大鼠严重烧伤早期RAS对心肌损害的影响及调控研究
|
摘要
烧伤后早期可迅速发生心肌损害。由于心脏的特殊重要性,其损害不仅引起心功能不全,还是诱发或加重休克的重要因素,我们称这一现象为“休克心”。阐明烧伤后迅即发生心肌损害和功能减退的机制,对防治心肌损害和烧伤休克治疗都有重要临床意义。
心脏局部存在有独立的肾素-血管紧张素系统(rennin angiotensin system,RAS),可身合成、释放肾素、血管紧张素。与循环RAS不同,心脏局部RAS采用自分泌,旁分泌等方式只作用于心脏局部,主要参与心肌局部血流量和血管紧张性和心肌收缩力的调节,在维持心血管正常功能活动及心血管疾病的发生、发展过程中起重要的作用。但该系统是否参与烧伤后迅即发生的心肌缺血损伤,尚无系统的研究报道。
本研究观察烧伤早期RAS的主要生物活性成分的变化及其与心肌损伤的影响,同时对RAS进行干预,为揭示烧伤早期心脏损伤的机制和寻找内源性保护措施奠定基础。
材料和方法
1、建立大鼠30%TBSAⅢ°烫伤模型,动态观察烧伤后24h大鼠心肌组织和血清中RAS活性成分变化,了解烧伤早期RAS的激活情况;并同时观察大鼠心肌力学和血流动力学指标,血清中CTn-I的变化。
2、调节RAS系统对烧伤早期大鼠心功能及心肌损害影响:根据第一部分实验选择心脏损伤最重的时相点,利用血管紧张素转化酶抑制剂(ACEi)依那普利拉和Ang(1-7)分别调节ACE-AngII轴和ACE2-Ang(1-7)轴,应用多导信息收集系统观察大鼠心肌力学和血流动力学指标,并检测血清中CTn-I的变化。
3、应用大鼠离体心脏Langendorff灌流系统,以大鼠烧伤血清模拟致伤,通过调节RAS系统观察大鼠心肌力学指标,冠脉流量以及冠脉流出液中的肌酸激酶(CK)、乳酸脱氢酶(LDH)的活性。
4、原代培养SD大鼠心脏微血管内皮细胞,观察调节RAS系统对烧伤血清刺激下大鼠心脏微血管内皮细胞细胞活力、NO、LDH、SOD等指标的变化。
主要结果:
1、大鼠严重烧伤后很快出现心肌损害,于6h心肌力学和血流动力学指标(SP、DP、LVSP、LVEDP及±dp/dtmax)达低谷,心肌损伤指标血清CTn-I达峰值,而大鼠心肌组织和血清中ACE和AngII轴于1h开始升高并于6h达到峰值,心肌组织中ACE2变化不明显。
2、利用血管紧张素转化酶抑制剂(ACEi)依那普利拉和Ang(1-7)分别调节ACE -AngII轴和ACE2 -Ang(1-7)轴,可使伤后6h心肌力学和血流动力学指标(SP、DP、LVSP、LVEDP及±dp/dtmax)明显提升,心肌损伤指标血清CTn-I明显降低。
3、应用烧伤后6h的大鼠血清对大鼠心脏进行Langendorff离体灌流模拟致伤后,离体心脏冠脉流量明显减少,左心功能指标LVSP、±dp/dtmax显著降低,LVEDP显著升高,提示左心功能明显减退;冠脉流出液中CK、LDH的活性亦明显升高,提示出现明显心肌损伤,心肌损伤可能是由于烧伤血清引起RAS激活造成冠脉血流剧减所致。使用依那普利拉和Ang(1-7)可明显增加冠脉流量,降低冠脉流出液中CK、LDH的活性。
4、成功培养了原代SD大鼠CMEC并鉴定,烧伤血清刺激12h后,SD大鼠CMEC细胞活力明显下降,培养液中SOD、NO下降,LDH升高。使用含有依那普利拉和Ang(1-7)的烧伤血清可明显提高CMEC细胞活力及培养液中SOD、NO的水平,降低LDH。
结论:
1、严重烧伤后很快即出现心功能下降和心肌损害,进一步验证了严重烧伤早期缺血缺氧损害的“休克心”学说。
2、作为循环的重要调节系统,烧伤早期RAS的ACE-AngII轴迅速激活,于伤后6h达到峰值,并与心肌损害存在时效关系。而ACE2无明显变化,导致了RAS的ACE2-Ang(1-7)轴和ACE-AngII轴失衡,提示RAS的失衡可能是导致烧伤早期心肌缺血损害的重要因素之一。
3、在烧伤早期,主动调节ACE2-Ang(1-7)轴和ACE-AngII轴的失衡状态可减轻心肌损害,证实了RAS失衡是导致烧伤早期心肌损害重要因素之一。提示在烧伤早期主动调节ACE2 -Ang(1-7)轴和ACE-AngII轴可能成为减轻烧伤早期心肌缺血损害的重要靶点。
4、通过调节RAS可提升烧伤血清离体灌流大鼠心脏的冠脉流量,改善左心功能,减轻心肌损害。提示RAS激活是造成烧伤早期冠脉血流量减少,引发心肌损伤的重要原因。
5、烧伤血清刺激可使SD大鼠CMEC细胞活力明显下降,培养液中SOD、NO下降,LDH升高,引发CMEC损伤。通过使用含有依那普利拉和Ang(1-7)的烧伤血清可明显改善CMEC功能。说明烧伤早期ACE- AngⅡ轴的激活不仅可直接影响心脏血流,还可通过导致CMEC功能损伤引起心肌损害。
Myocardial damage may occur due to severe burn at early stage. Because of the special importance of the heart, its damage may not only cause cardiac dysfunction, but also induce or exacerbate burn shock. Ischemia/hypoxia is the important factor for myocardial damage during early postburn stage.
Local rennin angiotensin system(RAS) existing in heart can synthesize and release rennin angiotensin. Different from circulatory RAS, the local RAS only effects on the heart itself to regulate myocardial regional blood flow, vascular tone and myocardial contractility. However, little is known about the contribution of RAS in myocardial damage during early postburn stage.
The purpose of present study is to observe the changes of RAS components and its effects on heart function and myocardial damage, and to reveal the mechanism of heart damage and endogenous protection at early stage postburn by regulating RAS.
Material and Methods
Both in vivo and in vitro experiments were carried out in the study.
1. In in vivo study, rats inflicting with 30% TBSA of full-thickness burns were used. The changes of RAS bioactive components in 24h postburn, and hemodynamics, myocardial mechanical indices, serum CTn-I level were investigated.
2. Effects on heart function and myocardial damage by using Enalaprilat and Ang(1-7) to regulate the ACE-AngII axis and the ACE2-Ang(1-7) axis were investigated. Hemodynamics, myocardial mechanical indices, serum CTn-I level were assayed.
3. An isolated heart Langendorff perfusion system was established. The isolated heart was inflicted with burn sera. Myocardial mechanical indices, coronary flow(CF) and LDH、CK level in coronary flow fluid were detected.
4. Primary SD rat cardiac microvascular endothelial cells (CMEC) were cultured , stimulated with burn sera. CMEC vitality, NO, LDH and SOD level in culture fluid were assessed.
Results:
1. Myocardial damage occurred soon after severe burn, hemodynamics, myocardial mechanical indices (reflected by LVSP、LVEDP and±dp/dtmax) decreased to the lowest at 6h. Serum CTn-I peaked at 6h. ACE–AngII axis in myocardial and serum reased rapidly at 1h, peaked at 6h postburn. However, myocardial ACE2 was not activated obviously .
2. After using Enalaprilat and Ang(1-7), the hemodynamics, myocardial mechanical indics including LVSP, LVEDP and±dp/dtmax were improved and serum CTn-I decreased obviously.
3. The results of the isolated heart Langendorff perfusion system showed that CF and left cardiac function decreased obviously, and LDH, CK level in coronary flow fluid increased obviously, indicating that decrease of left ventricle function and myocardial damage may cause the decreasing CF after RAS activation. CF increased, and CK, LDH decreased after Enalaprilat and Ang(1-7) treatment.
4. Primary CMEC from SD rat was uccessfully cultured. After stimulated by burn sera for 12h, the vitality of CMEC and levels of SOD, NO in culture fluid were decreased, and LDH increased. Cell vitality and level of SOD, NO in culture fluid increased, and LDH decreased by using burn sera containing Enalaprilat and Ang(1-7).
Conclusion:
1. Heart dysfunction and myocardial damage occurred immediately following severe burns, which further proved the“shock heart”theory of ischemic/hypoxic injury.
2. As the important regulating system of circulation, ACE-AngII axis of RAS was rapidly activated at early stage postburn, which showed time-effect relationship with myocardial damage. But ACE2 was not activated, causing imbalance of ACE2-Ang(1-7) axis and ACE-AngII axis. It was indicated the imbalance of RAS may be one of the important reasons for heart damage. Actively regulating ACE2-Ang(1-7) axis and ACE-AngII axis at early stage postburn may be the important target to lessen myocardial ischemic injury.
3. Myocardial damage was lessened by initiatively regulating the imbalance of ACE2-Ang(1-7) axis and ACE-AngII axis at early stage of severe burn, which indicated the imbalance of RAS was one of the important reasons for heart damage at early stage postburn.
