心肌缺血血浆尾加压素Ⅱ变化机制及心肌细胞表达的研究
|
摘要
研究背景：冠心病是当今危害人类健康的常见病。近年来随着医疗技术的发展，处理的方法由单纯的药物治疗发展到溶栓、经皮腔内冠状动脉成形术(PTCA)、支架植入术、冠状动脉旁路术(CABG)、激光再通、心肌打孔等方法。同时人们对心肌缺血病理机制实验和临床研究也在不断的前进和发展。现已明确心血管活性物质在其中起重要的调节作用，其作用机制的研究也趋深入。缩血管因子(内皮素、血管紧张素Ⅱ、去甲肾上腺素)和舒血管因子(降钙素基因相关肽、肾上腺髓质素、心钠肽)等在心肌缺血发生发展的病理生理过程中发挥很重要的作用，观察和研究这些活性物质在心肌缺血中的表达、含量的变化，对于心肌缺血的纠正和防止疾病的进一步发展有重要意义。因此既必要关注各种血管活性物质在心肌缺血中的作用及其之间相关关系，更需要发现和研究新型的血管活性物质在心肌缺血中可能存在的机制。人尾加压素Ⅱ(U-Ⅱ)是一种生长抑素样环形短肽。自从Pearson等从鱼的下垂体中提纯出来，已引起人们的极大关注，最近已从人体中克隆出来。1999年Ames等发现人类尾加压素Ⅱ(hU-Ⅱ)的受体是一种孤立的G蛋白偶联受体GPR14，hU-Ⅱ的受体GPR14的mRNA主要分布在心肌组织，在骨胳肌、丘脑、枕上回、黑质、主动脉、冠状动脉及脐静脉的内皮细胞、冠脉和主动脉的平滑肌细胞亦有不同程度的表达，并观察到hU-Ⅱ是目前所知体内最强的血管活性肽，其缩血管效应是内皮素-1(ET-1)的4-16倍。在病理状态下发现冠状动脉粥样硬化斑块和富含脂质沉积的组织有UⅡ高度表达，提示UⅡ在冠心病、动脉粥样硬化的发病可能有重要意义。随着UⅡ在人体内的生物学作用的进一步揭示，其临床研究也将逐渐深入。近期国内外学者关于缺血
性心脏病与UI工之间的关系有所研究，但不够全面细致，临床和基
础的相关研究结合很少。因此，本课题第一部分研究了冠心病患者
血浆UH的含量变化及其与其他血管活性物质之间的相互关系，证
明冠心病不同心肌缺血程度和临床表现与U1工的含量的变化有一定
的关系，为心肌缺血的程度及其临床预后的判断提供了理论依据和
客观指标。第二部分研究了在急性缺血模型中大鼠心肌组织UH蛋
白的表达，进一步阐明在心肌缺血时UI工分子水平的变化，为临床
的结果提供基础研究的依据。
目的:1、通过研究冠心病患者血浆Un水平的变化，阐明这一
新的血管活性物质在心肌缺血发生发展过程中变化的意义和可能发
挥的作用;2、通过对血浆Un和肾上腺髓质素(adrenomduilin，ADM)
的相关性研究，进一步阐明几种血管活性物质在心肌缺血发生发展
过程中的变化，及其相互作用机理;3、通过大鼠心肌组织的免疫组
化定性分析心肌细胞Un的表达，进一步阐明在急性心肌缺血时Ull
在蛋白质水平如何变化，来推测un来对心肌产生作用。
方法:1、选择50例CAG(冠状动脉脉造影术)证实为冠心病患者和
20例健康体检者进入研究;临床分组:稳定性心绞痛、不稳定性心
绞痛、急性心肌梗死。冠脉造影结果分组(根据2001年ACC/AHA的
冠脉病变分类系统):低危、中危、高危;2、所有研究对象于入院
时当天取肘静脉血2ml，对照组同期取血。行CAG和PCI的患者另取
手术前(穿刺股动脉成功后)和完成手术后即刻的股动脉血。所有
标本抗凝，低温离心，分离血浆置于一70℃冰箱保存:3、采用放射
免疫方法检测U工工、ADM的血浆含量;4、动物模型的制备:结扎大
鼠左冠状动脉前降支，建立急性心肌缺血30分钟、2小时、4小时、
6小时的大鼠缺血模型，血流动力学指标测定后，处死动物，心肌生
理盐水灌注后，4%多聚甲醛灌注，心肌常规石蜡包埋;5、免疫组化
方法检测大鼠急性心肌缺血状态下心肌细胞UH蛋白的表达。
结果:1、健康对照组静脉血浆UH含量为3.70士1.30 pg/m1，
冠心病患者的血浆Ull含量为1.61士1.02 pg/m1，两者有统计学差
异(P=0.000);稳定性心绞痛患者血浆UI工含量为2.62士1.ZOpg/m1，
不稳定心绞痛血浆患者UH含量为1.39士0.80pg/m1，急性心肌梗死
患者血浆UH含量为1.04士0.45 pg/m1，这三组之间的UH含量有
统计学差异(P=0 .004)。
2、冠脉血管病变不同组别中低危组静脉血浆UI工水平均数为1.86
士1.00 pg/ml，中危组为 1.63士1.01 pg/ml，高危组为1.29士1.02
Pg/ml，三者比较无统计学差异(P>0.05)。
3、PT以及支架植入术后，出现再狭窄患者组其血浆UH含量为2.28
士0.94Pg/ml，而非再狭窄病人的血浆UI工含量为1.40士0.96Pg/m1，
两者有统计学差异(P=0 .008)。
4、PTCA治疗前后，其股动脉血浆UH的含量分别为1 .18士1 .14
pg/ml、2.22土1.77 pg/ml，两者有统计学差异(P=0.001)。而ADM
的含量分别为22.55士0.82 pg/ml和22.88士0.84 pg/ml，两者有统
计学差异(P=0.001);
5、冠心病组血浆UI工和ADM的相关性:冠心病患者股动脉血浆Un
和ADM术前分别为1 .32士1 .1 1 pg/ml、22.55士0.82 pg/ml，它们之
间无明显相关关系(r==0.015，P>0 .05);CHD患者经过PTCA术前
后的Ull水平分别为1 .18士1 .1 4 pg/ml、2.22士1.77 pg/ml，ADM
水平分别为22.58土0.81 pg/ml、22.88士0.84 pg/ml，表明经过PCI
治疗后患者Un和ADM的值均是升高的，但经过统计学分析两
Background:
