曲美他嗪联用左旋精氨酸抗大鼠心肌缺血再灌注损伤的实验研究
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摘要
背景
良好的血液循环是组织细胞获得充足的氧和营养物质供应并排出代谢产物的基本保证，各种原因造成的组织血液灌流量减少可使细胞发生缺血性损伤，尽早恢复组织的血液灌流是减轻缺血性损伤的根本措施。近年来，溶栓疗法、动脉搭桥术、心脏外科体外循环、断肢再植和器官移植等方法的建立和推广应用，使许多组织、器官缺血后重新得到血液灌注。再灌注具有两重性。多数情况下，缺血后再灌注使组织、器官功能得到恢复，损伤的结构得到修复，患者病情好转、康复。但是有时缺血后再灌注不仅不能使组织、器官功能恢复，反而加重组织、器官的功能障碍和结构损伤，即缺血再灌注损伤(ischemia reperfusion injury，IRI)，表现为心肌坏死、心律失常、心肌顿抑以及包括“无复流现象”的微血管内皮损伤。再灌注损伤的发生机制复杂，包括氧自由基大量产生、中性粒细胞与内皮细胞相互作用、细胞凋亡、胞内钙超载和三磷酸腺苷(adenosine triphosphate，ATP)产生不足等。随着研究深入，人们逐渐发现炎症反应在缺血再灌注损伤中也扮演着重要的角色。
心肌缺血预适应(ischemic preconditioning，IPC)指反复几次短暂的心肌缺血再灌注，可对抗随后的较长时间持续缺血所造成的心肌损伤。其保护效应主要包括缩小IRI后心肌梗死范围，减少室性心律失常发生和促进心功能恢复。药理性预适应(pharmacological preconditioning，PPC)是应用药物模拟或激发机体内源性物质而诱导心肌保护，目前已成为一种研究趋势，将有利于开发抗心肌缺血药物和进一步探讨心肌预适应的机制。
曲美他嗪(trimetazidine，TMZ)是一种治疗缺血性心脏病、具有抗氧化效应的代谢类药物，已广泛应用于临床，许多实验和临床研究已经证实，它能通过增强葡萄糖氧化代谢、减轻细胞内酸中毒和高钙血症、限制炎症反应以及减少氧自由基生成等抗缺血再灌注损伤，保护心肌。左旋精氨酸(L-Arginine，L-Arg)是一氧化氮(nitrogen monoxidum，NO)的前体物质，NO是具有广泛生物学效应的自由基，它在心血管系统能维持血管平滑肌的紧张度、抑制血小板聚集、黏附和调节血管平滑肌细胞增生，从而减轻IRI。目前，关于TMZ和L-Arg抗缺血再灌注损伤的报道较多，但有关TMZ对再灌注损伤中炎症反应作用的报道国内尚未见到，而且TMZ与L-Arg抗心肌再灌注损伤的机制不同，联合应用是否对心肌保护有协同作用目前尚无定论。
目的
本实验拟探讨曲美他嗪和左旋精氨酸联合应用抗大鼠心肌缺血再灌注损伤的作用及其机制。
方法
雄性健康成年SD大鼠40只，体重180-220克。采用随机区组设计将动物随机分为4组：对照组(A组)、曲美他嗪组(B组)、左旋精氨酸组(C组)和联合用药组(D组)，每组各10例，各组均采用冠脉结扎法制作IRI模型，缺血30min，再灌注90min，记录动物心电图。根据L-Arg和TMZ作用机制的不同，B组于实验前6天，每日给予生理盐水稀释的TMZ10mg／kg灌胃，C组于缺血前30min腹腔注射5％L-Arg300mg／kg，D组联合应用上述两种药物。
分别于缺血前、再灌注30min、60min、90min后，取大鼠静脉血2ml，测血浆肿瘤坏死因子(tumor necrosis factor，TNF-α)的含量，实验结束后处死大鼠，取出心脏，制成10％心肌组织生理盐水匀浆，检测超氧化物歧化酶(superoxide dismutase，SOD)、丙二醛(malonaldehyde，MDA)、ATP。观察比较各组心律失常发生情况以及心肌组织内血管细胞黏附分子1(vascular cell adhesion molecule，VCAM-1)表达现象。
对上述数据进行统计分析，组间比较采用方差分析，组内比较采用t检验。P＜0.05为差异具有显著性，P＜0.01为差异具有非常显著性。
结果
1再灌注30min、60min、90min，各组血浆TNF-α水平较缺血前均升高(P＜0.05)；在同一时点，药物干预各组与对照组比较，TNF-α水平均降低(P＜0.05或P＜0.01)，而且D组与B组、C组相比较降低显著(P＜0.05)。
2药物干预组与对照组比较，可显著降低心肌组织内MDA的上升幅度，提高SOD活性和ATP含量，降低心律失常的发生和持续时间，减少VCAM-1的表达(P＜0.05或P＜0.01)，并且D组与B组、C组比较有显著差异性(P＜0.05)。
结论
1炎症反应参与大鼠心肌缺血再灌注损伤。
2曲美他嗪和左旋精氨酸可通过限制再灌注损伤中炎症反应、增加心肌能量供应等保护大鼠缺血再灌注损伤心肌。
3两药联合应用优于两药单用。
Background:
Several investigations indicated that reperfusion of ischemia myocardium induced ischemia reperfusion injury (IRI). This injury includes myocardial necrosis, arrhythmia, myocardial stunning and microvascular endothelial dysfunction including the no-reflow phenomenon. Myocardial reperfusion injury is a multifarious process including high lever of oxygen free radicals, neutrophil-endothelium interactions, apoptosis, intracellular calcium overload and low lever of ATP. As the development of investigations, people found gradually that inflammation also played a very important role in IRI.
