甘青铁线莲皂苷对大鼠心肌缺血/再灌注损伤的保护作用

摘 要 目的：研究甘青铁线莲皂苷（CTS）对大鼠心肌缺血/再灌注（MI/R）损伤的影响。 方法: 可逆性冠脉左前降支结扎缺血30 min 再灌注3 h 复制MI/R 模型,将SD大鼠随机分为假手术组、模型组、CTS低、中、高剂量组(50,100,200 mg·kg-1),每组10 只。采用伊文思蓝（EB）、2,3,5 氯化三苯基四氮唑蓝（TTC）双染法测定心肌梗死面积,苏木精 伊红（HE）染色法观察心肌病理学形态变化,并检测血清中乳酸脱氢酶（LDH）、肌酸激酶同工酶（CK MB）、肿瘤坏死因子 α (TNF α)、白细胞介素 6 (IL 6)、超氧化物歧化酶（SOD）及丙二醛（MDA）水平。 结果: 与模型组比较,中、高剂量的CTS可明显缩小心肌梗死面积,并显著降低血清中LDH、CK MB、TNF α、IL 6及 MDA的水平,显著增加血清中SOD的活性（P<0.05或P<0.01）,且CTS各剂量组心肌组织的病理损伤也低于模型组。 结论: CTS对大鼠MI/R 损伤具有保护作用,其机制可能与其抑制炎症因子的释放和调节氧化应激有关。     

三七总皂苷预处理对急性期缺血再灌注肾脏的保护作用

目的 探索三七总皂苷预处理对急性期肾缺血再灌注损伤的作用.方法 取75只SD雄性大鼠,随机分为3组,每组25只,分为:假手术组(C组)、缺血再灌注损伤组(RIRI组)、三七总皂苷组(PNS组).实验干预:(1)C组:实验前尾静脉注射与PNS组等量生理盐水,1次/d,共3d,麻醉后右肾切除,左肾暴露30 min后关腹;(2)RIRI组:切除右侧肾脏,左侧肾动脉夹闭30 min后恢复血流;(3)PNS组:实验前尾静脉注射PNS(150 mg/kg),其余同RIRI组.在缺血再灌注前1h及再灌注后1,6,12,24 h等5个时间点分别取5只大鼠,取血清测肌酐、尿素氮,肾组织匀浆检测肾组织超氧化物歧化酶活性(SOD)、丙二醛(MDA)含量,光镜下观察肾组织的病理变化,并分别进行比较.结果 与C组比较,RIRI组的肌酐、尿素氮、MDA水平在再灌注24 h内随着时间的延长逐渐升高,SOD活性则明显降低.PNS组的肌酐、尿素氮、MDA水平在再灌注6h后各组与RIRI组比较降低,SOD活性明显增强.结论 PNS对肾缺血再灌注损伤具有保护作用,其保护作用机制与增强SOD活性、清除自由基等有关.     

三七总皂苷对心血管作用的药理研究新进展

本文主要综述近5年三七总皂苷（PNS）对心血管系统作用的药理研究进展。研究证明，PNS除具有降血压、扩张血管、抗心律失常等生理活性外，还具有抑制心肌缺血．再灌注损伤、钙拮抗、减轻心肌损伤、对抗心肌肥大和心室重构作用，以及抑制血管平滑肌细胞的增殖、血拴形成和动脉粥样硬化及保护血管内皮细胞等的药理作用。提出应从其对细胞膜受体、细胞核受体及离子通道的作用及整体水平、细胞水平、分子水平或基因水平的表达，揭示PNS的药理作用机制。     

三七茎叶皂苷对大鼠离体心脏缺血/再灌注损伤的保护作用

目的研究三七茎叶皂苷对大鼠离体心脏缺血/再灌注(I/R)损伤的作用及其作用机制。方法 SD大鼠36只,随机分为6组(n=6),分别是空白对照组、模型组、阳性给药组(地奥心血康70 mg.kg-1)、三七茎叶皂苷低、中、高剂量组(20、40、80 mg.kg-1)。阳性给药组和三七茎叶皂苷给药组大鼠每日灌胃给药1次,连续给药7 d,空白对照组和模型组同时给予同体积生理盐水。末次给药60 min后,分离心脏置于Langendorff离体灌流装置上,平衡15 min后,全心停灌25 min,再灌注60 min,造成心肌缺血/再灌注损伤模型。于大鼠左心房插入水囊导管,记录三七茎叶皂苷对血流动力学指标的影响,测定再灌注60 min后灌流液中乳酸脱氢酶(LDH),肌酸激酶(CK)的活性及心肌组织中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、LDH、CK活性及丙二醛(MDA)的含量。HE染色观察组织形态学改变。结果三七茎叶皂苷不同剂量组(20、40、80 mg.L-1),可明显改善缺血/再灌注所致大鼠的心功能损伤,减少灌流液中LDH、CK释放和组织中MDA的产生,增加SOD、GSH-Px的活性。HE染色结果显示,阳性给药组与三七茎叶皂苷高、中、低剂量组均不同程度的减轻了I/R造成的心肌损伤。结论三七茎叶皂苷对心肌缺血/再灌注损伤具有保护作用,其机制可能与改善心肌舒缩功能,清除氧自由基,减少脂质过氧化反应有关。     