Coronary heart disease (CHD) is the most cardiovascular disease which damaged peoples health in the days. In recent years along with technical development in medical treatment, the processed method be developped from pure medicine to dissolve to bol, percutaneous transluminal coronary angioplasty, stents transplanted, coronary artery bypass grafting (CABG), trans myocardial Laser revascularization(TMLR, myocardial beats bore etc. Experiment and clinical research of myocardial ischemia also be developed. Circulating vasoactive substances play a very importent role in the CHD and myocardial ischemia. Contractile vessel substances (Endothelin , Angiotensn II, noradrenalin )and relaxing vessel substances (Calcition gene related peptide, adrenomedullin, Atrial natriuretic peptide)play a very important function in the the pathologic physiology process of myocardial ischemia. These live materials in myocardial ischemia do good to rectifing myocardial ischemia and preventing the development of heart disease. Ther
efore there is necessity paying attention to the role of every kind of vessel substances and their related relation, and need to find out and study the new vessel substances in the myocardial. Urotensin-II (U-II) is a vasoactive somatostatin-like' cyclic peptide which was originally isolated from fish spinal cords, and which has recently been cloned from man. Here we describe the identification of an orphan human G-protein-coupled receptor homologous to rat GPR14 and expressed predominantly in cardiovascular tissue, which functions as a U-II receptor, human U-II bind to recombinant human GPR14 with high affinity,.Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates. The potency of vasoconstriction of U-II is an order of 4-16 fold magnitude greater than that of endothelin-1, making human U-II the most potent mammalian vasoconstrictor identified so far. Pepole Discovered that there is a high expression of
UII in the part of coronary artery atherosclerosis. The study means UII may have effection on the development of coronary artery atherosclerosis.The biologic characteristic and distribution of UII and its receptor(UT-II)
prvide basis of cardiovascular modulation, which showed that Ullmay be a role in prognosis of cardiovascular diseases. With the more study of biologic characteristic of UII, the clinical research also be gradually thorough. Domestic and international scholar in near period have studied relation between CHD and UII, but it is not enough meticulous completely. Furthermore, the combination research of clinical and basic is a few . Therefore, the first part of the study invetigated the variety of blood plasma UII of patients with CHD and the correlation between UII and other vessel substances .It proves that these vasoactive substances in patients with CHD .Although their changes are not the same, they participate in compensatory regulation of CHD, so it may provide theory basis and objective guideline for diagnosis and treatment of CHD. The second part studies the expression of UII in model of mouse with AMI. it provide the basis of the foundation research for the clinical result.