4. By regulating RAS, CF was increased, left ventricle function was improved and myocardial damage was lessened,which imported that decrease of CF caused by RAS activation was the important reason for heart damage.
5. Following burn sera stimulation, vitality of CMEC and level of SOD、NO in culture fluid was decreased, LDH increased. CMEC function was improved after treating with burn sera containing Enalaprilat and Ang(1-7). It is concluded that RAS activation led to heart damage at early stage postburn not only by affecting heart perfusion but also function of endothelial cell.
心脏局部存在有独立的肾素-血管紧张素系统(rennin angiotensin system,RAS),可身合成、释放肾素、血管紧张素。与循环RAS不同,心脏局部RAS采用自分泌,旁分泌等方式只作用于心脏局部,主要参与心肌局部血流量和血管紧张性和心肌收缩力的调节,在维持心血管正常功能活动及心血管疾病的发生、发展过程中起重要的作用。但该系统是否参与烧伤后迅即发生的心肌缺血损伤,尚无系统的研究报道。
本研究观察烧伤早期RAS的主要生物活性成分的变化及其与心肌损伤的影响,同时对RAS进行干预,为揭示烧伤早期心脏损伤的机制和寻找内源性保护措施奠定基础。
材料和方法
1、建立大鼠30%TBSAⅢ°烫伤模型,动态观察烧伤后24h大鼠心肌组织和血清中RAS活性成分变化,了解烧伤早期RAS的激活情况;并同时观察大鼠心肌力学和血流动力学指标,血清中CTn-I的变化。
2、调节RAS系统对烧伤早期大鼠心功能及心肌损害影响:根据第一部分实验选择心脏损伤最重的时相点,利用血管紧张素转化酶抑制剂(ACEi)依那普利拉和Ang(1-7)分别调节ACE-AngII轴和ACE2-Ang(1-7)轴,应用多导信息收集系统观察大鼠心肌力学和血流动力学指标,并检测血清中CTn-I的变化。
3、应用大鼠离体心脏Langendorff灌流系统,以大鼠烧伤血清模拟致伤,通过调节RAS系统观察大鼠心肌力学指标,冠脉流量以及冠脉流出液中的肌酸激酶(CK)、乳酸脱氢酶(LDH)的活性。
4、原代培养SD大鼠心脏微血管内皮细胞,观察调节RAS系统对烧伤血清刺激下大鼠心脏微血管内皮细胞细胞活力、NO、LDH、SOD等指标的变化。
主要结果:
1、大鼠严重烧伤后很快出现心肌损害,于6h心肌力学和血流动力学指标(SP、DP、LVSP、LVEDP及±dp/dtmax)达低谷,心肌损伤指标血清CTn-I达峰值,而大鼠心肌组织和血清中ACE和AngII轴于1h开始升高并于6h达到峰值,心肌组织中ACE2变化不明显。
2、利用血管紧张素转化酶抑制剂(ACEi)依那普利拉和Ang(1-7)分别调节ACE -AngII轴和ACE2 -Ang(1-7)轴,可使伤后6h心肌力学和血流动力学指标(SP、DP、LVSP、LVEDP及±dp/dtmax)明显提升,心肌损伤指标血清CTn-I明显降低。
3、应用烧伤后6h的大鼠血清对大鼠心脏进行Langendorff离体灌流模拟致伤后,离体心脏冠脉流量明显减少,左心功能指标LVSP、±dp/dtmax显著降低,LVEDP显著升高,提示左心功能明显减退;冠脉流出液中CK、LDH的活性亦明显升高,提示出现明显心肌损伤,心肌损伤可能是由于烧伤血清引起RAS激活造成冠脉血流剧减所致。使用依那普利拉和Ang(1-7)可明显增加冠脉流量,降低冠脉流出液中CK、LDH的活性。
4、成功培养了原代SD大鼠CMEC并鉴定,烧伤血清刺激12h后,SD大鼠CMEC细胞活力明显下降,培养液中SOD、NO下降,LDH升高。使用含有依那普利拉和Ang(1-7)的烧伤血清可明显提高CMEC细胞活力及培养液中SOD、NO的水平,降低LDH。
结论:
1、严重烧伤后很快即出现心功能下降和心肌损害,进一步验证了严重烧伤早期缺血缺氧损害的“休克心”学说。
2、作为循环的重要调节系统,烧伤早期RAS的ACE-AngII轴迅速激活,于伤后6h达到峰值,并与心肌损害存在时效关系。而ACE2无明显变化,导致了RAS的ACE2-Ang(1-7)轴和ACE-AngII轴失衡,提示RAS的失衡可能是导致烧伤早期心肌缺血损害的重要因素之一。
3、在烧伤早期,主动调节ACE2-Ang(1-7)轴和ACE-AngII轴的失衡状态可减轻心肌损害,证实了RAS失衡是导致烧伤早期心肌损害重要因素之一。提示在烧伤早期主动调节ACE2 -Ang(1-7)轴和ACE-AngII轴可能成为减轻烧伤早期心肌缺血损害的重要靶点。
4、通过调节RAS可提升烧伤血清离体灌流大鼠心脏的冠脉流量,改善左心功能,减轻心肌损害。提示RAS激活是造成烧伤早期冠脉血流量减少,引发心肌损伤的重要原因。
5、烧伤血清刺激可使SD大鼠CMEC细胞活力明显下降,培养液中SOD、NO下降,LDH升高,引发CMEC损伤。通过使用含有依那普利拉和Ang(1-7)的烧伤血清可明显改善CMEC功能。说明烧伤早期ACE- AngⅡ轴的激活不仅可直接影响心脏血流,还可通过导致CMEC功能损伤引起心肌损害。
Myocardial damage may occur due to severe burn at early stage. Because of the special importance of the heart, its damage may not only cause cardiac dysfunction, but also induce or exacerbate burn shock. Ischemia/hypoxia is the important factor for myocardial damage during early postburn stage.
Local rennin angiotensin system(RAS) existing in heart can synthesize and release rennin angiotensin. Different from circulatory RAS, the local RAS only effects on the heart itself to regulate myocardial regional blood flow, vascular tone and myocardial contractility. However, little is known about the contribution of RAS in myocardial damage during early postburn stage.
The purpose of present study is to observe the changes of RAS components and its effects on heart function and myocardial damage, and to reveal the mechanism of heart damage and endogenous protection at early stage postburn by regulating RAS.
Material and Methods
Both in vivo and in vitro experiments were carried out in the study.
1. In in vivo study, rats inflicting with 30% TBSA of full-thickness burns were used. The changes of RAS bioactive components in 24h postburn, and hemodynamics, myocardial mechanical indices, serum CTn-I level were investigated.
2. Effects on heart function and myocardial damage by using Enalaprilat and Ang(1-7) to regulate the ACE-AngII axis and the ACE2-Ang(1-7) axis were investigated. Hemodynamics, myocardial mechanical indices, serum CTn-I level were assayed.
3. An isolated heart Langendorff perfusion system was established. The isolated heart was inflicted with burn sera. Myocardial mechanical indices, coronary flow(CF) and LDH、CK level in coronary flow fluid were detected.
4. Primary SD rat cardiac microvascular endothelial cells (CMEC) were cultured , stimulated with burn sera. CMEC vitality, NO, LDH and SOD level in culture fluid were assessed.
Results:
1. Myocardial damage occurred soon after severe burn, hemodynamics, myocardial mechanical indices (reflected by LVSP、LVEDP and±dp/dtmax) decreased to the lowest at 6h. Serum CTn-I peaked at 6h. ACE–AngII axis in myocardial and serum reased rapidly at 1h, peaked at 6h postburn. However, myocardial ACE2 was not activated obviously .
2. After using Enalaprilat and Ang(1-7), the hemodynamics, myocardial mechanical indics including LVSP, LVEDP and±dp/dtmax were improved and serum CTn-I decreased obviously.
3. The results of the isolated heart Langendorff perfusion system showed that CF and left cardiac function decreased obviously, and LDH, CK level in coronary flow fluid increased obviously, indicating that decrease of left ventricle function and myocardial damage may cause the decreasing CF after RAS activation. CF increased, and CK, LDH decreased after Enalaprilat and Ang(1-7) treatment.
4. Primary CMEC from SD rat was uccessfully cultured. After stimulated by burn sera for 12h, the vitality of CMEC and levels of SOD, NO in culture fluid were decreased, and LDH increased. Cell vitality and level of SOD, NO in culture fluid increased, and LDH decreased by using burn sera containing Enalaprilat and Ang(1-7).
Conclusion:
1. Heart dysfunction and myocardial damage occurred immediately following severe burns, which further proved the“shock heart”theory of ischemic/hypoxic injury.
2. As the important regulating system of circulation, ACE-AngII axis of RAS was rapidly activated at early stage postburn, which showed time-effect relationship with myocardial damage. But ACE2 was not activated, causing imbalance of ACE2-Ang(1-7) axis and ACE-AngII axis. It was indicated the imbalance of RAS may be one of the important reasons for heart damage. Actively regulating ACE2-Ang(1-7) axis and ACE-AngII axis at early stage postburn may be the important target to lessen myocardial ischemic injury.