Preconditioning the heart with a brief period of ischemia followed by reperfusion renders it very resistant to injury from a subsequent prolonged ischemia. The protection by preconditioning mainly lies in limiting infarct size, reducing the incidence of ventricular arrhythmia and improving post ischemic cardiac function. Pharmacological preconditioning protection against heart injury is trigged by medicines which can mimic beneficial effects of cardiac ischemic preconditioning. That would be helpful to probe the mechanism of IPC and develop novel access to treatment of the cardiovascular diseases.
Trimetazidine (TMZ), an antioxidant agent and metabolism medicine, has been extensively used in coronary artery disease and other cardiovascular disease, several experimental and clinical studies have demonstrated that it also exerts a cytoprotective effect, limiting IRI, through several mechanisms of action: potentiation of oxidative glucose metabolism, reduction of the degree of intracellular acidosis and hypercalcaemia, and attenuation of the inflammatory response and OFR production. L-Arginine (L-Arg) is a precursor of Nitric oxide (NO), NO is a free radical with extensive biological effect. It can maintain the tonicity of vascular smooth muscle, suppress platelet aggregation and adhesion, and regulate proliferation of vascular smooth muscle cell in cardio-vascular system, thus limit IRI. At present, the lots of reports about their limitation to IRI have emerged, but the effect of TMZ on inflammatory was blank in our country. Furthermore, the mechanism of TMZ on limiting IRI is different with L-Arg. It has not defined whether the combination of them would do more profit to myocardial preservation.
Objective:
This experiment plans to investigate the protective effects and mechanism of TMZ plus L-Arg on myocardial ischemia reperfusion injury in rat.
Methods:
Experiments were performed on adult male SD rats weighing 180-220g. They were randomly divided into four groups: the control group (A), the TMZ treated group (B), the L-Arg treated group (C) and the TMZ plus L-Arg group(D), 10 in each group. Myocardial ischemia-reperfusion injury models were made by ligating the coronary artery for 30min followed by reperfusion for 90 min. The electrocardiogram (ECG) was registered. Before establishment of ischemia reperfusion model, rats in group B were fed with 10mg/kg TMZ for six days. L-Arg (300mg/kg) was administered into peritoneal 30min before ischemia in C group, and both were applied in D group.
Venous blood was collected before ischemia and at 30min、60min、90min after reperfusion, and then, tumor necrosis factor (TNF-α) was detected. After experiment, rats were executed and the hearts were taken out. Heart 10% tissue homogenate was made and then superoxide dismutase (SOD), malondialdehyde (MDA), ATP, was detected. The occurrence of arrhythmia and the generation of myocardial vascular cell adhesion molecule (VCAM-1) were compared among groups.
Data was presented with statistical analysis, and analysis of Variances was used to determine changed between groups, Student's test was used to determine changed within group. Results were significant when P<0.05 and even significant when P<0.01. Results:
1 The level of TNF-αin blood plasma 60min after reperfusion was higher than before ischemia in group A (P<0.05). Compared with the group A, the treated groups could lower the level of TNF-α(P<0.05 or P<0.01).And the difference was significant when the group D contrasted with the group B and the group C (P<0.05).
2 The treated groups could significant lower the rising tendency of MDA; depress the occurrence and duration of arrhythmia; enhance the activity of SOD and the level of ATP; reduce the express of VCAM-1 (P<0.05 or P<0.01). And the difference was significant when the group D contrasted with the group B and the group C (P<0.05).
Conclusions:
1 Inflammation is one of the reasons causing myocardial ischemia reperfusion injury.
2 Trimetazidine、L-arginine has notable protective effect on myocardial ischemia reperfusion injury through limiting the inflammation and enhancing ATP.