Objective:
1. We study changes of plasma levels of urotensin II in patients ith CHD and our aim is to illustrate clinical signification and action of urotendin II.
2. By studying the relationship between urotensin II and the 20 peptides of proadrenomdullin N- terminal, we can further clarify that the changes of these vessel substances and their action in the process of myocardial ischemia and its interaction mechanism.
3. We want to illuminate action during acute myocardial ischemia by qualitative analyzing the expression of UII in myocardial cell.
Methods:
1. Fifty patients with coronary heart disease(CHD) who coronary angiography indicated coronary stenosis and twenty healths were studied; Clinical group:the stable angina, unstable angina, AMI. coronary vessel cha
性心脏病与UI工之间的关系有所研究，但不够全面细致，临床和基
础的相关研究结合很少。因此，本课题第一部分研究了冠心病患者
血浆UH的含量变化及其与其他血管活性物质之间的相互关系，证
明冠心病不同心肌缺血程度和临床表现与U1工的含量的变化有一定
的关系，为心肌缺血的程度及其临床预后的判断提供了理论依据和
客观指标。第二部分研究了在急性缺血模型中大鼠心肌组织UH蛋
白的表达，进一步阐明在心肌缺血时UI工分子水平的变化，为临床
的结果提供基础研究的依据。
目的:1、通过研究冠心病患者血浆Un水平的变化，阐明这一
新的血管活性物质在心肌缺血发生发展过程中变化的意义和可能发
挥的作用;2、通过对血浆Un和肾上腺髓质素(adrenomduilin，ADM)
的相关性研究，进一步阐明几种血管活性物质在心肌缺血发生发展
过程中的变化，及其相互作用机理;3、通过大鼠心肌组织的免疫组
化定性分析心肌细胞Un的表达，进一步阐明在急性心肌缺血时Ull
在蛋白质水平如何变化，来推测un来对心肌产生作用。
方法:1、选择50例CAG(冠状动脉脉造影术)证实为冠心病患者和
20例健康体检者进入研究;临床分组:稳定性心绞痛、不稳定性心
绞痛、急性心肌梗死。冠脉造影结果分组(根据2001年ACC/AHA的
冠脉病变分类系统):低危、中危、高危;2、所有研究对象于入院
时当天取肘静脉血2ml，对照组同期取血。行CAG和PCI的患者另取
手术前(穿刺股动脉成功后)和完成手术后即刻的股动脉血。所有
标本抗凝，低温离心，分离血浆置于一70℃冰箱保存:3、采用放射
免疫方法检测U工工、ADM的血浆含量;4、动物模型的制备:结扎大
鼠左冠状动脉前降支，建立急性心肌缺血30分钟、2小时、4小时、
6小时的大鼠缺血模型，血流动力学指标测定后，处死动物，心肌生
理盐水灌注后，4%多聚甲醛灌注，心肌常规石蜡包埋;5、免疫组化
方法检测大鼠急性心肌缺血状态下心肌细胞UH蛋白的表达。
结果:1、健康对照组静脉血浆UH含量为3.70士1.30 pg/m1，
冠心病患者的血浆Ull含量为1.61士1.02 pg/m1，两者有统计学差
异(P=0.000);稳定性心绞痛患者血浆UI工含量为2.62士1.ZOpg/m1，
不稳定心绞痛血浆患者UH含量为1.39士0.80pg/m1，急性心肌梗死
患者血浆UH含量为1.04士0.45 pg/m1，这三组之间的UH含量有
统计学差异(P=0 .004)。
2、冠脉血管病变不同组别中低危组静脉血浆UI工水平均数为1.86
士1.00 pg/ml，中危组为 1.63士1.01 pg/ml，高危组为1.29士1.02
Pg/ml，三者比较无统计学差异(P>0.05)。
3、PT以及支架植入术后，出现再狭窄患者组其血浆UH含量为2.28
士0.94Pg/ml，而非再狭窄病人的血浆UI工含量为1.40士0.96Pg/m1，
两者有统计学差异(P=0 .008)。
4、PTCA治疗前后，其股动脉血浆UH的含量分别为1 .18士1 .14
pg/ml、2.22土1.77 pg/ml，两者有统计学差异(P=0.001)。而ADM
的含量分别为22.55士0.82 pg/ml和22.88士0.84 pg/ml，两者有统
计学差异(P=0.001);
5、冠心病组血浆UI工和ADM的相关性:冠心病患者股动脉血浆Un
和ADM术前分别为1 .32士1 .1 1 pg/ml、22.55士0.82 pg/ml，它们之
间无明显相关关系(r==0.015，P>0 .05);CHD患者经过PTCA术前
后的Ull水平分别为1 .18士1 .1 4 pg/ml、2.22士1.77 pg/ml，ADM
水平分别为22.58土0.81 pg/ml、22.88士0.84 pg/ml，表明经过PCI
治疗后患者Un和ADM的值均是升高的，但经过统计学分析两
Background:
Coronary heart disease (CHD) is the most cardiovascular disease which damaged peoples health in the days. In recent years along with technical development in medical treatment, the processed method be developped from pure medicine to dissolve to bol, percutaneous transluminal coronary angioplasty, stents transplanted, coronary artery bypass grafting (CABG), trans myocardial Laser revascularization(TMLR, myocardial beats bore etc. Experiment and clinical research of myocardial ischemia also be developed. Circulating vasoactive substances play a very importent role in the CHD and myocardial ischemia. Contractile vessel substances (Endothelin , Angiotensn II, noradrenalin )and relaxing vessel substances (Calcition gene related peptide, adrenomedullin, Atrial natriuretic peptide)play a very important function in the the pathologic physiology process of myocardial ischemia. These live materials in myocardial ischemia do good to rectifing myocardial ischemia and preventing the development of heart disease. Ther
efore there is necessity paying attention to the role of every kind of vessel substances and their related relation, and need to find out and study the new vessel substances in the myocardial. Urotensin-II (U-II) is a vasoactive somatostatin-like' cyclic peptide which was originally isolated from fish spinal cords, and which has recently been cloned from man. Here we describe the identification of an orphan human G-protein-coupled receptor homologous to rat GPR14 and expressed predominantly in cardiovascular tissue, which functions as a U-II receptor, human U-II bind to recombinant human GPR14 with high affinity,.Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates. The potency of vasoconstriction of U-II is an order of 4-16 fold magnitude greater than that of endothelin-1, making human U-II the most potent mammalian vasoconstrictor identified so far. Pepole Discovered that there is a high expression of
UII in the part of coronary artery atherosclerosis. The study means UII may have effection on the development of coronary artery atherosclerosis.The biologic characteristic and distribution of UII and its receptor(UT-II)
prvide basis of cardiovascular modulation, which showed that Ullmay be a role in prognosis of cardiovascular diseases. With the more study of biologic characteristic of UII, the clinical research also be gradually thorough. Domestic and international scholar in near period have studied relation between CHD and UII, but it is not enough meticulous completely. Furthermore, the combination research of clinical and basic is a few . Therefore, the first part of the study invetigated the variety of blood plasma UII of patients with CHD and the correlation between UII and other vessel substances .It proves that these vasoactive substances in patients with CHD .Although their changes are not the same, they participate in compensatory regulation of CHD, so it may provide theory basis and objective guideline for diagnosis and treatment of CHD. The second part studies the expression of UII in model of mouse with AMI. it provide the basis of the foundation research for the clinical result.