3. Myocardial damage was lessened by initiatively regulating the imbalance of ACE2-Ang(1-7) axis and ACE-AngII axis at early stage of severe burn, which indicated the imbalance of RAS was one of the important reasons for heart damage at early stage postburn.
4. By regulating RAS, CF was increased, left ventricle function was improved and myocardial damage was lessened,which imported that decrease of CF caused by RAS activation was the important reason for heart damage.
5. Following burn sera stimulation, vitality of CMEC and level of SOD、NO in culture fluid was decreased, LDH increased. CMEC function was improved after treating with burn sera containing Enalaprilat and Ang(1-7). It is concluded that RAS activation led to heart damage at early stage postburn not only by affecting heart perfusion but also function of endothelial cell.
引文
1.杨宗城。重视创伤后脏器损害的研究[J]。中华创伤杂志,1998,14(1): 4-5。
2.黄跃生,杨宗城,迟路湘,梁晚益,闰柏刚。烧伤后“休克心”的研究[J]。中华烧伤杂志,2000 16(5): 275-278。
3.黄跃生。烧伤后“休克心”与早期损害[J]。中国医师杂志,2002, 4(2): 120-121。
4.黄跃生。重视缺血缺氧与细胞因子在“休克心”发生机制中的作用[J]。中华烧伤杂志,2002,18(5):261-262。
5. Lindpaintner K, N iedermajer H, D rexler I, et al. Left ventricular remodeling after myocardial infaract;Does the cardiac rennin-angio tensin system play a role? [J]. J Cardiovasc Pharmacol, 1992, 20: 341-349.
6. Lindpaintner K, Ganten D. The cardiac renin-angiotensin system[J]. Circ Res, 1991, 68: 905-921.
7. Yamazaki T, Yazaki Y, Z-Kardiol. Molecular basis of cardiac hypertrophy[J]. 2000,89(1): 1-6.
8. Hayashida W, Kihara Y, Yasaka A, et al. Stage-specific differential activation of mitogen- activated protein kinases in hypertrophied and failing rat hearts[J]. J-Mol- Cell-Cardiol, 2001, 33(4): 733-44.
9. Cai H. Harrison D.G. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress[J]. Circ Res, 2000, 87: 840–844.
10. Nickenig G, Harrison D.G. The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I:oxidative stress and atherogenesis[J]. Circulation,2002.105:393–396
11. Tipnis SR,Hooper NM,Hyde R,et al.A human homolog of angiotensin-converting enzyme. cloning and functional expression as a captoprilin sensitive carboxypeptidase.J Biol Chem,2000,275:33238-33243.
12. Oudit GY,Crackower MA ,Backx PH ,et a1. The role of ACE2 in cardiovascular physiology[J] . Trends Cardiovasc Med ,2003 ,13 (1) :93-101.
13. Lambert DW, Hooper NM, Turner AJ. Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system[J]. Biochem Pharmacol. 2008, 75(4): 781-6
14.杨建民,杨宗城,陈发明。大鼠严重烧伤早期心肌局部肾素-血管紧张素系统的变化[J]。中华整形烧伤外科杂志,1998,14(2):15-17。
15.杨建民,杨宗城,陈发明。烧伤早期心肌局部肾素-血管紧张素系统对心脏的作用[J]。中华外科杂志,1996,34(11):66-7。
16.黄跃生,严重烧伤后早期心肌损害的细胞分子机制与防治策略研究进展[J]。中华烧伤杂志,2006,22(3):161-163。
17. Lindpaintner K, N iedermajer H, D rexler I, et al. Left ventricular remodeling after myocardial infaract;Does the cardiac rennin-angio tensin system play a role? [J] J Cardiovasc Pharmacol, 1992, 20: 341-349.
18. Jasmina Varagic, Edward D Frohlich. Local Cardiac Renin–Angiotensin System: Hypertension and Cardiac Failure[J]. Journal of Molecular and Cellular Cardiology, 2002,34(11):1435-1442.
19. Shlomo Keidar, Marielle Kaplan, Aviva Gamliel-Lazarovich, ACE2 of the heart: From angiotensin I to angiotensin (1–7) [J]. Cardiovascular Research, 2007, 73(3):463-469.
20. Sun,Y; Weber, K.T. RAS and connective tissue in the heart[J]. Int-J-Biochem-Cell-Biol, 2003 ,35(6): 919-31.
21. Heeneman,-S; Sluimer,-J-C; Daemen,-M-J. Angiotensin-converting enzyme and vascular remodeling[J]. Circ-Res. 2007; 101(5): 441-54.
22. Suzuki,-H; Frank,-G-D; Utsunomiya,-H; Higuchi,-S; Eguchi,-S. Current understanding of the mechanism and role of ROS in angiotensin II signal transduction[J]. Curr- Pharm- Biotechnol, 2006, 7(2): 81-6.
23. Nakashima H, Suzuki H, Ohtsu H. Angiotensin II regulates vascular and endothelial dysfunction: recent topics of Angiotensin II type-1 receptor signaling in the vasculature[J]. Curr-Vasc-Pharmacol, 2006,4(1): 67-78.
24. TurnerAJ , HooperNM. The angiotensin2 converting enzyme gene family: genomics and pharmacology[J]. Trends Pharmacol, 2002, 23 (4) : 177-183.
25. Vickers C, Hales P, Kaushik V, et al. Hydrolysis of biological pep tides by humanangiotensin converting enzyme2 related carboxypep tidase[J]. J B iol Chem, 2002,277 (17) : 14838-14843.
26. Zisman,-L-S; Meixell,-G-E; Bristow,-M-R; Canver,-C-C. Angiotensin-(1-7) formationin the intact human heart: in vivo dependence on angiotensin II as substrate. Circulation,2003,108(14): 1679-81
27. Bernstein KE. Physiology: Two ACEs and a heart[J]. Nature, 2002, 417(6891): 799-802.
28. Crackower M.A,Sarao R,Oudit G.Y, et a1.angiotensin-converting enzyme 2 is an essential regulator of heart function,2002,417(6891), 822-8.
29. Burrell LM,Risvanis J,Kubota E,et a1 . Myocardial infarction increases ACE2 expression in rat and humans[J].Europearl Heart Journal,2005,26(4):369-375.
30. Meredith P.A. Candesartan cilexetil-a review of effects on cardiovascular complications in hypertension and chronic heart failure[J]. Curr-Med-Res-Opin,2007,23(7): 1693-705.
31.袁春萍吲哒帕胺联合依那普利对自发性高血压大鼠的降压效果[J]。上海交通大学学报(医学版),2007(02): 197-199。
32.赵榆华;迟路湘;陈一茂。血管紧张素Ⅱ诱导乳鼠心肌细胞凋亡的研究[J]。第三军医大学学报,2004,26(20):1819-22。
33. Suzuki Y, Ruiz-Ortega M, Lorenzo O.Inflammation and angiotensin II[J]. Int-J-Biochem -Cell-Biol, 2003, 35(6): 881-900.
34. Fernandes L,Fortes ZB,Nigro D,et al.Potentiation of bradykinin by angiotensin(1-7) on arteriales of spontaneously hypertensive rats studied in vivo[J]. Hypertension, 2001, 37(2): 703-709.
35. Castro C H, SantosR A, FerreiraA J, et al. Evidence for a functional interaction of the angiotensin-(1-7) receptor Mas with AT1 and AT2 receptors in the mouse heart[J]. Hypertension, 2005,46(4): 937-42.
36. Donoghue M, Wakimoto H , Maguire CT ,et al . Heart block,ventriculartachycardia,and sudden death in ACE2 transgenic mice with downregulated connexins[J].J Mol Cell Cardiol, 2003 ,35 (9) :1043-1053.
37. Oudot-A, Vergely-C, Ecarnot-Laubriet-A, Rochette-L. Pharmacological concentration of angiotensin-(1-7) activates NADPH oxidase after ischemia-reperfusion in rat heart through AT1 receptor stimulation.Regul-Pept. 2005, 127(1-3): 101-10.
38.罗向东,杨宗城,黎鳌.烧伤病人血清对培养脐静脉内皮细胞的影响[J].解放军医学杂志,1996,18(5):469-471。
39. Langendorff O. Untersuchungen am uberlebenden saugetierherz[J]. Arch Ges Physiol, 1895, 61: 291-316.
40. Porter W.T. A new method for the study of the isolated mammalian heart [J]. Am J Physiol, 1898 ,1:511-517.
41. Podesser B , Hausleithner V ,Seitelberger R ,et al. New development s in the isolated working heart : a comparision of neonatal ,immature ,and adult rabbit s after sixty minutes of ischemia in respect to hemodynamic and biochemical parameters[J].J Pharmacol Toxicol Methods ,1993 ,30 (4) :189-197.
42. Neely J R ,Liebermeister H ,Battersby EJ , et al1 Effects of pressure development on oxygen consumption by isolated rat heart [J]. Am J Physiol ,1967 ,212 (4) :804-814.
43. Finegan BA , Gandhi M , Clanachan AS. Phentolamine prevent s the adverse effects of adenosine on glycolysis and mechanical function in isolated working rat hearts subjected to antecedent ischemia [J]. J Mol Cell Cardiol ,2000 ,32 (6) :1075-1086.