3 Trimetazidine plus L-arginine is better than using the 2 medicines separately.
良好的血液循环是组织细胞获得充足的氧和营养物质供应并排出代谢产物的基本保证，各种原因造成的组织血液灌流量减少可使细胞发生缺血性损伤，尽早恢复组织的血液灌流是减轻缺血性损伤的根本措施。近年来，溶栓疗法、动脉搭桥术、心脏外科体外循环、断肢再植和器官移植等方法的建立和推广应用，使许多组织、器官缺血后重新得到血液灌注。再灌注具有两重性。多数情况下，缺血后再灌注使组织、器官功能得到恢复，损伤的结构得到修复，患者病情好转、康复。但是有时缺血后再灌注不仅不能使组织、器官功能恢复，反而加重组织、器官的功能障碍和结构损伤，即缺血再灌注损伤(ischemia reperfusion injury，IRI)，表现为心肌坏死、心律失常、心肌顿抑以及包括“无复流现象”的微血管内皮损伤。再灌注损伤的发生机制复杂，包括氧自由基大量产生、中性粒细胞与内皮细胞相互作用、细胞凋亡、胞内钙超载和三磷酸腺苷(adenosine triphosphate，ATP)产生不足等。随着研究深入，人们逐渐发现炎症反应在缺血再灌注损伤中也扮演着重要的角色。
心肌缺血预适应(ischemic preconditioning，IPC)指反复几次短暂的心肌缺血再灌注，可对抗随后的较长时间持续缺血所造成的心肌损伤。其保护效应主要包括缩小IRI后心肌梗死范围，减少室性心律失常发生和促进心功能恢复。药理性预适应(pharmacological preconditioning，PPC)是应用药物模拟或激发机体内源性物质而诱导心肌保护，目前已成为一种研究趋势，将有利于开发抗心肌缺血药物和进一步探讨心肌预适应的机制。
曲美他嗪(trimetazidine，TMZ)是一种治疗缺血性心脏病、具有抗氧化效应的代谢类药物，已广泛应用于临床，许多实验和临床研究已经证实，它能通过增强葡萄糖氧化代谢、减轻细胞内酸中毒和高钙血症、限制炎症反应以及减少氧自由基生成等抗缺血再灌注损伤，保护心肌。左旋精氨酸(L-Arginine，L-Arg)是一氧化氮(nitrogen monoxidum，NO)的前体物质，NO是具有广泛生物学效应的自由基，它在心血管系统能维持血管平滑肌的紧张度、抑制血小板聚集、黏附和调节血管平滑肌细胞增生，从而减轻IRI。目前，关于TMZ和L-Arg抗缺血再灌注损伤的报道较多，但有关TMZ对再灌注损伤中炎症反应作用的报道国内尚未见到，而且TMZ与L-Arg抗心肌再灌注损伤的机制不同，联合应用是否对心肌保护有协同作用目前尚无定论。
目的
本实验拟探讨曲美他嗪和左旋精氨酸联合应用抗大鼠心肌缺血再灌注损伤的作用及其机制。
方法
雄性健康成年SD大鼠40只，体重180-220克。采用随机区组设计将动物随机分为4组：对照组(A组)、曲美他嗪组(B组)、左旋精氨酸组(C组)和联合用药组(D组)，每组各10例，各组均采用冠脉结扎法制作IRI模型，缺血30min，再灌注90min，记录动物心电图。根据L-Arg和TMZ作用机制的不同，B组于实验前6天，每日给予生理盐水稀释的TMZ10mg／kg灌胃，C组于缺血前30min腹腔注射5％L-Arg300mg／kg，D组联合应用上述两种药物。
分别于缺血前、再灌注30min、60min、90min后，取大鼠静脉血2ml，测血浆肿瘤坏死因子(tumor necrosis factor，TNF-α)的含量，实验结束后处死大鼠，取出心脏，制成10％心肌组织生理盐水匀浆，检测超氧化物歧化酶(superoxide dismutase，SOD)、丙二醛(malonaldehyde，MDA)、ATP。观察比较各组心律失常发生情况以及心肌组织内血管细胞黏附分子1(vascular cell adhesion molecule，VCAM-1)表达现象。
对上述数据进行统计分析，组间比较采用方差分析，组内比较采用t检验。P＜0.05为差异具有显著性，P＜0.01为差异具有非常显著性。
结果
1再灌注30min、60min、90min，各组血浆TNF-α水平较缺血前均升高(P＜0.05)；在同一时点，药物干预各组与对照组比较，TNF-α水平均降低(P＜0.05或P＜0.01)，而且D组与B组、C组相比较降低显著(P＜0.05)。
2药物干预组与对照组比较，可显著降低心肌组织内MDA的上升幅度，提高SOD活性和ATP含量，降低心律失常的发生和持续时间，减少VCAM-1的表达(P＜0.05或P＜0.01)，并且D组与B组、C组比较有显著差异性(P＜0.05)。
结论
1炎症反应参与大鼠心肌缺血再灌注损伤。
2曲美他嗪和左旋精氨酸可通过限制再灌注损伤中炎症反应、增加心肌能量供应等保护大鼠缺血再灌注损伤心肌。
3两药联合应用优于两药单用。
Background:
Several investigations indicated that reperfusion of ischemia myocardium induced ischemia reperfusion injury (IRI). This injury includes myocardial necrosis, arrhythmia, myocardial stunning and microvascular endothelial dysfunction including the no-reflow phenomenon. Myocardial reperfusion injury is a multifarious process including high lever of oxygen free radicals, neutrophil-endothelium interactions, apoptosis, intracellular calcium overload and low lever of ATP. As the development of investigations, people found gradually that inflammation also played a very important role in IRI.
Preconditioning the heart with a brief period of ischemia followed by reperfusion renders it very resistant to injury from a subsequent prolonged ischemia. The protection by preconditioning mainly lies in limiting infarct size, reducing the incidence of ventricular arrhythmia and improving post ischemic cardiac function. Pharmacological preconditioning protection against heart injury is trigged by medicines which can mimic beneficial effects of cardiac ischemic preconditioning. That would be helpful to probe the mechanism of IPC and develop novel access to treatment of the cardiovascular diseases.
Trimetazidine (TMZ), an antioxidant agent and metabolism medicine, has been extensively used in coronary artery disease and other cardiovascular disease, several experimental and clinical studies have demonstrated that it also exerts a cytoprotective effect, limiting IRI, through several mechanisms of action: potentiation of oxidative glucose metabolism, reduction of the degree of intracellular acidosis and hypercalcaemia, and attenuation of the inflammatory response and OFR production. L-Arginine (L-Arg) is a precursor of Nitric oxide (NO), NO is a free radical with extensive biological effect. It can maintain the tonicity of vascular smooth muscle, suppress platelet aggregation and adhesion, and regulate proliferation of vascular smooth muscle cell in cardio-vascular system, thus limit IRI. At present, the lots of reports about their limitation to IRI have emerged, but the effect of TMZ on inflammatory was blank in our country. Furthermore, the mechanism of TMZ on limiting IRI is different with L-Arg. It has not defined whether the combination of them would do more profit to myocardial preservation.
Objective:
This experiment plans to investigate the protective effects and mechanism of TMZ plus L-Arg on myocardial ischemia reperfusion injury in rat.