Objective:
1. We study changes of plasma levels of urotensin II in patients ith CHD and our aim is to illustrate clinical signification and action of urotendin II.
2. By studying the relationship between urotensin II and the 20 peptides of proadrenomdullin N- terminal, we can further clarify that the changes of these vessel substances and their action in the process of myocardial ischemia and its interaction mechanism.
3. We want to illuminate action during acute myocardial ischemia by qualitative analyzing the expression of UII in myocardial cell.
Methods:
1. Fifty patients with coronary heart disease(CHD) who coronary angiography indicated coronary stenosis and twenty healths were studied; Clinical group:the stable angina, unstable angina, AMI. coronary vessel cha
引文
1. Webb DJ. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Endothelin antagonism in heart failure.Circulation. 1995 Dec 15;92(12):3372
2. Lerman A,Edwards BS, Hailer JW etal. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis.N Engl J Med. 1991 Oct 3;325(14):997-1001.
3. ToyookoT,AizawaT,SuzukiNetal. Increased plasma level of endothelin-1 and coronary spasm induction in patients with vasospastic angina pectoris.Circulation. 1991 Feb;83(2):476-83.
4. TomodaH. Plasma endothelin-1 in acute myocardial infarction with heart failure.Am Heart J. 1993 Mar;125(3):667-72.
5．裴建明，臧益民．CGRP和ANP对心肌缺血犬冠脉循环及离体冠脉的影响．中国病理生理杂志，1996，12(1)：37～40．
6. Neal G,Charles S,Graharr J.Effectsofintravenouscallitoningenerelatedpep tideonischemiathresholdandcoronarystenosisseverityinhumans.Cardio vascularResearch, 1993,27:1477～1481.
7．李晓艳．降钙素基因相关肽对人主动脉平滑肌细胞增殖的影响。湖北医科大学学报，1998，19(4)：323～325．
8. Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction.Circulation. 1998 May 19;97(19): 1921-9.
9. Kano H,Kohno M,Yasunart,et al. Adrenomedullin as a novel antiproliferative factor of vascular smooth muscle cells.J Hypertens. 1996 Feb;14(2):209-13.
10. Horio T, Kano H,Yoshihara F, et al. Adrenomedullin as a novel antimigration factor of vascular smooth muscle cells.Circ Res. 1995 Oct;77(4):660-4
11. Cormier Regard S,Neuyen SV,Claycomb WC. Adrenomedullin gene
expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes.J Biol Chem. 1998 Jul 10;273(28):17787-92.
12. Horio T. Nishikimi T,Yoshiharra F,et al Production and secretion of adrenomedullin in cultured rat cardiac myocytes and nonmyocytes: stimulation by interleukin-lbeta and tumor necrosis factor-alpha.Endocrinology. 1998 Nov; 139(11):4576-80
13. Malatino LS, Leonardi C,Stancanelli B,et al. Transient myocardial ischemia stimulates atrial natriuretic factor release.Am Heart J. 1992 Mar; 123(3):693-8.