44.王忠,徐美英,朱文忠,等两种离体心脏灌注模型全心缺血前后左室功能的比较[J]。中华实验外科杂志,2002 ,19 (2) :180。
45.杨建民,杨宗城,陈发明,等。大鼠烧伤后心肌局部肾素一血管紧张素系统的改变[J]。中华整形烧伤外科杂志,1999;15(2):102—104。
46. De Mello W. Effect of extracellular and intracellular angiotensins on heart cell function; on the cardiac renin-angiotensin system[J]. Regul-Pept. 2003,114(2-3): 87-90.
47.张兵钱黄跃生等。依那普利拉对严重烫伤大鼠早期心肌损害的防治作用[J]。中华烧伤杂志,2007,23(5) :335-338。
48.耿红业,主编。实用治疗药物学,第2版[M]。人民卫生出版社,2000:688-700。
49. LinksCohn JN. Reducing cardiovascular risk by blockade of the renin-angiotensin aldosterone system[J]. Adv Ther,2007 ,24(6):1290-304.
50. Castro C H, Santos R A, Ferreira A J. Evidence for a functional interaction of the angiotensin-(1-7) receptor Mas with AT1 and AT2 receptors in the mouse heart. Hypertension[J]. 2005 , 46(4): 937-42.
51. Santos RA, Ferreira AJ. Angiotensin-(1-7) and the renin-angiotensin system[J]. Curr Opin Nephrol Hypertens,2007,16(2):122-8.
52. Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensinsystems[J].Physiol Rev, 2006,86:747–803.
53.冯兵。心肌微血管内皮细胞培养及生物学特性的初步观察[J]。微循环学杂志,2000,10 (3):19～21。
54. Nishida M , Carley WW, Gerrit sen ME , et al . Isolation and characterization of human and rat cardiac microvascular endot helial cells[J]. Am J Physiol , 1993 , 264 (2 Pt 2) : H639～652.
55.迟路湘,杨宗城,吴军,等。大鼠严重烧伤早期心肌细胞膜阴离子位点改变的研究[J]。第三军医大学学报,1998,(1):1-3。
56.杨建民,杨宗城,陈发明,等.大鼠烧伤早期心肌营养性血流的变化与心肌损伤的关系[J].中国微循环,1998;2(3):142-43.
57.迟路湘,杨宗城,王旭,等。细胞内钙稳态失控在缺氧及烧伤血清损伤心肌细胞中的意义[J]。解放军医学杂志,1998,23(2):95-97。
58.迟路湘,杨宗城,王旭,等。烧伤后心肌细胞间隙连接通讯变化的机制研究[J]。第三军医大学学报,1999,21(3):172-174。
59.迟路湘,杨宗城,王旭,等。缺氧、烧伤血清对培养心肌细胞膜生物物理特性影响的实验研究[J]。第三军医大学学报,1999,21(2):75-77。
60. Cigola E, Kajstura J,Li B, et al. Angiotensin II activates programmed myocyte cell death in vitro[J]. Exp Cell Res, 1997, 231: 363～371
61. Nitahara JA, ChengW, liu Y, et al. Intracellular calcium, DNAse activity and myocyte apop tosis in the aging Fischer 344 rats[J]. J Mol Cell Cardiol, 1998, 30: 519～535
62. Pueyo ME, Gonzalez W, Nicoletti A , et al . Angiotensin II stimulates endothelial vascular cell adhesion molecule21 via nuclear factor-kappa B activation induced by intracellularoxidative stress [J] . Arterioscler Thromb Vasc Biol , 2000 ,20(3) :645 - 651.
63. Numagami Y, Zubrow AB , Mishra OP , et al . Lipid free radical generation and brain cell membrane alteration following nitric oxide synthase inhibition during cerebral hypoxia in the newborn piglet [J] . J Neurochem , 1997 ,755(1 - 2) :1542 - 1547.
64. Pryor WA , Squadrito GL. The chemistry of peroxynitrite : a product from the reaction of nitric oxide with superoxide [J] .Am J Physiol , 1995 ,268 (5 Pt 1) :L699 - L722.
65. Flesch M,Cremers B,Kilter H,et al.Exposure of human myoxardium to endotoxin leads to a reduction in cardial contractivity and to gene expression of the inducible nitricoxide synthase[J].circulation,1996,94(1):162-169.
66. Comez L hH,Manni F,La PP,et al.Myocardial contractility is modulated by angotensin II via nitric oxide[J].Hypertension,1996 27(3 pt 2):704-8.
67. Kumar A,Bar R,Wang P,et al.Role of nitric oxide and cGMP in human septic-serum induced depression cardiac myocyte contractility[J]. Am J Physiol,1999,276(1 pt 2):R265-R276.
68. M Godecke A, Molojavyi A, Heger J, et al. Myoglobin protects the heart from iNOS-mediated nitrosative stress[J]. J Biol Chem, 2003, 278(24): 21761-6.
1. Ng KK,Vane JR.Fate of angiotensin I in the circulation[J].Nature,1968,218:144-150.
2. Ng KK,Vane JR.The conversion of angiotensin I to angiotensinII in vivo[J].Naunyn Schmiedebergs Arch Exp Pathol Pharmakol,1968,259:188-189.
3. Rastaldo R,Paolocci N,Chiribiri A,et al.Cytochrome P-450metabolite of arachidonic acid mediates bradykinin-induced nega-tive inotropic effect[J]. Am J Physiol Heart CircPhysiol,2001,280:H2823-H2832.
4. Nicholls MG, Richards AM, Agarwal M. The importance of the reninan-giotensin system in cardiovascular disease [J ] . J Hum Hypertens , 1998 ,12(3) :295-299.
5. Tipnis SR,Hooper NM,Hyde R,et al.A human homolog of angiotensin-converting enzyme.cloning and functional expression as a captoprilin sensitive carboxypeptidase[J]. J Biol Chem,2000,275:33238-33243.
6. Stegbauer J, Vonend O, Oberhauser V. Effects of angiotensin2(1-7) and other bioactive components of the renin2angiotensin systemon vascular resistance and noradrenaline release in rat kidney[J] . J Hypertens , 2003,21(7) : 1 391-1 399.
7. Oudit GY, Crackower MA, Backx PH, et a1. The role of ACE2 in cardiovascular physiology[J] . Trends Cardiovasc Med ,2003,13 (1) :93-101.
8.王江,田颖,聂凌等。心力衰竭患者心肌组织ACE2表达与心功能的关系[J]。局解手术学杂志,2007,16(1) :13-15。
9.王安才,汪俊元,曹晓霞等。自发性高血压大鼠一侧颈动脉去外膜后结构和功能的变化[J]。中国病理生理杂志,2007,23 (2) :311-315。
10. Valdes G, Neves LA, Anton L. Distribution of angiotensin (1-7) and ACE2 in human placentas of normal and pathological pregnancies [J] . Placenta,2006,27(223) :200-207.
11. Santos RAS, Ferreira AJ, Nadu AP, et al . Expression of an angiotensin (1-7) producing fusion protein produces cardioprotective effects in rats[J] . Physiological Genomics , 2004,17 (3) :292-299.
12.何建桂,彭龙云,马虹等。Ang(1-7)预处理减轻大鼠离体心脏缺血再灌注损伤[J ]。中山大学学报(医学科学版) ,2006,27 (5) :515-524。
13.彭龙云,马虹,何建桂等。血管紧张素(1-7)对心肌肥厚大鼠体外心脏缺血再灌注损伤的影响[J]。临床心血管病杂志,2007,23 (1) :62-64。
14. Donoghue M, Wakimoto H, Maguire CT, et al. Heart block,ventriculartachycardia,and sudden death in ACE2 transgenic mice with downregulated connexins[J] . J Mol Cell Cardiol, 2003,35 (9) :1 043-1 053.
15. Fernandes L, Fortes ZB, Nigro D, et al . Potentiation of bradykinin by angiotensin (1-7) on arteriales of spontaneously hypertensive rats studied in vivo[J] . Hypertension ,2001,37 (2):703-709 .
16. Muthalif MM, Benter IF, Uddin MR, et al. Signal transduction mechanism involved in angiotensin (1-7) stimulated arachidonic acid release and prostanoid synthesis in rabbit aortic smooth cells [J] . J Pharmacol Exper Ther,1998,284 (2):388-398 .
17. Soares de Moura R, Resende AC, Emiliano AF, et al . The role of bradykinin , AT2 and angiotensin 1-7 receptors in the EDRF-dependent vasodilator effect of angiotensin II on the isolated mesenteric vascular bed of the rat [J]. Br J Pharmacol,2004,141(5):860- 866.
18. Loot AE , Roks AJM, Henning RH , et al . Angiotensin (1-7) attenuates the development of heart failure after myocardial infarction in rats [J]. Circulation,2002,105 (13):1548- 1550.
19. Gironacci MM, Valera MS, Yujnovsky I , et al. Angiotensin (1-7) inhibitory mechanism of norepinephrine release in hypertensive rats [J] . Hypertension, 2004,44(5) :783-787.
20.张卉,文志斌,何晓凡,等。Ang(1-7)对AngII诱导人脐静脉血管内皮细胞株细胞组织因子表达的影响[J]。中华血液学杂志,2005,26 (9) :557-559。
21. Kucharewicz I, Pawlak R, Matys T, et al. Antithrombotic effect of captopril and losartan is mediated by angiotensin2(1-7) [J]. Hypertension,2002,40 (5) : 774-779.