Methods:
Experiments were performed on adult male SD rats weighing 180-220g. They were randomly divided into four groups: the control group (A), the TMZ treated group (B), the L-Arg treated group (C) and the TMZ plus L-Arg group(D), 10 in each group. Myocardial ischemia-reperfusion injury models were made by ligating the coronary artery for 30min followed by reperfusion for 90 min. The electrocardiogram (ECG) was registered. Before establishment of ischemia reperfusion model, rats in group B were fed with 10mg/kg TMZ for six days. L-Arg (300mg/kg) was administered into peritoneal 30min before ischemia in C group, and both were applied in D group.
Venous blood was collected before ischemia and at 30min、60min、90min after reperfusion, and then, tumor necrosis factor (TNF-α) was detected. After experiment, rats were executed and the hearts were taken out. Heart 10% tissue homogenate was made and then superoxide dismutase (SOD), malondialdehyde (MDA), ATP, was detected. The occurrence of arrhythmia and the generation of myocardial vascular cell adhesion molecule (VCAM-1) were compared among groups.
Data was presented with statistical analysis, and analysis of Variances was used to determine changed between groups, Student's test was used to determine changed within group. Results were significant when P<0.05 and even significant when P<0.01. Results:
1 The level of TNF-αin blood plasma 60min after reperfusion was higher than before ischemia in group A (P<0.05). Compared with the group A, the treated groups could lower the level of TNF-α(P<0.05 or P<0.01).And the difference was significant when the group D contrasted with the group B and the group C (P<0.05).
2 The treated groups could significant lower the rising tendency of MDA; depress the occurrence and duration of arrhythmia; enhance the activity of SOD and the level of ATP; reduce the express of VCAM-1 (P<0.05 or P<0.01). And the difference was significant when the group D contrasted with the group B and the group C (P<0.05).
Conclusions:
1 Inflammation is one of the reasons causing myocardial ischemia reperfusion injury.
2 Trimetazidine、L-arginine has notable protective effect on myocardial ischemia reperfusion injury through limiting the inflammation and enhancing ATP.
3 Trimetazidine plus L-arginine is better than using the 2 medicines separately.
引文
1 Ferrari R, Ceconi C, Curello S, et al. Role of oxygen free radicals in ischemic and myocardium. Am J Clin Nutr, 1991, 53: 2155-2225.
2 Peralta C, Rull R, Rimola A, et al. Endogenous nitric oxide and exogenous nitric oxide supplementation in hepatic ischemia-reperfusion injury in the rat. Transplantation, 2001, 71: 529-536.
3 Meldrum DR, Cleveland JC Jr, Cain BS, et al. Increased myocardial tumor necrosis factor-alpha in a crystalloid-perfused model of cardiac ischemia reperfusion injury. Ann Thorac Surg, 1998, 65(2): 439-443.
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24 Detry JM, Leclercq PJ. Trimetazidine European Multicenter Study versus propranoloo in stable angina pectoris: contribution of Holter electrocardiographic ambulatory monitoring. Am J Cardiol, 1995, 76: 8B-11B.
25 De Leiris J, Boucher F. Rationale for trimetazidine administration in myocardial ischemia-reperfusion syndrome. Eur Heart J, 1993,14(Suppl G): 34-40.
26 Birand A, Kudaiberdieva GZ, Batyraliev TA, et al. Effects of trimetazidine on heart rate variability and left ventricular systolic performance in patients with coronary artery disease after percutaneous transluminal angioplasty. Angiology, 1997,48(5): 413-422.
27 Lopaschuk GD, Kozak R. Trimetazidine inhibits fatty acid oxidation in the heart. J Mol Cell Cardiol, 1998,30: A112.
28 Neely JR, Morgan HE. Relationship between carbohydrate metabolism and energy balance of heart muscle. Ann Rev Physiol, 1974, 36: 413-59.
29 Randke PJ, Hales CN, Garland PB, et al. The glucose fatty-acid cycle. It's role in insulin sensitivity and the metabolic disturbances of diabetic mellitus. Lancet, 1963,1:785-9.
30 Patel MS, Roche TE. Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEB J, 1990, 4: 3224-3233.
31 Lopaschuk GD, Wambolt RB, Barr RL. An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts. J Pharmacol Exp Ther, 1993, Jan, 264(1): 135-44.
32 Lopaschuk GD, Kozak R. Trimetazidine inhibits fatty acid oxidation in the heart. J Mol Cell Cardiol, 1998, 93: 135-42.
33 Renaud JF. Internal pH, Na~+, and Ca~(2+) regulation by trimetazdine during cardiac cell acidosis. Cardiovasc Drug Ther, 1988, 1: 677-86.
34 Lagadic-Gossmann D, Le Prigent K, Feuvary K. Effects of trimetazidine on phi regulation in the rat isolated ventricular myocyte. Br J Pharmacol, 1996, 117(5): 831-838.
35 Palmer RMJ, Ferrige AG, Moncada A. Nitric oxide release accounts for the biological activity of endothelium derived relaxing factor. Nature, 1987, 327: 524-529.
36 Inglott FS, Mathie RT. Nitric oxide and hepatic ischemia reperfusion injury. Hepatogastroenterology, 2000, 47: 1722-5.
37 Ozakyol AH, Tuncel N, Saricam T, et al. Effect of nitric oxide inhibition on rat liver ischemia reperfusion injury. Pathophysiology, 2000, 7: 183-188.
38 Tsao PS, Aoki N, Lefer DJ, et al. Time course of endothelial dysfunction myocardial injury during myocardial ischemia and reperfusion in the rats. Circulation, 1990, 82: 1402-1405.