14．韩树池，林治湖，徐文林，等．冠心病患者心钠素水平与心功能的关系探讨[J]．临床心血管病杂志，1994，10：149～150
15．李淑敏，车试衡，王丽君，等．血浆心钠素水平对冠心病患者心功能的评价[J]．临床心血管病杂志，1990，6：202～204
16．王庆东，邵建华，王培仁．急性心肌梗塞患者血浆心钠素浓度变化及与心功能的关系[J]．山东医科大学学报，1992，30：137～139
17. Harbrecht BG, Stadler J, DemetrisAJetal. Tumor necrosis factor-alpha regulates in vivo nitric oxide synthesis and induces liver injury during endotoxemia. Hepatology. 1994 Oct;20(4 Pt 1):1055-60.
18. RaySG,McMurryJJ,MortorJJetal. Nitric oxide and prostaglandins interact to prevent hepatic damage during murine endotoxemia.Am J Physiol. 1994 Jtm;266(6 Pt 1):G1004-10.
19. Kolmo M,MurakawaK,YokokawaKetal. Prolonged blood pressure elevation after endothelin administration in bilaterally nephrectomized rats.Metabolism. 1989 Aug;38(8):712-3.
20．陈炜，王永志，邢红云，等．冠心病患者血浆血管活性肽的动态变化及意义[J]．铁道医学，1999，27(4)：235．
21．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．
22. shumi Y, Shoji H,Sugo S,et al. Regulation of adrenomedullin production in rat endothelial cells.Endocrinology. 1998 Mar; 139(3):838-46.
23. Bern.H.A et al. Neurohormones from fish tails: the caudal neurosecretory system .I. "Urophysiology" and the caudal neurosecretory ystem of fishes. Recent Prog. Hormone Res. 41,533-552.
24. Coulouarn y,et al. Cloning of eDNA encoding the urotensin Ⅱ precusor in frog and human reveals intense expression of the urotensin Ⅱ gene in motoneurons of the spinal cord. Proc.Natl.Acd.Sci.USA.1998,95:15803-15808
25. Ames RS, Sarau hm, et al. Human urotensin-Ⅱ is a potent vasoconstrictor and agonist for the orphan receptor GPR14.Nature, 1999,401:282-286.
26. Heller J, Schepke M, Neef M et al. Increased urotensin Ⅱ plasma levels in patients with cirrhosis (Comment). April 21 ;2001,18-19.
27. Totesune K, Takahashi K, Arihara Z.et al. Increased plasma urotensin Ⅱ levels in patients with diabetes mellitus (J).Clin Sci 2003; 104(1): 1-5.
28. Richards AM, Nicholls MG, Lainchbury JG, et al. Plasma urotensin liin heart failure(J). Lancet, 2002; 360 (9332): 545-546.
29．钟萍．李志梁．吴宏超等。充血性心力衰竭患者血浆尾加压素Ⅱ变化的临床研究[J]。第一军大学学报，2003 1，23(2)：121-3。
30. Lapp H, Boerrigter G, Costello-Boerrigter LC, et al. Elevated plasma human urotensin-Ⅱ-like immunoreactivity in ischemic cardiomyopathy(J).Int J Cardiol.2004 Mar;94(1):93-7.
31. Gilliany A.Gray, et al. Human urotensin Ⅱ increases coronary perfusion pressure in the isolated rat heart Potentiation by nitric oxide syntuase and cyclooxygenase inhibition. Life Sciences 69 (2001)175-180.
32. Katano,-Y. et al .Vasodilator effect of urotensin Ⅱ, one of the most potent vasoconstricting factors, on rat coronary arteries.Eur-J-Pharmacol.2000 Aug
18;402(1-2):R5-7.
33. Fraser D.Russell et al. Cardiostimulant effects of urotensin-Ⅱ in human heart in vitro.British Journal of Pharmacology (2001)132,5-9.
34．涂晓文，刘映峰，李志梁等．尾加压素Ⅱ在冠状动脉中的表达和冠状动脉粥样硬化(J)．第一军医大学学报，2003，23(6)890-893．
35. Watanabe T, Pakala R, Katagiri T, et al. Synergistic effect of urotensin Ⅱ with mildly oxidized LDL on DNA synthesis in vascular smooth muscle cells[J]. Circulation, 2001 Jul 3, 104(1):16-8.