22. Brosnihan KB, Neves LA, Anton L, et al. Enhanced expression of Ang (1-7) during pregnancy[J]. Braz J Med Biol Res,2004,37 (8) :1255-1262.
23. Lara LS ,Cavalcante F ,Axelband F ,et al Involvement of the GiPoPcGMPP PKGpathway in the AT2 mediated inhibition of outer cortex proximal tubule Na +-ATPase by Ang(1-7) [J] . Biochem J , 2006 ,395 (1) :183-190.
24. Walters PE , Gaspari TA , Widdop RE. Angiotensin (1-7) acts as a vasodepressor agent via angiotensin II type 2 receptors in conscious rats[J].Hypertension, 2005, 45(5) :960-966 .
25. Castro CH , Santos RA , Ferreira AJ . et al . Evidence for a functional interaction of the angiotensin2(1-7) receptor Mas with AT1 and AT2 receptors in the mouse heart [J] . Hypertension ,2005 ,46 (4) :937-942.
26.王安才,李俊,曹蘅,等。Ang(1-7)对自发性高血压大鼠去外膜颈动脉内膜增生的影响[J]。中华临床医学实践杂志,2006 ,5 (4) :333-335。
27. Ishiyama Y,Gallagher PE ,Averill DB ,et a1. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by , blockade of angiotensin II receptors[J] . Hypertension ,2004 ,43 (5) :970-976.
28. BoehmM,Nabel EG. Angiotensin converting enzyme 22a new cardiac regulator[J] . N Engl J Med ,2002 ,347(22) :1 795-1 797.
29. Donoghue M,Wakimoto H ,Maguire CT ,et a1. Heart block , ventriculartachycardia,and sudden death in ACE2 transgenic mice with downregulated connexins[J] . J Mol Cell Cardiol ,2003 ,35(9) :1 043-1 053.
30. Crackower MA ,Sarao R ,Oudit GY,et a1. Angiotensin converting enzyme2 is an essential regulator of heart function [J] . Nature ,2002 ,417 (1) :822-828.
31.许昌声,翁智远,王华军等。SHR、WKY大鼠心、肾及胸主动脉ACE、ACE2表达的差异与高血压的关系[J]。中国比较医学杂志,2006,27(13) :402-407。
32. Strazzullo P , Galletti F. Impact of the renin2angiotensin system on lipid and carbohydrate metabolism[J] . Curr Opin Nephrol Hypertens ,2004 ,13 (3) :325-332.
33.钟久昌,黄东阳,余细勇。高血压大鼠ACE2的表达及其与一氧化氮相关性分析[J ]。高血压杂志,2005 ,13(9) :564-567。
34. Koike G, HoriuchiM, Yamada T, et al. Human type 2 angiotensinⅡrecep torgene: cloned,mapped to the X chromosome, and its mRNA is exp ressed in the human lung. [ J ] Biochem B iophys Res Commun, 1994 , 203 (3) : 1842-1850.
35. de Gasparo M, Catt KJ , Inagami T, et al. International union of pharmacology.XX III. The angiotensinⅡrecep tors [J]. Pharmacol Rev, 2000, 52 ( 3 ) : 415-472.
36. MartinMM, Elton TS. The sequence and genomic organization of the human type 2 angiotensin II recep tor [J]. B iochem B iophys Res Commun, 1995, 209 ( 2 ) : 554-562.
37. HayashidaW, HoriuchiM,Dzau VJ. Intracellular third loop domain of angiotensinⅡtype22 recep tor, role inmediating signal transduction and cellular function[J]. J B iol Chem, 1996, 271 (36) : 21985-21992.
38. L i Z, IwaiM, Wu L, et al. Role of AT2 recep tor in the brain in regulation of blood p ressure and water intake[J]. Am J Physiol Heart Circ Physiol, 2003, 284(1) :H116-H121.
39. Lucius R, Gallinat S,Busche S, et al. Beyond blood p ressure: new roles for angiotensin Ⅱ[J]. CellMol L ife Sci, 1999, 56 (11212) : 1008-1019.
40. Nio Y,Matsubara H,Murasawa S, et al. Regulation of gene transcrip tion of angiotensin Ⅱrecep tor subtypes in myocardial infarction [J]. J Clin Invest, 1995, 95(1) : 46-54.
41. Unger T, Culman J , Gohlke P. AngiotensinⅡrecep tor blockade and end organ protection pharmacological rationale and evidence[J]. J Hypertens Supp l, 1998,16 (7) : s3-s9.
42. Ichiki T,Labosky PA, Shiota C, et al. Effects on blood p ressure and exp loratory behaviour ofmice lacking angiotensinⅡtype22 recep tor[J]. Nature, 1995, 377(6551) : 748-750.
43. Hein L,Barsh GS, Pratt RE, et al. Behavioural and cardiovascular effects of disrup ting the angiotensinⅡtype22 recep tor in mice [J]. Nature, 1995, 377(6551) : 744-747.
44. MunzenmaierDH, Greene AS. Opposing actions of angiotensinⅡon microvascular growth and arterial blood p ressure[J]. Hypertension, 1996, 27 (3 p t 2) :760-765.
45. Arima S, Endo Y, Yaoita H, et al. Possible role of P2450 metabolite of arachidonic acid in vasodilatormechanism of angiotensinⅡtype 2 receptor in the isolated microperfused rabbit afferent arteriole [J]. J Clin Invest, 1997, 100(11) : 2816-2823.
46. Tsutsumi Y,Matsubara H,MasakiH, et al. AngiotensinⅡtype 2 receptor over expression activates the vascular kinin system and causes vasodilation [J]. J Clin Invest, 1999, 104 (7) : 925-935.
47. Siragy HM, Inagami T, Ichiki T, et al. Sustained hypersensitivity to angiotensinⅡand itsmechanism in mice lacking the subtype22 (AT2) angiotensin receptor[J]. Proc NatlAcad SciUSA, 1999, 96 (11) : 6506-6510.
48. Siragy HM, de GasparoM, Carey RM, et al. Angiotensin type 2 receptor mediates valsartan2induced hypotension in conscious rats[J]Hypertension, 2000, 35 (5) : 1074-1077.
49. J iao H, Cui XL, TortiM, et al. Arachidonic acid mediates angiotensinⅡeffectson p21 ras in renal proximal tubular cells via the tyrosine kinase-Shc-Grb2-Sos pathway[J].Proc NatlAcad Sci USA, 1998, 95 (13) : 7417-7421.
50. Henrion D, KubisN,Levy B I. Physiological and pathophysiological functions of the AT(2) subtype recep tor of angiotensinⅡ: from large arteries to the microcirculation [J]. Hypertension, 2001, 38 (5) : 1150-1157.
51. MifuneM, Sasamura H, Shimizu HR, et al. AngiotensinⅡtype 2 receptors stimulate collagen synthesis in cultured vascular smooth muscle cells[J]. Hypertension, 2000, 36 (5) : 845-850.
52. Wu L, IwaiM,Nakagami H, et al. Roles of angiotensinⅡtype 2 recep tor stimulation associated with selective angiotensinⅡtype 1 recep tor blockade with valsartan in the imp rovement of inflammation induced vascular injury[J]. Circulation, 2001, 104 (22) : 2716-2721.
53. VolpeM,MusumeciB, de Paolis P, et al. AngiotensinⅡAT2 recep tor subtype: an up rising frontier in cardiovascular disease [J]. J Hypertens, 2003, 21 ( 8) :1429-1443.
54. Harada K, Komuro I, Shiojima I, et al. Pressure overload induces cardiac hypertrophy in angiotensinⅡtype 1A recep tor knockout mice [J]. Circulation,1998, 97 (19) : 1952-1959.
55. Yang Z,Bove CM, French BA, et al. AngiotensinⅡtype 2 recep tor overexp ression preserves left ventricular function after myocardial infarction [J]. Circulation, 2002, 106 (1) : 106-111.
56. Ichihara S, Senbonmatsu T, Price E J r, et al. Targeted deletion of angiotensinⅡtype 2 recep tor caused cardiac rupture after acute myocardial infarction [J]. Circulation, 2002, 106 (17) : 2244-2249.
57. ZhangM,Ma H,Wang BS, et al. AngiotensinⅡtype 2 recep tor gene polymorphisms and cardiop rotective role in essential hypertension [J]. Heart Vessels, 2006, 21 (2) : 95-101.
58. L iu YH, Yang XP,Victor G, et al. Effects of angiotensin2converting enzyme inhibitors and angiotensinⅡtype 1 recep tor antagonists in ratswith heart failure[J]. J Clin Invest, 1997, 99: 1926-1935.
59. Matsumoto T,Ozono R,Oshima T, et al. Type 2 angiotensinⅡrecep tor (AT2) incardiomyocytes is up regulated in patientswith congestive heart failure (CHF)[J]. Hypertension, 1998, 32 (3) : 630.
60. O ishi Y, Ozono R, Yano Y, et al. Cardiop rotective role of AT2 recep tor in postinfarction left ventricular remodeling[J]. Hypertension, 2003, 41 (3 p t 2) :814-818.