39 Mery PF, Pavoine C, Belhassen L, et al. Nitric oxide regulates cardiac Ca~(2+) current: involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activation. J Biol Chem, 1993, 268(35): 26286-26295.
40 Balligand JL, Kelly RA, Marsden PA, et al. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci USA, 1993, 90(1): 347-351.
41 Shinbo A, Iijima T. Potentiation by nitric oxide of the ATP-sensitive K~+ current induced by K~+ channel openers in guinea-pig ventricular cells. Br J Pharmacol, 1997, 120(8): 1568-1574.
42 Sasaki N, Sato T, Ohler A, et al. Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation, 2000, 101 (4): 439-445.
43 Heusch G, Post H, Michel MC, et al. Endogenous nitric oxide and myocardial adaptation to ischemia. Cir Res, 2000, 87(2): 146-152.
44 Shinmura K, Xuan YT, Tang XL, et al. Inducible nitric oxide synthase modulates cyclooxygenase-2 activity in the heart of conscious rabbits during the late phase of ischemic preconditioning. Circ Res, 2002, 90(5): 602-608.
45 Knox LK, Angel MF, Gamper T, et al. Secondary ischemic tolerance improved by administration of L-NAME in rat flaps. Microsurgery, 1996, 17(8): 425-7.
46 Turnage RH, Wright JK, Iglesias J, et al. Intestinal reperfusion induced pulmonary edema is related to increased pulmonary inducible nitric oxide synthase activity. Surgery, 1998, 124(2): 457-62.
47 Meldrum DR, Cleveland JC J r, Cain BS, et al. Increased myocardial tumor necrosis factor-alpha in a crystalloid-perfused model of cardiac ischemia-reperfusion injury. Ann Thorac Surg, 1998, 65(2): 439-443.
48 Kapadia S, Lee J, Torre-Amione G, et al. Tumor necrosis factor-α gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest, 1995, 96: 1042-1052.
49 Chandrasekar B, Smith JB, Freeman GL. Ischemia-reperfusion of rat myocardium activates nuclear factor-κβ and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine. Circulation, 2001, 103: 2296-2302.
50 Henriksen PA, Newby DE. Therapeutic inhibition of tumor necrosis factor alpha in patients with heart failure: cooling an inflamed heart. Heart, 2003, 89(1): 14218.
51 Communal C, Sumandea M, Solaro J R, et al. Functional consequences of apoptosis in cardiac myocytes: Myofibrillar proteins are targets for caspase-3. Circulation, 2001, 104: 162.
52 Communal C, Sumandea M, de Tombe P, et al. Functional consequences of caspase activation in cardiac myocytes. Proc Natl Acad Sci USA, 2002, 99(9): 6252-6256.
53 范钦华．细胞间粘附分子-1 在细菌性角膜炎角膜组织表达的试验研究[J]．解放军医学杂志，2001，26(8)：585-589．
54 Laude K, Thuillez C, Richard V. Coronary endothelial dysfunction after ischemia and reperfusion: a new therapeutic target. Braz J Med Biol Res, 2001, 34(1): 1-7.
55 李醒三，陈聿峰，文宏，等．伊贝沙坦抑制兔心肌缺血／再灌注ICAM-1和VCAM-1的表达[J]．中国病理生理杂志，2006，22(4)：692-695．
56 Flitter WD. Free radicals and myocardial reperfusion injury. Br Med Bull, 1993, 49(3): 545-555.
57 Dart RC, Sanders AB. Oxygen free radicals and myocardial reperfusion injury. Ann Emerg Med, 1998, 17: 53.
58 Neumar R W, Lathers C M, Tumer N, et al. Myocardial high energy phosphate metabolism during ventricular fibrillation with total circulatory crest. Resusitation, 1990, 19(3): 199.
59 Jarmakani JM, Nagamoto T, Langer GA. Effects of calcium and high energy phosphate compounds on myocardial contracture in the newborn and adult rabbit. J Mol Cell Cardiol, 1978, 10: 1017.
60 Takami H, Matauda H, Kaneko M, et al. Myocardial energy metabolism in preserved heart: comparison of simple storage and hypothermic perfusion. J heart Transplant, 1988, 7: 205-212.
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18 张希全，李守先，张供，等．体外循环改良超滤对血浆内皮素1、肿瘤坏死因子α及凝血功能的影响．中华外科杂志，2004；42：1149-1150．
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29 Lopaschuk GD, Kozak R. Trimetazidine inhibits fatty acid oxidation in the heart. J Mol Cell Cardiol, 1998, 30: A112.
30 Hayashida N, Tomoeda H, Oda T, et al. Effects of supplemental L-arginine during warm blood cardioplegia. Ann Thorac Cardiovasc Surg, 2000, (1): 27-33.
31 Tiefenbacher CP, Kapitza J, Dietz V, et al. Reduction of myocardial infarct size by fluvastatin. Am J Physiol Heart Circ Physiol, 2003, 285(1): H59-64.
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3 Yamada K, Tojo SJ, Hayashi M, et al. The role of P-selectin, sialyl Lewis X and sulfatide in myocardial ischemia and reperfusion injury. Eur J Pharmacol, 1998 Apr 10, 346(2-3): 217-25.
4 Ohnishi M, Yamada K, Morooka S, et al. Inhibition of P-selectin attenuates neutrophil-mediated myocardial dysfunction in isolated rat heart. Eur J Pharmacol, 1999 Feb 5, 366(2-3): 271-9.