36．扎拥，贾国良，张玉顺等。内皮素与冠心病患者冠状动脉病变的相关性研究(J)，心脏杂志(chin Heart J)，2001，13(5)：220-223。
37. Russell FD。Meyers D, Galbraith AJ, et al .Elevated plasma levels of human urotensin-Ⅱ immunoreactivity in congestive heart failure[J]. Am J Physiol Heart Circ Physiol, 2003 Oct;, 285(4):H1576-81. Epub 2003 Jun 05.
38. Douglas SA et al.Congestive heart failure and expression of myocardial urotensin Ⅱ. Lancet 2002 Jun 8;359(9322): 1990-7
2. Lerman A,Edwards BS, Hailer JW etal. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis.N Engl J Med. 1991 Oct 3;325(14):997-1001.
3. ToyookoT,AizawaT,SuzukiNetal. Increased plasma level of endothelin-1 and coronary spasm induction in patients with vasospastic angina pectoris.Circulation. 1991 Feb;83(2):476-83.
4. TomodaH. Plasma endothelin-1 in acute myocardial infarction with heart failure.Am Heart J. 1993 Mar;125(3):667-72.
5．裴建明，臧益民．CGRP和ANP对心肌缺血犬冠脉循环及离体冠脉的影响．中国病理生理杂志，1996，12(1)：37～40．
6. Neal G,Charles S,Graharr J.Effectsofintravenouscallitoningenerelatedpep tideonischemiathresholdandcoronarystenosisseverityinhumans.Cardio vascularResearch, 1993,27:1477～1481.
7．李晓艳．降钙素基因相关肽对人主动脉平滑肌细胞增殖的影响。湖北医科大学学报，1998，19(4)：323～325．
8. Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction.Circulation. 1998 May 19;97(19): 1921-9.
9. Kano H,Kohno M,Yasunart,et al. Adrenomedullin as a novel antiproliferative factor of vascular smooth muscle cells.J Hypertens. 1996 Feb;14(2):209-13.
10. Horio T, Kano H,Yoshihara F, et al. Adrenomedullin as a novel antimigration factor of vascular smooth muscle cells.Circ Res. 1995 Oct;77(4):660-4
11. Cormier Regard S,Neuyen SV,Claycomb WC. Adrenomedullin gene
expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes.J Biol Chem. 1998 Jul 10;273(28):17787-92.
12. Horio T. Nishikimi T,Yoshiharra F,et al Production and secretion of adrenomedullin in cultured rat cardiac myocytes and nonmyocytes: stimulation by interleukin-lbeta and tumor necrosis factor-alpha.Endocrinology. 1998 Nov; 139(11):4576-80
13. Malatino LS, Leonardi C,Stancanelli B,et al. Transient myocardial ischemia stimulates atrial natriuretic factor release.Am Heart J. 1992 Mar; 123(3):693-8.
14．韩树池，林治湖，徐文林，等．冠心病患者心钠素水平与心功能的关系探讨[J]．临床心血管病杂志，1994，10：149～150
15．李淑敏，车试衡，王丽君，等．血浆心钠素水平对冠心病患者心功能的评价[J]．临床心血管病杂志，1990，6：202～204
16．王庆东，邵建华，王培仁．急性心肌梗塞患者血浆心钠素浓度变化及与心功能的关系[J]．山东医科大学学报，1992，30：137～139
17. Harbrecht BG, Stadler J, DemetrisAJetal. Tumor necrosis factor-alpha regulates in vivo nitric oxide synthesis and induces liver injury during endotoxemia. Hepatology. 1994 Oct;20(4 Pt 1):1055-60.
18. RaySG,McMurryJJ,MortorJJetal. Nitric oxide and prostaglandins interact to prevent hepatic damage during murine endotoxemia.Am J Physiol. 1994 Jtm;266(6 Pt 1):G1004-10.