61. Bove CM, Yang Z, GilsonWD, et al. Nitric oxidemediates benefits of angiotensinⅡtype 2 receptor overexp ression during post2infarct remodeling[J]. Hypertension, 2004, 43: 680-685.
62. PittB, Segal R,Martinez FA, et al. Randomised trial of losartan versus cap top rilin patients over 65 with heart failure ( Evaluation of Losartan in the ElderlyStudy, EL ITE) [J]. Lancet, 1997, 349 (9054) : 747-752.
2.黄跃生,杨宗城,迟路湘,梁晚益,闰柏刚。烧伤后“休克心”的研究[J]。中华烧伤杂志,2000 16(5): 275-278。
3.黄跃生。烧伤后“休克心”与早期损害[J]。中国医师杂志,2002, 4(2): 120-121。
4.黄跃生。重视缺血缺氧与细胞因子在“休克心”发生机制中的作用[J]。中华烧伤杂志,2002,18(5):261-262。
5. Lindpaintner K, N iedermajer H, D rexler I, et al. Left ventricular remodeling after myocardial infaract;Does the cardiac rennin-angio tensin system play a role? [J]. J Cardiovasc Pharmacol, 1992, 20: 341-349.
6. Lindpaintner K, Ganten D. The cardiac renin-angiotensin system[J]. Circ Res, 1991, 68: 905-921.
7. Yamazaki T, Yazaki Y, Z-Kardiol. Molecular basis of cardiac hypertrophy[J]. 2000,89(1): 1-6.
8. Hayashida W, Kihara Y, Yasaka A, et al. Stage-specific differential activation of mitogen- activated protein kinases in hypertrophied and failing rat hearts[J]. J-Mol- Cell-Cardiol, 2001, 33(4): 733-44.
9. Cai H. Harrison D.G. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress[J]. Circ Res, 2000, 87: 840–844.
10. Nickenig G, Harrison D.G. The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I:oxidative stress and atherogenesis[J]. Circulation,2002.105:393–396
11. Tipnis SR,Hooper NM,Hyde R,et al.A human homolog of angiotensin-converting enzyme. cloning and functional expression as a captoprilin sensitive carboxypeptidase.J Biol Chem,2000,275:33238-33243.
12. Oudit GY,Crackower MA ,Backx PH ,et a1. The role of ACE2 in cardiovascular physiology[J] . Trends Cardiovasc Med ,2003 ,13 (1) :93-101.
13. Lambert DW, Hooper NM, Turner AJ. Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system[J]. Biochem Pharmacol. 2008, 75(4): 781-6
14.杨建民,杨宗城,陈发明。大鼠严重烧伤早期心肌局部肾素-血管紧张素系统的变化[J]。中华整形烧伤外科杂志,1998,14(2):15-17。
15.杨建民,杨宗城,陈发明。烧伤早期心肌局部肾素-血管紧张素系统对心脏的作用[J]。中华外科杂志,1996,34(11):66-7。
16.黄跃生,严重烧伤后早期心肌损害的细胞分子机制与防治策略研究进展[J]。中华烧伤杂志,2006,22(3):161-163。
17. Lindpaintner K, N iedermajer H, D rexler I, et al. Left ventricular remodeling after myocardial infaract;Does the cardiac rennin-angio tensin system play a role? [J] J Cardiovasc Pharmacol, 1992, 20: 341-349.
18. Jasmina Varagic, Edward D Frohlich. Local Cardiac Renin–Angiotensin System: Hypertension and Cardiac Failure[J]. Journal of Molecular and Cellular Cardiology, 2002,34(11):1435-1442.
19. Shlomo Keidar, Marielle Kaplan, Aviva Gamliel-Lazarovich, ACE2 of the heart: From angiotensin I to angiotensin (1–7) [J]. Cardiovascular Research, 2007, 73(3):463-469.
20. Sun,Y; Weber, K.T. RAS and connective tissue in the heart[J]. Int-J-Biochem-Cell-Biol, 2003 ,35(6): 919-31.
21. Heeneman,-S; Sluimer,-J-C; Daemen,-M-J. Angiotensin-converting enzyme and vascular remodeling[J]. Circ-Res. 2007; 101(5): 441-54.
22. Suzuki,-H; Frank,-G-D; Utsunomiya,-H; Higuchi,-S; Eguchi,-S. Current understanding of the mechanism and role of ROS in angiotensin II signal transduction[J]. Curr- Pharm- Biotechnol, 2006, 7(2): 81-6.
23. Nakashima H, Suzuki H, Ohtsu H. Angiotensin II regulates vascular and endothelial dysfunction: recent topics of Angiotensin II type-1 receptor signaling in the vasculature[J]. Curr-Vasc-Pharmacol, 2006,4(1): 67-78.
24. TurnerAJ , HooperNM. The angiotensin2 converting enzyme gene family: genomics and pharmacology[J]. Trends Pharmacol, 2002, 23 (4) : 177-183.
25. Vickers C, Hales P, Kaushik V, et al. Hydrolysis of biological pep tides by humanangiotensin converting enzyme2 related carboxypep tidase[J]. J B iol Chem, 2002,277 (17) : 14838-14843.
26. Zisman,-L-S; Meixell,-G-E; Bristow,-M-R; Canver,-C-C. Angiotensin-(1-7) formationin the intact human heart: in vivo dependence on angiotensin II as substrate. Circulation,2003,108(14): 1679-81
27. Bernstein KE. Physiology: Two ACEs and a heart[J]. Nature, 2002, 417(6891): 799-802.
28. Crackower M.A,Sarao R,Oudit G.Y, et a1.angiotensin-converting enzyme 2 is an essential regulator of heart function,2002,417(6891), 822-8.
29. Burrell LM,Risvanis J,Kubota E,et a1 . Myocardial infarction increases ACE2 expression in rat and humans[J].Europearl Heart Journal,2005,26(4):369-375.
30. Meredith P.A. Candesartan cilexetil-a review of effects on cardiovascular complications in hypertension and chronic heart failure[J]. Curr-Med-Res-Opin,2007,23(7): 1693-705.
31.袁春萍吲哒帕胺联合依那普利对自发性高血压大鼠的降压效果[J]。上海交通大学学报(医学版),2007(02): 197-199。
32.赵榆华;迟路湘;陈一茂。血管紧张素Ⅱ诱导乳鼠心肌细胞凋亡的研究[J]。第三军医大学学报,2004,26(20):1819-22。
33. Suzuki Y, Ruiz-Ortega M, Lorenzo O.Inflammation and angiotensin II[J]. Int-J-Biochem -Cell-Biol, 2003, 35(6): 881-900.
34. Fernandes L,Fortes ZB,Nigro D,et al.Potentiation of bradykinin by angiotensin(1-7) on arteriales of spontaneously hypertensive rats studied in vivo[J]. Hypertension, 2001, 37(2): 703-709.
35. Castro C H, SantosR A, FerreiraA J, et al. Evidence for a functional interaction of the angiotensin-(1-7) receptor Mas with AT1 and AT2 receptors in the mouse heart[J]. Hypertension, 2005,46(4): 937-42.
36. Donoghue M, Wakimoto H , Maguire CT ,et al . Heart block,ventriculartachycardia,and sudden death in ACE2 transgenic mice with downregulated connexins[J].J Mol Cell Cardiol, 2003 ,35 (9) :1043-1053.
37. Oudot-A, Vergely-C, Ecarnot-Laubriet-A, Rochette-L. Pharmacological concentration of angiotensin-(1-7) activates NADPH oxidase after ischemia-reperfusion in rat heart through AT1 receptor stimulation.Regul-Pept. 2005, 127(1-3): 101-10.
38.罗向东,杨宗城,黎鳌.烧伤病人血清对培养脐静脉内皮细胞的影响[J].解放军医学杂志,1996,18(5):469-471。
39. Langendorff O. Untersuchungen am uberlebenden saugetierherz[J]. Arch Ges Physiol, 1895, 61: 291-316.
40. Porter W.T. A new method for the study of the isolated mammalian heart [J]. Am J Physiol, 1898 ,1:511-517.
41. Podesser B , Hausleithner V ,Seitelberger R ,et al. New development s in the isolated working heart : a comparision of neonatal ,immature ,and adult rabbit s after sixty minutes of ischemia in respect to hemodynamic and biochemical parameters[J].J Pharmacol Toxicol Methods ,1993 ,30 (4) :189-197.
42. Neely J R ,Liebermeister H ,Battersby EJ , et al1 Effects of pressure development on oxygen consumption by isolated rat heart [J]. Am J Physiol ,1967 ,212 (4) :804-814.
43. Finegan BA , Gandhi M , Clanachan AS. Phentolamine prevent s the adverse effects of adenosine on glycolysis and mechanical function in isolated working rat hearts subjected to antecedent ischemia [J]. J Mol Cell Cardiol ,2000 ,32 (6) :1075-1086.
44.王忠,徐美英,朱文忠,等两种离体心脏灌注模型全心缺血前后左室功能的比较[J]。中华实验外科杂志,2002 ,19 (2) :180。
45.杨建民,杨宗城,陈发明,等。大鼠烧伤后心肌局部肾素一血管紧张素系统的改变[J]。中华整形烧伤外科杂志,1999;15(2):102—104。
46. De Mello W. Effect of extracellular and intracellular angiotensins on heart cell function; on the cardiac renin-angiotensin system[J]. Regul-Pept. 2003,114(2-3): 87-90.