5 Seko Y, Enokawa Y, Nakao T, et al. Reduction of rat myocardial ischaemia/reperfusion injury by a synthetic selectin oligopeptide. J Pathol, 1996 Mar, 178(3): 335-42.
6 Hayward R, Campbell B, Shin YK, et al. Recombinant soluble P-selectin glycoprotein ligand-1 protects against myocardial ischemic reperfusion injury in cats. Cardiovasc Res, 1999 Jan, 41(1): 65-76.
7 Lefer DJ, Flynn DM, Anderson DC, et al. Combined inhibition of P-selectin and ICAM-1 reduces myocardial injury following ischemia and reperfusion. Am J Physiol, 1996 Dec, 271(6 Pt 2): H2421-9
8 Lefer DJ, Flynn DM, Buda AJ. Effects of a monoclonal antibody directed against P-selectin after myocardial ischemia and reperfusion. Am J Physiol, 1996 Jan, 270(1 Pt 2): H88-98.
9 Kogaki S, Sawa Y, Sano T, et al. Selectin on activated platelets enhances neutrophil endothelial adherence in myocardial reperfusion injury. Cardiovasc Res, 1999 Sep, 43(4): 968-73.
10 Jones SP, Girod WG, Granger DN, et al. Reperfusion injury is not affected by blockade of P-selectin in the diabetic mouse heart. Am J Physiol, 1999 Aug, 277(2 Pt 2): H76.
11 Briaud SA, Ding ZM, Michael LH, et al. Leukocyte trafficking and myocardial reperfusion injury in ICAM-1/P-selectin-knockout mice. Am J Physi Briaud SA ol Heart Circ Physiol, 2001 Jan, 280(1): H60-7.
12 Jones SP, Trocha SD, Strange MB, et al. Leukocyte and endothelial cell adhesion molecules in a chronic murine model of myocardial reperfusion injury. Am J Physiol Heart Circ Physiol, 2000 Nov, 279(5): H2196-201.
13 Palazzo AJ, Jones SP, Anderson DC, et al. Coronary endothelial P-selectin in pathogenesis of myocardial ischemia-reperfusion injury. Am J Physiol, 1998 Nov, 275(5 Pt 2): H1865-72.
14 Lipton BP, Bautista AP, Delcarpio JB, et al. Effects of endotoxin on neutrophil-mediated I/R injury in isolated perfused rat hearts. Am J Physiol Heart Circ Physiol, 2001 Feb, 280(2): H802-11.
15 Ilton MK, Langton PE, Taylor ML, et al. Differential expression of neutrophil adhesion molecules during coronary artery surgery with cardiopulmonary bypass. J Thorac Cardiovasc Surg, 1999 Nov, 118(5): 930.
16 Hill GE. Cardiopulmonary bypass-induced inflammation: is it important? J Cardiothorac Vasc Anesth, 1998 Apr, 12(2 Supp1): 21-5.
17 Palazzo AJ, Jones SP, Girod WG, et al. Myocardial ischemia-reperfusion injury in CD18- and ICAM-1-deficient mice. Am J Physiol, 1998 Dec, 275(6 Pt 2): H2300-7.
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19 Hartman JC, Anderson DC, Wiltse AL, et al. Protection of ischemic/reperfused canine myocardium by CL18/6, a monoclonal antibody to adhesion molecule ICAM-1. Cardiovasc Res, 1995 Jul, 30(1): 47-54.
20 Feeley BT, Park AK, Hoyt EG, et al. Sulfasalazine inhibits reperfusion injury and prolongs allograft survival in rat cardiac transplants. J Heart Lung Transplant, 1999 Nov, 18(11): 1088-95.
21 Kupatt C, Habazettl H, Becker BF, et al. Endothelial activation—a strategic event during postischemic myocardial inflammation. Z Kardiol, 2000, 89 Suppl 9: IX/96-100.
22 Squadrito F, Altavilla D, Squadrito G, et al. Tacrolimus limits polymorphonuclear leucocyte accumulation and protects against myocardial ischemia-reperfusion injury. J Mol Cell Cardiol, 2000 Mar, 32(3): 429-40.
23 Zund G, Dzus AL, Pretre R, et al. Endothelial cell injury in cardiac surgery: salicylate may be protective by reducing expression of endothelial adhesion molecules. Eur J Cardiothorac Surg, 1998 Mar, 13(3): 293-7.
24 Altavilla D, Squadrito F, Campo GM, et al. The reduction of myocardial damage and leukocyte polymorphonuclear accumulation following coronary artery occlusion by the tyrosine kinase inhibitor tyrphostin AG 556. Life Sci, 2000 Oct 13, 67(21): 2615-29.
25 Buerke M, Prufer D, Dahm M, et al. Blocking of classical complement pathway inhibits endothelial adhesion molecule expression and preserves ischemic myocardium from reperfusion injury. J Pharmacol Exp Ther, 1998 Jul, 286(1): 429-38.
26 Zingarelli B, Salzman AL, Szabo C. Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury. Circ Res, 1998 Jul 13, 83(1): 85-94.
27 Engelman DT, Watanabe M, Maulik N, et al. L-arginine reduces endothelial inflammation and myocardial stunning during ischemia/reperfusion. Ann Thorac Surg, 1995 Nov, 60(5): 1275-81.
28 Jones SP, Girod WG, Palazzo AJ, et al. Myocardial ischemia-reperfusion injury is exacerbated in absence of endothelial cell nitric oxide synthase. Am J Physiol, 1999 May, 276(5 Pt 2): H1567-73.