19. Kolmo M,MurakawaK,YokokawaKetal. Prolonged blood pressure elevation after endothelin administration in bilaterally nephrectomized rats.Metabolism. 1989 Aug;38(8):712-3.
20．陈炜，王永志，邢红云，等．冠心病患者血浆血管活性肽的动态变化及意义[J]．铁道医学，1999，27(4)：235．
21．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．
22. shumi Y, Shoji H,Sugo S,et al. Regulation of adrenomedullin production in rat endothelial cells.Endocrinology. 1998 Mar; 139(3):838-46.
23. Bern.H.A et al. Neurohormones from fish tails: the caudal neurosecretory system .I. "Urophysiology" and the caudal neurosecretory ystem of fishes. Recent Prog. Hormone Res. 41,533-552.
24. Coulouarn y,et al. Cloning of eDNA encoding the urotensin Ⅱ precusor in frog and human reveals intense expression of the urotensin Ⅱ gene in motoneurons of the spinal cord. Proc.Natl.Acd.Sci.USA.1998,95:15803-15808
25. Ames RS, Sarau hm, et al. Human urotensin-Ⅱ is a potent vasoconstrictor and agonist for the orphan receptor GPR14.Nature, 1999,401:282-286.
26. Heller J, Schepke M, Neef M et al. Increased urotensin Ⅱ plasma levels in patients with cirrhosis (Comment). April 21 ;2001,18-19.
27. Totesune K, Takahashi K, Arihara Z.et al. Increased plasma urotensin Ⅱ levels in patients with diabetes mellitus (J).Clin Sci 2003; 104(1): 1-5.
28. Richards AM, Nicholls MG, Lainchbury JG, et al. Plasma urotensin liin heart failure(J). Lancet, 2002; 360 (9332): 545-546.
29．钟萍．李志梁．吴宏超等。充血性心力衰竭患者血浆尾加压素Ⅱ变化的临床研究[J]。第一军大学学报，2003 1，23(2)：121-3。
30. Lapp H, Boerrigter G, Costello-Boerrigter LC, et al. Elevated plasma human urotensin-Ⅱ-like immunoreactivity in ischemic cardiomyopathy(J).Int J Cardiol.2004 Mar;94(1):93-7.
31. Gilliany A.Gray, et al. Human urotensin Ⅱ increases coronary perfusion pressure in the isolated rat heart Potentiation by nitric oxide syntuase and cyclooxygenase inhibition. Life Sciences 69 (2001)175-180.
32. Katano,-Y. et al .Vasodilator effect of urotensin Ⅱ, one of the most potent vasoconstricting factors, on rat coronary arteries.Eur-J-Pharmacol.2000 Aug
18;402(1-2):R5-7.
33. Fraser D.Russell et al. Cardiostimulant effects of urotensin-Ⅱ in human heart in vitro.British Journal of Pharmacology (2001)132,5-9.
34．涂晓文，刘映峰，李志梁等．尾加压素Ⅱ在冠状动脉中的表达和冠状动脉粥样硬化(J)．第一军医大学学报，2003，23(6)890-893．
35. Watanabe T, Pakala R, Katagiri T, et al. Synergistic effect of urotensin Ⅱ with mildly oxidized LDL on DNA synthesis in vascular smooth muscle cells[J]. Circulation, 2001 Jul 3, 104(1):16-8.
36．扎拥，贾国良，张玉顺等。内皮素与冠心病患者冠状动脉病变的相关性研究(J)，心脏杂志(chin Heart J)，2001，13(5)：220-223。
37. Russell FD。Meyers D, Galbraith AJ, et al .Elevated plasma levels of human urotensin-Ⅱ immunoreactivity in congestive heart failure[J]. Am J Physiol Heart Circ Physiol, 2003 Oct;, 285(4):H1576-81. Epub 2003 Jun 05.
38. Douglas SA et al.Congestive heart failure and expression of myocardial urotensin Ⅱ. Lancet 2002 Jun 8;359(9322): 1990-7