47.张兵钱黄跃生等。依那普利拉对严重烫伤大鼠早期心肌损害的防治作用[J]。中华烧伤杂志,2007,23(5) :335-338。
48.耿红业,主编。实用治疗药物学,第2版[M]。人民卫生出版社,2000:688-700。
49. LinksCohn JN. Reducing cardiovascular risk by blockade of the renin-angiotensin aldosterone system[J]. Adv Ther,2007 ,24(6):1290-304.
50. Castro C H, Santos R A, Ferreira A J. Evidence for a functional interaction of the angiotensin-(1-7) receptor Mas with AT1 and AT2 receptors in the mouse heart. Hypertension[J]. 2005 , 46(4): 937-42.
51. Santos RA, Ferreira AJ. Angiotensin-(1-7) and the renin-angiotensin system[J]. Curr Opin Nephrol Hypertens,2007,16(2):122-8.
52. Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensinsystems[J].Physiol Rev, 2006,86:747–803.
53.冯兵。心肌微血管内皮细胞培养及生物学特性的初步观察[J]。微循环学杂志,2000,10 (3):19～21。
54. Nishida M , Carley WW, Gerrit sen ME , et al . Isolation and characterization of human and rat cardiac microvascular endot helial cells[J]. Am J Physiol , 1993 , 264 (2 Pt 2) : H639～652.
55.迟路湘,杨宗城,吴军,等。大鼠严重烧伤早期心肌细胞膜阴离子位点改变的研究[J]。第三军医大学学报,1998,(1):1-3。
56.杨建民,杨宗城,陈发明,等.大鼠烧伤早期心肌营养性血流的变化与心肌损伤的关系[J].中国微循环,1998;2(3):142-43.
57.迟路湘,杨宗城,王旭,等。细胞内钙稳态失控在缺氧及烧伤血清损伤心肌细胞中的意义[J]。解放军医学杂志,1998,23(2):95-97。
58.迟路湘,杨宗城,王旭,等。烧伤后心肌细胞间隙连接通讯变化的机制研究[J]。第三军医大学学报,1999,21(3):172-174。
59.迟路湘,杨宗城,王旭,等。缺氧、烧伤血清对培养心肌细胞膜生物物理特性影响的实验研究[J]。第三军医大学学报,1999,21(2):75-77。
60. Cigola E, Kajstura J,Li B, et al. Angiotensin II activates programmed myocyte cell death in vitro[J]. Exp Cell Res, 1997, 231: 363～371
61. Nitahara JA, ChengW, liu Y, et al. Intracellular calcium, DNAse activity and myocyte apop tosis in the aging Fischer 344 rats[J]. J Mol Cell Cardiol, 1998, 30: 519～535
62. Pueyo ME, Gonzalez W, Nicoletti A , et al . Angiotensin II stimulates endothelial vascular cell adhesion molecule21 via nuclear factor-kappa B activation induced by intracellularoxidative stress [J] . Arterioscler Thromb Vasc Biol , 2000 ,20(3) :645 - 651.
63. Numagami Y, Zubrow AB , Mishra OP , et al . Lipid free radical generation and brain cell membrane alteration following nitric oxide synthase inhibition during cerebral hypoxia in the newborn piglet [J] . J Neurochem , 1997 ,755(1 - 2) :1542 - 1547.
64. Pryor WA , Squadrito GL. The chemistry of peroxynitrite : a product from the reaction of nitric oxide with superoxide [J] .Am J Physiol , 1995 ,268 (5 Pt 1) :L699 - L722.
65. Flesch M,Cremers B,Kilter H,et al.Exposure of human myoxardium to endotoxin leads to a reduction in cardial contractivity and to gene expression of the inducible nitricoxide synthase[J].circulation,1996,94(1):162-169.
66. Comez L hH,Manni F,La PP,et al.Myocardial contractility is modulated by angotensin II via nitric oxide[J].Hypertension,1996 27(3 pt 2):704-8.
67. Kumar A,Bar R,Wang P,et al.Role of nitric oxide and cGMP in human septic-serum induced depression cardiac myocyte contractility[J]. Am J Physiol,1999,276(1 pt 2):R265-R276.
68. M Godecke A, Molojavyi A, Heger J, et al. Myoglobin protects the heart from iNOS-mediated nitrosative stress[J]. J Biol Chem, 2003, 278(24): 21761-6.
1. Ng KK,Vane JR.Fate of angiotensin I in the circulation[J].Nature,1968,218:144-150.
2. Ng KK,Vane JR.The conversion of angiotensin I to angiotensinII in vivo[J].Naunyn Schmiedebergs Arch Exp Pathol Pharmakol,1968,259:188-189.
3. Rastaldo R,Paolocci N,Chiribiri A,et al.Cytochrome P-450metabolite of arachidonic acid mediates bradykinin-induced nega-tive inotropic effect[J]. Am J Physiol Heart CircPhysiol,2001,280:H2823-H2832.
4. Nicholls MG, Richards AM, Agarwal M. The importance of the reninan-giotensin system in cardiovascular disease [J ] . J Hum Hypertens , 1998 ,12(3) :295-299.
5. Tipnis SR,Hooper NM,Hyde R,et al.A human homolog of angiotensin-converting enzyme.cloning and functional expression as a captoprilin sensitive carboxypeptidase[J]. J Biol Chem,2000,275:33238-33243.
6. Stegbauer J, Vonend O, Oberhauser V. Effects of angiotensin2(1-7) and other bioactive components of the renin2angiotensin systemon vascular resistance and noradrenaline release in rat kidney[J] . J Hypertens , 2003,21(7) : 1 391-1 399.
7. Oudit GY, Crackower MA, Backx PH, et a1. The role of ACE2 in cardiovascular physiology[J] . Trends Cardiovasc Med ,2003,13 (1) :93-101.
8.王江,田颖,聂凌等。心力衰竭患者心肌组织ACE2表达与心功能的关系[J]。局解手术学杂志,2007,16(1) :13-15。
9.王安才,汪俊元,曹晓霞等。自发性高血压大鼠一侧颈动脉去外膜后结构和功能的变化[J]。中国病理生理杂志,2007,23 (2) :311-315。
10. Valdes G, Neves LA, Anton L. Distribution of angiotensin (1-7) and ACE2 in human placentas of normal and pathological pregnancies [J] . Placenta,2006,27(223) :200-207.
11. Santos RAS, Ferreira AJ, Nadu AP, et al . Expression of an angiotensin (1-7) producing fusion protein produces cardioprotective effects in rats[J] . Physiological Genomics , 2004,17 (3) :292-299.
12.何建桂,彭龙云,马虹等。Ang(1-7)预处理减轻大鼠离体心脏缺血再灌注损伤[J ]。中山大学学报(医学科学版) ,2006,27 (5) :515-524。
13.彭龙云,马虹,何建桂等。血管紧张素(1-7)对心肌肥厚大鼠体外心脏缺血再灌注损伤的影响[J]。临床心血管病杂志,2007,23 (1) :62-64。
14. Donoghue M, Wakimoto H, Maguire CT, et al. Heart block,ventriculartachycardia,and sudden death in ACE2 transgenic mice with downregulated connexins[J] . J Mol Cell Cardiol, 2003,35 (9) :1 043-1 053.
15. Fernandes L, Fortes ZB, Nigro D, et al . Potentiation of bradykinin by angiotensin (1-7) on arteriales of spontaneously hypertensive rats studied in vivo[J] . Hypertension ,2001,37 (2):703-709 .
16. Muthalif MM, Benter IF, Uddin MR, et al. Signal transduction mechanism involved in angiotensin (1-7) stimulated arachidonic acid release and prostanoid synthesis in rabbit aortic smooth cells [J] . J Pharmacol Exper Ther,1998,284 (2):388-398 .
17. Soares de Moura R, Resende AC, Emiliano AF, et al . The role of bradykinin , AT2 and angiotensin 1-7 receptors in the EDRF-dependent vasodilator effect of angiotensin II on the isolated mesenteric vascular bed of the rat [J]. Br J Pharmacol,2004,141(5):860- 866.
18. Loot AE , Roks AJM, Henning RH , et al . Angiotensin (1-7) attenuates the development of heart failure after myocardial infarction in rats [J]. Circulation,2002,105 (13):1548- 1550.
19. Gironacci MM, Valera MS, Yujnovsky I , et al. Angiotensin (1-7) inhibitory mechanism of norepinephrine release in hypertensive rats [J] . Hypertension, 2004,44(5) :783-787.
20.张卉,文志斌,何晓凡,等。Ang(1-7)对AngII诱导人脐静脉血管内皮细胞株细胞组织因子表达的影响[J]。中华血液学杂志,2005,26 (9) :557-559。
21. Kucharewicz I, Pawlak R, Matys T, et al. Antithrombotic effect of captopril and losartan is mediated by angiotensin2(1-7) [J]. Hypertension,2002,40 (5) : 774-779.
22. Brosnihan KB, Neves LA, Anton L, et al. Enhanced expression of Ang (1-7) during pregnancy[J]. Braz J Med Biol Res,2004,37 (8) :1255-1262.
