Sousa JE, Costa MA, Sousa AG, et al .Twayear angiographic and ultrasound follow-up after implantation of sirolimus-eluting stants in human coronary arteries. Culation 2003,107;381-383.
[44] PARK S-J, shim WH, HoDs, et al. Paclitaxel-eluting stent for the prevention of coronary resternosis. N Engl J Med. 2003, 348:1537-1545.
[45] 乔树宾远端保护装置在介入治疗中的应用心脏病学实践 2003 人民卫生出版社
[46] Morishita R, Recent progress in gene therapy for cardiovascular disease. Circulation. 2002;66: 1077-1086.
[47] Vale PR, Losordo DW, Miliken CE, et al. Left ventricular electromechanical mapping to assess efficacy of ph VEGF165 gene transfer therapeutic angiogenesis in chronic myocardial ischemia. Circulation, 2000; 102:965-974.
[48] Jackson KA, Majka SM, et al. Kegeneration of ischemic cardiac muscle and vascular endothelium by adult stem cell. J Clin Invest, 2001;107(11):1395-1402.
[49] Kehat I, Kenyagin-Karsenti D, snir M. Human embryonic stem cell can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest, 2001, 108;407-414.
[50] 石刚 黄芪注射液对冠状动直接作用的研究[J]．中药新药与临床，1999，(1)：64 65．
[51] 杨立新 黄芪注射液在慢性心力衰竭治疗中的作用[J]．上海医药，1996，(2)：17 18．
[52] 曾治宇黄芪对大鼠心肌梗死后左室重构的影响急诊医学 1999年6月第8卷第3期
[53] 陆丰 西洋参叶20S-原人参二醇组皂苷对急性心肌梗死大鼠交感神经递质及肾素-血管紧张素系统的影响中草药2001年第32卷第7期
[54] 杨兴田，．实验动物复苏及缺氧时川芎嗪对心脑的作用[J]．中国急救医学，1997；17(1)：7．
[55] Feng J, Wug, Tang S.The effect soft extra methyl praline on the incidence of arrhythmias and the release of PGI_2 and TXA_2 in the ischemic rat heart [J].Plant a Med, 1999;65(3):268.
[56] Zeng Z,Zhu W, Zhou X, etal. Tetra ethyl pyridine, a chine drug, block coronary raccoons Lincoln beyond the inland decreases plasma end the line 1 levels in experimental animals.[J] J Cardiovascular Pharmacol. 1998: 31Supp
11:S313.
[57] 左保华．丹参制剂和川芎嗪对再灌注心律失常的作用[J]．中国药理与临床，1996；(1)：31．
[58] 王质良，关超然，陈孟勤．川芎嗪对心血管系统的作用[J]．生理科学进展，1992；23(4)：313．
[59] 朱晓琴 川芎嗪对急性心肌梗死大鼠血浆TXB_2、6Keto PGF1α的影响咸宁医学院学报2002年第16卷第3期
[60] 左晓莉 赤芍801治疗冠心病心绞痛的临床观察齐齐哈尔医学院学报2002(23)1
[61] 廖晖 红花注射液对急性心肌缺血大鼠的保护作用及机理探讨中国药房2003(14)5
[62] 王达理 红花水提物抗自由基保护心肌细胞的作用[J] 中国中医基础医学杂志，2001，7(2)：35
[63] 卢健棋 水蛭注射液溶栓治疗急性心肌梗死临床观察中国中西医结合急救杂志2000(5)73
[64] 阎农．栓体舒、尿激酶溶栓治疗急性心肌梗死80例疗效观察．中国中西医结合急救杂志，1998，5(8)：366367．
[65] 牛祝琴，丛月珠主编．水蛭的临床应用．第1版．北京：人民军医出版社，1994．630．
[66] 李红梅．蚯蚓的化学成分和药理作用研究[J]．1995，18：(9)．
[67] 卫泽华．地龙注射液治疗不稳定型心绞痛疗效观察．中医药研究2002(4)49
[68] 刘亚平 川参桃红汤治疗冠心病心绞痛60例 陕西中医2002(23)8
[69] 李建 复方丹参滴丸对急性心肌梗死左心室重构的影响天津药学2003．2(15)1．
[70] 幸志强等．丹参对冠心病患者血清脂质过氧化反应及超氧化物歧化酶的影响．中国中西医结合杂志，1996，16(5)：287
[71] 张恬．高血压左室肥厚及其药物逆转．国外医学．心血管分册，1999．26(5)：275
[72] 黄英 开搏通对心肌梗死大鼠胶原生化改建影响的研究中国病理生理杂志1996．12(4)：341～344。
[73] 刘子泉 高血压性心肌肥大逆转过程心肌胶原的变化．解放军预防医学杂志
2003年4月第21卷第2期105～108
[74] 唐震宇 阿司匹林对大鼠脑缺血再灌注损伤的影响广州医学院学报2002，9(3)9-11
[75] 吕雄文．卡托普利和低剂量阿司匹林相互作用对心衰大鼠左室重建的影响中国医院药学杂志 2002 11(1)656～658
[76] 徐淑云，卞如濂，陈修．药理实验方法学[M]．北京：人民卫生出版社，2002．1042-1058．
[77] 汤健，丁金凤，唐朝枢．心血管疾病基础与临床[M]．北京：北京医科大学、中国协和医科大学联合出版社，1990．166～190．
[78] Chert D, Krasinski K, Sylvester, et al. Down-regulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in VSMC by P27, an inhibitor of neointima formation in the rat cortid artery. J. Clin Invest 1997,99:2334-2341.
[79] Gallo R, Padurean A, Jayaramen T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999,99:2164～2170.
[80] Marx SO, jayaraman T, GOLO, Marks AR, Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ. Res. 1995, 76: 412-417.
[81] 胡大—心脏病学实践2003人民卫生出版社
[82] Morales PA, Heuser RR.Embolic protection devices. J Interven Cardiol. 2002,15:485～490.
[83] Marco J, Serruys P, Biamino G. The paris course on revascularization.2002,132～138.
[84] 陈鸣，王士雯．冠状动脉的内皮功能障碍[J]．国外医学老年医学分册，1996，17(5)：196-198．
[85] 曹润武，蔡俊坚，张凯伦．内皮素与心肌缺血再灌注损伤[J]．国外医学·生理、病理科学与临床分册，1998，18(2)：135-137．
[86] 张亚东，陈彤延，胡小琴．内皮细胞松驰因子的病理生理及有关治疗[J]．中国循环杂志，1996，11(2)：126—127．
[87] 唐巍 抗凝护心Ⅱ号对急性心肌梗死后大鼠的保护及治疗作用研究，天津药
学，2001．10(13)：5
[88] 闫晓霞硕士答辩论文抗凝护心Ⅱ号对大鼠急性心肌梗死保护作用研究 2001 4