2 Peralta C, Rull R, Rimola A, et al. Endogenous nitric oxide and exogenous nitric oxide supplementation in hepatic ischemia-reperfusion injury in the rat. Transplantation, 2001, 71: 529-536.
3 Meldrum DR, Cleveland JC Jr, Cain BS, et al. Increased myocardial tumor necrosis factor-alpha in a crystalloid-perfused model of cardiac ischemia reperfusion injury. Ann Thorac Surg, 1998, 65(2): 439-443.
4 Lopaschuk GD, Belke DD, Gamble J, et al. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Bilchim Biophys Acta, 1994 Aug 4, 1213(3): 263-76.
5 Liu B, EI Alaoui-Talibi Z, Clanachan AS, et al. Uncoupling if contractile function from mitochondrial tricarboxylic acid cycle activity and oxygen consumption during reperfusion of ischemic rat hearts. Am J Physiol, 1996, 270: H 72-H 80.
6 Liedtke AJ, DeMaison L, Eggelstan AM, et al. Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium. Circ Res, 1988: 62: 535-542.
7 Lopaschuk GD, Wambolt RB, Barr RL. An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts. J Pharm Exp Therap, 1993 Jan, 264(1): 135-44.
8 Steg PG, Grollier G, Gallay P, et al. A randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction. Int J Cardiol, 2001, 77(2-3): 263-273.
9 Polonski L, Dec I, Wojnar R, et al. Trimetazidine limits the effects of myocardial ischemia during percutaneous coronary angioplasty. Curr Med Res Opin, 2002, 18(7): 389-396.
10 Peralta C, Rull R, Rimola A, et al. Endogenous nitric oxide and exogenous nitric oxide supplementation in hepatic ischemia-reperfusion injury in the rat. Transplantation, 2001, 71: 529-536.
11 Inglott FS, Mathie RT. Nitric oxide and hepatic ischemia reperfusion injury. Hepatogastroenterology, 2000, 47: 1722-5.
12 Jiang Z, Kejian H, Lei CY, et al. Effects of L-arginine cardioplegia on myocardium. J Extra Corpor Technol, 2001 Feb, 33(1): 10-4.
13 Verma S, Fedak PW, Weisel RD, et al. Fundamentals of reperfusion injury for the clinical cardiologist. Circulation. 2002 May 21, 105(20): 2332-6.
14 Moens AL, Claeys MJ, Timmermans JP, et al. Myocardial ischemia reperfusion-injury, a clinical view on a complex pathophysiological process. Int J Cardiol, 2005 Apr 20, 100(2): 179-90.
15 刘福林，周玉娟．1，6．二磷酸果糖对心肌缺血再灌注损伤的保护[J]．心血管病学进展，2004，25(5)：342-344．
16 Hansen PR. Role of neutrophils in myocardial ischemia and reperfusion. Circulation, 1995. 91: 1872-1885.
17 Marx N, Neumann F J, Ott I, et al. Induction of cytokine expression in leukocytes in acute myocardial infarction. J Am Coll Cardiol, 1997, 30(1): 165-170.
18 Pudil R, Krejsek J, Pidrman V, et al. Inflammatory response to acute myocardial infarction complicated by cardiogenic shock. Acta Medica (Hradec Kralove), 2001, 44(4): 149-151.
19 Harlan JM, Winn RK. Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy. Crit Care Med, 2002, 30(5 Suppl): S214-S219.
20 Baxter GF. The neutrophil as a mediator of myocardial ischemia-reperfusion injury: time to move on. Basic Res Cardiol, 2002, 97(4): 2682275.
21 Komai H, Rusy BR. Effects of inhibition of transsar colemmal calciam inlux by nickel on force of postrest contraction on contracture induced by rapid colling. Cardiovasc Res, 1993, 27: 801.
22 Kark M, Ziemer G, Zoeller M, et al. Protection of the chronic hypoxic immature rat heart during global ischemia. Ann Thorac Surg, 1995, 59: 699.
23 Malhotra R, Brosius FC. Glucose uptake and glycolysis reduce hypoxia-induced apoptosis in cultured neonatal rat cardiac myocytes. J Biol Chem, 1999, 274(18): 12567-12575.
24 Detry JM, Leclercq PJ. Trimetazidine European Multicenter Study versus propranoloo in stable angina pectoris: contribution of Holter electrocardiographic ambulatory monitoring. Am J Cardiol, 1995, 76: 8B-11B.
25 De Leiris J, Boucher F. Rationale for trimetazidine administration in myocardial ischemia-reperfusion syndrome. Eur Heart J, 1993,14(Suppl G): 34-40.
26 Birand A, Kudaiberdieva GZ, Batyraliev TA, et al. Effects of trimetazidine on heart rate variability and left ventricular systolic performance in patients with coronary artery disease after percutaneous transluminal angioplasty. Angiology, 1997,48(5): 413-422.
27 Lopaschuk GD, Kozak R. Trimetazidine inhibits fatty acid oxidation in the heart. J Mol Cell Cardiol, 1998,30: A112.
28 Neely JR, Morgan HE. Relationship between carbohydrate metabolism and energy balance of heart muscle. Ann Rev Physiol, 1974, 36: 413-59.
29 Randke PJ, Hales CN, Garland PB, et al. The glucose fatty-acid cycle. It's role in insulin sensitivity and the metabolic disturbances of diabetic mellitus. Lancet, 1963,1:785-9.
30 Patel MS, Roche TE. Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEB J, 1990, 4: 3224-3233.
31 Lopaschuk GD, Wambolt RB, Barr RL. An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts. J Pharmacol Exp Ther, 1993, Jan, 264(1): 135-44.