白藜芦醇预处理对心肌缺血/再灌注损伤的保护作用

目的:观察白藜芦醇预处理对心肌缺血再灌注损伤的保护作用.方法:45只雄性SD大鼠随机分为假手术组、缺血再灌组及白藜芦醇预处理组,结扎左冠状动脉制作心肌缺血再灌注模型,比较各组左室最大收缩压(LVSP)、左室等容收缩/舒张期压力上升最大速率(LVdP/dtmax),心肌一氧化氮(NO)、丙二醛(MDA)含量变化及心肌梗死范围.结果:白藜芦醇预处理组LVSP、LVdP/dtmax较缺血再灌组显著升高,心肌NO含量显著升高、MDA含量则显著降低,心肌梗死范围明显减小.结论:白藜芦醇预处理对心肌缺血再灌注损伤有明显保护作用,其机制与白藜芦醇抗氧化、清除自由基及增加NO合成有关.     

卡托普利对Langendorff灌注大鼠全心缺血-再灌注损伤的保护作用

目的：探讨卡托普利对Langendorff灌注大鼠全心缺血-再灌注损伤的保护作用及机制。方法：采用Langendorff离体全心灌流装置，模拟缺血-再灌注，观察卡托普利对大鼠全心缺血-再灌注引起的心律失常的作用及体内CPK、LDH、MDA、SOD及AngⅡ含量的变化。结果：卡托普利减少缺血及再灌注期心律失常的发生，加快再灌注期高度房室传导阻滞的恢复。缺血期：CPK及LDH缺血-再灌注(B组)组较对照组(A组)明显增加，卡托普利治疗组(C组)较B组显著降低，再灌注期：CPK及LDH B组较A组明显增加，C组较B组明显降低，心肌组织MDA，Ang II的含量B组明显高于A组，C组明显低于B组，而SOD含量两组比较无显著性差异。结论：卡托普利具有拮抗离体大鼠全心缺血一再灌注损伤的作用，拮抗作用是通过抑制血管紧张素转换酶(ACE)而抑制Ang II的生成，抑制氧自由基的产生而实现的。     

人参果皂苷注射液对大鼠心肌缺血再灌注损伤的保护作用

目的 研究人参果皂苷注射液(1GFS)对大鼠心肌缺血再灌注损伤的保护作用。方法 采用在对大鼠结扎冠状动脉前降支30min后．松扎再灌注120min造成心肌缺血再灌注损伤模型，计算心肌梗死范围(MIS)．测定血清磷酸肌酸激酶(CK)、乳酸脱氢酶(LDH)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶((GSH-Px)活性及脂质过氧化物(LPO)含量，血浆内皮素(ET)、血管紧张素Ⅱ(AngⅡ)、前列环素(PGI2)及血栓素A2(TXA2)水平。同时测心肌梗死及非梗死区游离脂肪酸(FFA)含量。结果 IGFS对心肌缺血30min再灌注损伤120min大鼠，可明显缩小MIS，降低血清CK、LDH活性及LPO含量，提高SOD及GSH-Px活性．能使血浆ET、AngⅡ、TXA2水平明显下降，PGI2水平及PGI2/TXA2比值明显增高，亦可使心肌梗死及非梗死区FFA含量明显降低。结论 IGFS对大鼠心肌缺血再灌注损伤具有明显保护作用．可能与其增强抗氧化酶活性，减少自由基对心肌的氧化损伤，纠正心肌缺血时FFA代谢紊乱，减少内源性血管活性物质ET及AngⅡ释放，纠正PGI2／TXA2失衡等机制有关。     

三七总皂甙对清醒兔心肌缺血再灌注损伤的保护作用

在清醒兔心肌缺血再灌注损伤模型,50mg/kg和100mg/kg三七总皂甙(PNGS)能明显减少心电图缺血性改变,使再灌注期间CPK活性不出现进一步升高。在PNGS处理组,结扎冠脉后和再通后的LD活性明显低于对照组。PNGS明显缩小心肌缺血区面积。提示PNGS具有保护心肌缺血再灌注损伤的作用。     