23. Lara LS ,Cavalcante F ,Axelband F ,et al Involvement of the GiPoPcGMPP PKGpathway in the AT2 mediated inhibition of outer cortex proximal tubule Na +-ATPase by Ang(1-7) [J] . Biochem J , 2006 ,395 (1) :183-190.
24. Walters PE , Gaspari TA , Widdop RE. Angiotensin (1-7) acts as a vasodepressor agent via angiotensin II type 2 receptors in conscious rats[J].Hypertension, 2005, 45(5) :960-966 .
25. Castro CH , Santos RA , Ferreira AJ . et al . Evidence for a functional interaction of the angiotensin2(1-7) receptor Mas with AT1 and AT2 receptors in the mouse heart [J] . Hypertension ,2005 ,46 (4) :937-942.
26.王安才,李俊,曹蘅,等。Ang(1-7)对自发性高血压大鼠去外膜颈动脉内膜增生的影响[J]。中华临床医学实践杂志,2006 ,5 (4) :333-335。
27. Ishiyama Y,Gallagher PE ,Averill DB ,et a1. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by , blockade of angiotensin II receptors[J] . Hypertension ,2004 ,43 (5) :970-976.
28. BoehmM,Nabel EG. Angiotensin converting enzyme 22a new cardiac regulator[J] . N Engl J Med ,2002 ,347(22) :1 795-1 797.
29. Donoghue M,Wakimoto H ,Maguire CT ,et a1. Heart block , ventriculartachycardia,and sudden death in ACE2 transgenic mice with downregulated connexins[J] . J Mol Cell Cardiol ,2003 ,35(9) :1 043-1 053.
30. Crackower MA ,Sarao R ,Oudit GY,et a1. Angiotensin converting enzyme2 is an essential regulator of heart function [J] . Nature ,2002 ,417 (1) :822-828.
31.许昌声,翁智远,王华军等。SHR、WKY大鼠心、肾及胸主动脉ACE、ACE2表达的差异与高血压的关系[J]。中国比较医学杂志,2006,27(13) :402-407。
32. Strazzullo P , Galletti F. Impact of the renin2angiotensin system on lipid and carbohydrate metabolism[J] . Curr Opin Nephrol Hypertens ,2004 ,13 (3) :325-332.
33.钟久昌,黄东阳,余细勇。高血压大鼠ACE2的表达及其与一氧化氮相关性分析[J ]。高血压杂志,2005 ,13(9) :564-567。
34. Koike G, HoriuchiM, Yamada T, et al. Human type 2 angiotensinⅡrecep torgene: cloned,mapped to the X chromosome, and its mRNA is exp ressed in the human lung. [ J ] Biochem B iophys Res Commun, 1994 , 203 (3) : 1842-1850.
35. de Gasparo M, Catt KJ , Inagami T, et al. International union of pharmacology.XX III. The angiotensinⅡrecep tors [J]. Pharmacol Rev, 2000, 52 ( 3 ) : 415-472.
36. MartinMM, Elton TS. The sequence and genomic organization of the human type 2 angiotensin II recep tor [J]. B iochem B iophys Res Commun, 1995, 209 ( 2 ) : 554-562.
37. HayashidaW, HoriuchiM,Dzau VJ. Intracellular third loop domain of angiotensinⅡtype22 recep tor, role inmediating signal transduction and cellular function[J]. J B iol Chem, 1996, 271 (36) : 21985-21992.
38. L i Z, IwaiM, Wu L, et al. Role of AT2 recep tor in the brain in regulation of blood p ressure and water intake[J]. Am J Physiol Heart Circ Physiol, 2003, 284(1) :H116-H121.
39. Lucius R, Gallinat S,Busche S, et al. Beyond blood p ressure: new roles for angiotensin Ⅱ[J]. CellMol L ife Sci, 1999, 56 (11212) : 1008-1019.
40. Nio Y,Matsubara H,Murasawa S, et al. Regulation of gene transcrip tion of angiotensin Ⅱrecep tor subtypes in myocardial infarction [J]. J Clin Invest, 1995, 95(1) : 46-54.
41. Unger T, Culman J , Gohlke P. AngiotensinⅡrecep tor blockade and end organ protection pharmacological rationale and evidence[J]. J Hypertens Supp l, 1998,16 (7) : s3-s9.
42. Ichiki T,Labosky PA, Shiota C, et al. Effects on blood p ressure and exp loratory behaviour ofmice lacking angiotensinⅡtype22 recep tor[J]. Nature, 1995, 377(6551) : 748-750.
43. Hein L,Barsh GS, Pratt RE, et al. Behavioural and cardiovascular effects of disrup ting the angiotensinⅡtype22 recep tor in mice [J]. Nature, 1995, 377(6551) : 744-747.
44. MunzenmaierDH, Greene AS. Opposing actions of angiotensinⅡon microvascular growth and arterial blood p ressure[J]. Hypertension, 1996, 27 (3 p t 2) :760-765.
45. Arima S, Endo Y, Yaoita H, et al. Possible role of P2450 metabolite of arachidonic acid in vasodilatormechanism of angiotensinⅡtype 2 receptor in the isolated microperfused rabbit afferent arteriole [J]. J Clin Invest, 1997, 100(11) : 2816-2823.
46. Tsutsumi Y,Matsubara H,MasakiH, et al. AngiotensinⅡtype 2 receptor over expression activates the vascular kinin system and causes vasodilation [J]. J Clin Invest, 1999, 104 (7) : 925-935.
47. Siragy HM, Inagami T, Ichiki T, et al. Sustained hypersensitivity to angiotensinⅡand itsmechanism in mice lacking the subtype22 (AT2) angiotensin receptor[J]. Proc NatlAcad SciUSA, 1999, 96 (11) : 6506-6510.
48. Siragy HM, de GasparoM, Carey RM, et al. Angiotensin type 2 receptor mediates valsartan2induced hypotension in conscious rats[J]Hypertension, 2000, 35 (5) : 1074-1077.
49. J iao H, Cui XL, TortiM, et al. Arachidonic acid mediates angiotensinⅡeffectson p21 ras in renal proximal tubular cells via the tyrosine kinase-Shc-Grb2-Sos pathway[J].Proc NatlAcad Sci USA, 1998, 95 (13) : 7417-7421.
50. Henrion D, KubisN,Levy B I. Physiological and pathophysiological functions of the AT(2) subtype recep tor of angiotensinⅡ: from large arteries to the microcirculation [J]. Hypertension, 2001, 38 (5) : 1150-1157.
51. MifuneM, Sasamura H, Shimizu HR, et al. AngiotensinⅡtype 2 receptors stimulate collagen synthesis in cultured vascular smooth muscle cells[J]. Hypertension, 2000, 36 (5) : 845-850.
52. Wu L, IwaiM,Nakagami H, et al. Roles of angiotensinⅡtype 2 recep tor stimulation associated with selective angiotensinⅡtype 1 recep tor blockade with valsartan in the imp rovement of inflammation induced vascular injury[J]. Circulation, 2001, 104 (22) : 2716-2721.
53. VolpeM,MusumeciB, de Paolis P, et al. AngiotensinⅡAT2 recep tor subtype: an up rising frontier in cardiovascular disease [J]. J Hypertens, 2003, 21 ( 8) :1429-1443.
54. Harada K, Komuro I, Shiojima I, et al. Pressure overload induces cardiac hypertrophy in angiotensinⅡtype 1A recep tor knockout mice [J]. Circulation,1998, 97 (19) : 1952-1959.
55. Yang Z,Bove CM, French BA, et al. AngiotensinⅡtype 2 recep tor overexp ression preserves left ventricular function after myocardial infarction [J]. Circulation, 2002, 106 (1) : 106-111.
56. Ichihara S, Senbonmatsu T, Price E J r, et al. Targeted deletion of angiotensinⅡtype 2 recep tor caused cardiac rupture after acute myocardial infarction [J]. Circulation, 2002, 106 (17) : 2244-2249.
57. ZhangM,Ma H,Wang BS, et al. AngiotensinⅡtype 2 recep tor gene polymorphisms and cardiop rotective role in essential hypertension [J]. Heart Vessels, 2006, 21 (2) : 95-101.
58. L iu YH, Yang XP,Victor G, et al. Effects of angiotensin2converting enzyme inhibitors and angiotensinⅡtype 1 recep tor antagonists in ratswith heart failure[J]. J Clin Invest, 1997, 99: 1926-1935.
59. Matsumoto T,Ozono R,Oshima T, et al. Type 2 angiotensinⅡrecep tor (AT2) incardiomyocytes is up regulated in patientswith congestive heart failure (CHF)[J]. Hypertension, 1998, 32 (3) : 630.
60. O ishi Y, Ozono R, Yano Y, et al. Cardiop rotective role of AT2 recep tor in postinfarction left ventricular remodeling[J]. Hypertension, 2003, 41 (3 p t 2) :814-818.
61. Bove CM, Yang Z, GilsonWD, et al. Nitric oxidemediates benefits of angiotensinⅡtype 2 receptor overexp ression during post2infarct remodeling[J]. Hypertension, 2004, 43: 680-685.
62. PittB, Segal R,Martinez FA, et al. Randomised trial of losartan versus cap top rilin patients over 65 with heart failure ( Evaluation of Losartan in the ElderlyStudy, EL ITE) [J]. Lancet, 1997, 349 (9054) : 747-752.