32 Lopaschuk GD, Kozak R. Trimetazidine inhibits fatty acid oxidation in the heart. J Mol Cell Cardiol, 1998, 93: 135-42.
33 Renaud JF. Internal pH, Na~+, and Ca~(2+) regulation by trimetazdine during cardiac cell acidosis. Cardiovasc Drug Ther, 1988, 1: 677-86.
34 Lagadic-Gossmann D, Le Prigent K, Feuvary K. Effects of trimetazidine on phi regulation in the rat isolated ventricular myocyte. Br J Pharmacol, 1996, 117(5): 831-838.
35 Palmer RMJ, Ferrige AG, Moncada A. Nitric oxide release accounts for the biological activity of endothelium derived relaxing factor. Nature, 1987, 327: 524-529.
36 Inglott FS, Mathie RT. Nitric oxide and hepatic ischemia reperfusion injury. Hepatogastroenterology, 2000, 47: 1722-5.
37 Ozakyol AH, Tuncel N, Saricam T, et al. Effect of nitric oxide inhibition on rat liver ischemia reperfusion injury. Pathophysiology, 2000, 7: 183-188.
38 Tsao PS, Aoki N, Lefer DJ, et al. Time course of endothelial dysfunction myocardial injury during myocardial ischemia and reperfusion in the rats. Circulation, 1990, 82: 1402-1405.
39 Mery PF, Pavoine C, Belhassen L, et al. Nitric oxide regulates cardiac Ca~(2+) current: involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activation. J Biol Chem, 1993, 268(35): 26286-26295.
40 Balligand JL, Kelly RA, Marsden PA, et al. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci USA, 1993, 90(1): 347-351.
41 Shinbo A, Iijima T. Potentiation by nitric oxide of the ATP-sensitive K~+ current induced by K~+ channel openers in guinea-pig ventricular cells. Br J Pharmacol, 1997, 120(8): 1568-1574.
42 Sasaki N, Sato T, Ohler A, et al. Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation, 2000, 101 (4): 439-445.
43 Heusch G, Post H, Michel MC, et al. Endogenous nitric oxide and myocardial adaptation to ischemia. Cir Res, 2000, 87(2): 146-152.
44 Shinmura K, Xuan YT, Tang XL, et al. Inducible nitric oxide synthase modulates cyclooxygenase-2 activity in the heart of conscious rabbits during the late phase of ischemic preconditioning. Circ Res, 2002, 90(5): 602-608.
45 Knox LK, Angel MF, Gamper T, et al. Secondary ischemic tolerance improved by administration of L-NAME in rat flaps. Microsurgery, 1996, 17(8): 425-7.
46 Turnage RH, Wright JK, Iglesias J, et al. Intestinal reperfusion induced pulmonary edema is related to increased pulmonary inducible nitric oxide synthase activity. Surgery, 1998, 124(2): 457-62.
47 Meldrum DR, Cleveland JC J r, Cain BS, et al. Increased myocardial tumor necrosis factor-alpha in a crystalloid-perfused model of cardiac ischemia-reperfusion injury. Ann Thorac Surg, 1998, 65(2): 439-443.
48 Kapadia S, Lee J, Torre-Amione G, et al. Tumor necrosis factor-α gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest, 1995, 96: 1042-1052.
49 Chandrasekar B, Smith JB, Freeman GL. Ischemia-reperfusion of rat myocardium activates nuclear factor-κβ and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine. Circulation, 2001, 103: 2296-2302.
50 Henriksen PA, Newby DE. Therapeutic inhibition of tumor necrosis factor alpha in patients with heart failure: cooling an inflamed heart. Heart, 2003, 89(1): 14218.
51 Communal C, Sumandea M, Solaro J R, et al. Functional consequences of apoptosis in cardiac myocytes: Myofibrillar proteins are targets for caspase-3. Circulation, 2001, 104: 162.
52 Communal C, Sumandea M, de Tombe P, et al. Functional consequences of caspase activation in cardiac myocytes. Proc Natl Acad Sci USA, 2002, 99(9): 6252-6256.
53 范钦华．细胞间粘附分子-1 在细菌性角膜炎角膜组织表达的试验研究[J]．解放军医学杂志，2001，26(8)：585-589．
54 Laude K, Thuillez C, Richard V. Coronary endothelial dysfunction after ischemia and reperfusion: a new therapeutic target. Braz J Med Biol Res, 2001, 34(1): 1-7.
55 李醒三，陈聿峰，文宏，等．伊贝沙坦抑制兔心肌缺血／再灌注ICAM-1和VCAM-1的表达[J]．中国病理生理杂志，2006，22(4)：692-695．
56 Flitter WD. Free radicals and myocardial reperfusion injury. Br Med Bull, 1993, 49(3): 545-555.
57 Dart RC, Sanders AB. Oxygen free radicals and myocardial reperfusion injury. Ann Emerg Med, 1998, 17: 53.
58 Neumar R W, Lathers C M, Tumer N, et al. Myocardial high energy phosphate metabolism during ventricular fibrillation with total circulatory crest. Resusitation, 1990, 19(3): 199.
59 Jarmakani JM, Nagamoto T, Langer GA. Effects of calcium and high energy phosphate compounds on myocardial contracture in the newborn and adult rabbit. J Mol Cell Cardiol, 1978, 10: 1017.
60 Takami H, Matauda H, Kaneko M, et al. Myocardial energy metabolism in preserved heart: comparison of simple storage and hypothermic perfusion. J heart Transplant, 1988, 7: 205-212.
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