三七总皂甙对鸡胚神经细胞缺氧及大鼠脑缺血再灌注损伤的作用

观察了三七总皂甙（ＰＮＳ）对氰化钠引起鸡胚脑神经细胞缺氧和大鼠全脑缺血纹状体细胞外嘌呤类代谢产物的影响。结果表明：ＰＮＳ（５０和１００ｍｇ·Ｌ－１）明显延缓缺氧２ｈ神经细胞的能量耗竭，促进再给氧期细胞内高能磷酸化合物的合成。大鼠脑缺血前给予ＰＮＳ（２００ｍｇ·ｋｇ－１，ｉｐ）能明显降低缺血和再灌注期纹状体细胞外液次黄嘌呤，黄嘌呤和肌苷含量的升高。提示：ＰＮＳ对神经细胞氰化钠损伤及大鼠脑缺血再灌注损伤具有保护作用，其机理可能与改善能量代谢有关。     

灯盏乙素对心肌缺血/再灌注损伤的保护作用及机制

目的研究灯盏乙素对大鼠离体心脏缺血/再灌注损伤的保护作用及机制。方法 SD大鼠随机分为空白组、模型组、灯盏乙素低、中、高剂量组(0.3、3、30 mg·kg~(-1)),预给药7 d,应用Langendorff离体灌流大鼠心脏复制急性心肌缺血/再灌注损伤模型。离体灌注时,给药组用含灯盏乙素的K-H液进行灌流(0. 3、3、30 mg·L~(-1))。记录心肌收缩功能;试剂盒检测大鼠心肌组织中AST、CK、LDH的活性; ELISA检测炎性因子ICAM-1、IL-1β、IL-6、IL-18、TNF-α的含量; HE染色观察心肌组织形态学的改变; Western blot检测IL-1β、NLRP3、NF-кB相关蛋白表达。结果与空白组相比,模型组大鼠离体心脏收缩功能明显降低,心肌组织AST、CK、LDH活性明显升高,ICAM-1、IL-1β、IL-6、IL-18、TNF-α等炎性因子的含量明显升高,IL-1β、NLRP3蛋白表达水平及NF-кB核转位明显升高。灯盏乙素能明显改善上述病理改变。结论灯盏乙素对心肌缺血/再灌注损伤的保护作用可能与抑制NF-кB/NLRP3/IL-1β通路有关。     

三七总皂苷对大鼠心肌缺血的保护作用

目的探讨三七总皂苷(PNS)预处理对急性心肌缺血的作用。方法 SD大鼠ig给予PNS 25～800 mg·kg-1,每天2次连续7次,末次给药30 min后,结扎冠状动脉前降支缺血24 h。氯化三苯基四氮唑染色法测定心肌梗死面积,颈总动脉插管测定左心室内血流动力学变化,自动生化分析仪检测心肌酶谱。结果与急性心肌缺血模型组相比,PNS 50,100,200和400 mg·kg-1能显著降低心肌缺血大鼠的心肌梗死面积(P<0.05),降低心肌缺血后左心室舒张末压,提高左心室收缩压,增强等容收缩期左心室内压最大上升速率和等容舒张期左心室内压最大下降速率;显著降低血清中乳酸脱氢酶和肌酸激酶活性,降低α-羟丁酸脱氢酶和天冬氨酸氨基转移酶活性。结论 PNS在50～400 mg·kg-1剂量范围内能显著降低心肌缺血大鼠的心肌梗死面积,提高左心室舒张和收缩功能,明显抑制急性心肌缺血大鼠心肌酶的释放,具有改善心肌缺血的作用。     

Antioxidants in the prevention of myocardial ischemia/reperfusion injury

In acute myocardial ischemia (AMI) the optimal treatment is rapid revascularization by angioplasty or pharmacological thrombolysis. While this is essential to resuscitate the ischemic myocardium, it results in further reperfusion injury and extension of the infarction. The main hypothesis for the mechanism of reperfusion injury is the generation of reactive oxygen species (ROS) to such a degree that endogenous antioxidant mechanisms are overcome and tissue injury results. There is growing evidence that ROS-induced injury may continue for weeks to months as a result of activation of apoptosis. In the longer term, this may result in ventricular remodeling and cardiac failure. Although a number of antioxidants have produced beneficial effects in animal models of AMI, none have proved efficacious in subsequent clinical trials. Drugs that are more specific for the source of ROS generation and that are better able to target the sources of oxidant stress may have greater potential for the prevention of reperfusion injury.     

番茄红素对大鼠心脏缺血再灌注的保护作用及其机制研究

目的 观察番茄红素对SD大鼠在体心脏缺血再灌注损伤的影响,并探求其作用机制。方法 SD大鼠随机分为假手术组,缺血再灌注损伤组,番茄红素5、15 mg/kg+缺血再灌注损伤组。番茄红素组术前15 d开始ig给药,其他组给予生理盐水,1次/d。制备大鼠缺血再灌注损伤模型后再灌3 h,收集血液,测定血清中心肌酶谱相关指标肌酸激酶（CK）和乳酸脱氢酶（LDH）、氧化应激相关指标超氧化物歧化酶（SOD）和丙二醛（MDA）,以及炎症相关指标肿瘤坏死因子α（TNF-α）和白介素1β（IL-1β）的水平,Western blotting法检测心肌中生存素的表达。再灌24 h后取心脏,依文思蓝–氯化三苯基四氮唑双染色测定心肌梗死面积。结果 与缺血再灌注损伤组比较,番茄红素可显著减小心肌缺血再灌注损伤后心肌梗死面积（P<0.05）,显著降低缺血再灌注损伤后血清中CK、LDH水平（P<0.05）,显著升高缺血再灌注损伤后血清中SOD水平而降低MDA水平（P<0.05）,显著降低缺血再灌注损伤后血清中TNF-α和IL-1β水平（P<0.05）,显著逆转缺血再灌注损伤下调的生存素表达（P<0.05）。结论 番茄红素对SD大鼠在体心肌缺血再灌注损伤具有保护作用,其机制与减轻缺血再灌注损伤后氧化应激损伤、抑制炎症反应和激活生存素通路有关。     

Neuroprotective antioxidant STAZN protects against myocardial ischemia/reperfusion injury

BACKGROUND: Protecting the myocardium from ischemia-reperfusion injury has significant potential to reduce the complications of myocardial infarction and interventional revascularization procedures. Reperfusion damage is thought to result, in part, from oxidative stress. Here we use a novel method of percutaneous coronary occlusion to show that the potent antioxidant and neuroprotective free-radical scavenger, stilbazulenyl nitrone (STAZN), confers marked cardioprotection when given immediately prior to reperfusion. METHODS AND RESULTS: Physiologically controlled male Sprague-Dawley rats were anesthetized with isoflurane, paralyzed with pancuronium and mechanically ventilated. A guide wire was introduced via the femoral artery and advanced retrogradely via the aorta into the left coronary artery under fluoroscopic guidance. Rats with established coronary ischemia (85 min after occlusion) were given STAZN 3.5 mg/kg or its vehicle 5 min before and 2 h after reperfusion, and were subjected to functional and histopathologic studies at 3 days. Ischemia-associated Q wave amplitude was reduced by 73% in STAZN-treated rats (P=0.01), while infarct-related ejection fraction, fractional shortening and severe regional wall-motion impairments were improved by 48%, 54% and 37%, respectively, relative to vehicle-treated controls (P=0.05). Total myocardial infarct volume in STAZN-treated rats was correspondingly reduced by 43% (P<0.05), representing a sparing of 14% of the total left ventricular myocardium. CONCLUSIONS: STAZN, a second-generation azulenyl nitrone with potent neuroprotective efficacy in brain ischemia, is also a rapidly acting and highly effective cardioprotective agent in acute coronary ischemia. Our results suggest the potential for clinical benefit in the setting of acute coronary syndromes.     

Na+ overload-induced mitochondrial dysfunction in myocardial ischemia/reperfusion injury

An accumulation of Na+ is induced in the ischemic myocardium, which is so-called "Na+ overload". The exact role of Na+ overload in the genesis of myocardial ischemia/reperfusion injury remains unclear except for the role as a driving force of Ca2+ overload in the reperfused myocardium. Excessive activation of Na+/H+ exchanger (NHE) and Na+ channels may contribute to Na+ influx into the ischemic myocardium, resulting in sodium overload under ischemic conditions. A decrease in energy-producing ability of mitochondria in the ischemic myocardium is also observed in an ischemic duration-dependent manner. Attenuation of Na+ overload by an NHE inhibitor or a Na+ channel blocker preserved mitochondrial energy production in the ischemic myocardium and enhanced post-ischemic contractile recovery. To mimic Na+ overload in the ischemic myocardium, isolated mitochondria were incubated with sodium lactate, a possible end product of anaerobic glycolysis. Sodium lactate induced an irreversible reduction in the mitochondrial energy production. The mitochondrial damage induced by sodium lactate was not attenuated by the NHE inhibitor or the Na+ channel blocker, suggesting that these agents may indirectly preserve mitochondrial function in the ischemic myocardium. Taken together, Na+ overload in the ischemic myocardium may induce mitochondrial dysfunction, leading to contractile failure of the reperfused myocardium.     

New developments in the treatment of ischemia/reperfusion injury

Currently, the treatment of reperfusion following ischemia is primarily supportive. Preventative measures may help in combating the occurrence of ischemia, but minimizing the secondary damage that occurs with the onset of reperfusion would improve outcomes. In this review, using a Medline search, we have outlined the current knowledge with respect to the pathophysiology of this disease process and focused primarily on the basic science investigations of drugs, including natural therapies, which have shown potential. It is becoming increasingly clear that no one method or drug is the magic elixir that solely treats reperfusion injury due to the complex and interconnected processes involved.