缺血预适应对大鼠肢体缺血/再灌注后肺损伤的影响

目的:观察肢体缺血预适应对大鼠肢体缺血/再灌注(I/R)后肺损伤的影响并探讨其机制。方法:将雄性Wistar大鼠随机分为4组(n=8):对照组(C),肢体缺血/再灌注组(LI/R),缺血预适应组(IPC)和L-NAME组。各组大鼠均于肢体缺血4h再灌注4h处死,分别测定其动脉血氧分压(PaO2)和二氧化碳分压(PaCO2),血浆及肺组织丙二醛(MDA)、一氧化氮(NO)、内皮素(ET)含量,计算血浆NO/ET比值;以及肺湿干比(W/D)、肺系数(LI),肺组织髓过氧化物酶(MPO)含量。结果:大鼠LI/R后4h,PaO2明显降低;W/D、LI、血浆及肺组织的MDA、NO、ET和肺组织MPO活性均明显增加,而血浆NO/ET比值明显减小。与LI/R组比较,IPC组各项损伤指标明显减轻,NO水平升高,血浆NO/ET比值明显增大。与对照组和IPC组比较,L-NAME处理组,各项损伤指标数值明显增加,NO水平降低;血浆NO/ET比值明显减小,差异均具有显著性。各组大鼠PaCO2的变化无显著性。结论:缺血预适应对肢体缺血/再灌注后肺损伤具有保护作用,其机制可能与内源性NO合成增加有关。     

高频电刺激股神经减小大鼠心肌缺血-再灌注后的梗塞范围

通过氨基甲酸乙酯麻醉大鼠观察股神经电刺激对缺血- 再灌注心肌的影响,旨在证实外周神经刺激对心肌有无保护效应,并明确其可能的作用机制。心肌缺血区和梗塞区分别用伊文思蓝和氯化硝基四氮唑蓝染色确定,心肌梗塞范围定义为心肌梗塞区重量占心肌缺血区重量的百分比。所得结果如下:(1)在心肌缺血30 min 和再灌注120 min 过程中,梗塞心肌占缺血心肌的(54.96±0.82)%。 高频电刺激(10 V,100 Hz,1ms)股神经5 min 可使心肌梗塞范围减少到(36.94±1.34)% (P<0.01), 表明 (2)高频电刺激股神经对缺血-再灌注心肌有保护作用。然而,低频电刺激(10 V, 10 Hz, 1 ms)股神经对缺血-再灌注心肌梗塞范围无影响。 预先应用非选择性阿片肽受体阻断剂纳洛酮(5 mg/kg, i.v.)或非选择性KATP 通道阻断剂格列苯脲(5 mg/kg, i.v.)均能完全 (3)取消高频电刺激股神经对缺血-再灌注心肌的保护作用。以上结果提示,高频外周神经刺激可以减小缺血- 再灌注心肌的梗塞范围,其可能的作用机制是: 高频电刺激股神经时中枢神经系统内释放的内源性阿片肽和由此激活的心肌KATP通道的开放介导了这种保护作用。     

一氧化氮在大鼠肢体缺血再灌注后肺损伤中的作用

在大鼠肢体缺血再灌注（LIR）损伤模型上,观察应用一氧化氮合酶（NOS）抑制剂氨基胍（AG）及一氧化氮（NO）合成前体物质L－精氨酸（L－Arg)对大鼠骨骼肌和肺组织的NOS活性、NO含量、丙二醛（MDA）、髓过氧化物酶（MPO）和湿／干重（W／D）值的影响以及肺磷脂酰胆碱（PC）的改变,并观察了肺组织在光镜下形态学的变化。结果显示,与对照组比较,LIR组骨骼肌和肺组织NOS活性均增强,MDA值、MPO活性增加,W／D值增大,肺PC含量降低;光镜下,肺间质多形核粒细胞（PMN）聚集和浸润,肺间隔面密度值增加。给予AG后,与LIR组相比NOS活性降低,NO产生下降,而MPO活性、W／D比值增加,肺PC含量进一步降低;镜下PMN聚集和浸润增加,肺间隔面密度值增大。而给予L－Arg后能 减轻LIR引起的上述变化。上述结果提示,LIR后2h时,骨骼肌和肺组织NOS活性增加,NO产生增多;内源性NO可能在LIR所诱发的早期急性肺损伤中起保护作用。     

大鼠肢体缺血/再灌注后的心肌损伤和NO的保护效应

目的:探讨大鼠肢体缺血/再灌注(LI/R)后心肌的损伤性变化及NO的保护效应。方法:制备LI/R动物模型,将Wistar大鼠随机分为4组(n=10):C(control)组、I/R组、L-Arg组和L-NAME组。用生物化学方法测定大鼠血浆CK、CK-MB及NO水平,测定心肌组织XOD、SOD、MDA含量。用BL-420生物机能实验系统监测大鼠MAP、LVSP、±dp/dtmax等。结果:LI/R后,血浆CK、CK-MB水平均明显升高(P<0.01);心肌组织SOD活性降低而MDA、XOD含量增加(P<0.01或P<0.05);MAP、LVSP、dp/dtmax、-dp/dtmax均降低(P<0.01或P<0.05);血浆NO水平在L-Arg组明显升高(P<0.01),在L-NAME组显著降低(P<0.05)。结论:大鼠LI/R可引起心肌损伤,机体的氧化应激状态可能是其发生机制之一;提高体内NO水平可在一定程度上减轻LI/R后心肌损伤的程度。     

肢体缺血-再灌注大鼠脑组织iNOS基因表达的半定量检测

目的检测大鼠肢体缺血-再灌注后脑组织iNOS基因表达的变化.方法SD大鼠,随机分为肢体缺血-再灌注(I-R)组、肢体单纯缺血(I)组及正常对照(N)组,通过夹闭腹主动脉末端4?h,或/和开放2～24?h,复制I、I-R组动物模型,半定量RT-PCR方法检测脑组织iNOSmRNA表达的变化,免疫组化染色法观测脑组织内iNOS及过氧亚硝基阴离子(ONOO-)的硝基化产物硝基酪氨酸(NT)的生成与分布.结果N组脑组织iNOSmRNA未检出,I组及I-R组脑组织iNOSmRNA均有表达,再灌注2?h,iNOSmRNA表达量显著升高(P<0.01,vsN组),再灌注6?h达到高峰,随后下降,24?h仍有少量表达;I及I-R组脑组织均有iNOS阳性细胞,I-R组见于大脑皮层各区、海马、尾状核,I组仅见于皮层后肢区及尾状核.I-R组脑组织可见弥散分布的NT阳性神经元,I组偶见NT阳性神经元.结论大鼠肢体缺血-再灌后脑组织iNOS基因表达显著增强,且有时相变化特征.     

牛磺酸对大鼠肢体缺血/再灌注后肺组织损伤的保护作用

目的:观察大鼠肢体缺血再灌注(LIR)后肺组织形态学的变化及牛磺酸对其影响.方法:Wistar大鼠随机分为3组,对照组(control)、缺血/再灌注组(LIR)、牛磺酸 缺血/再灌注组(Tau LIR),各组动物通过大体、光镜和透射电镜观察肺组织形态学变化,并测定肺系数和肺通透指数及肺组织活性氧和MDA含量.结果:大鼠LIR后肺组织出现以肺泡毛细血管膜通透性增加为特征的组织细胞损伤,光镜下显示毛细血管扩张充血、血管周围间隙增大、肺泡腔中有大量蛋白渗出物,电镜下可见肺泡上皮细胞之间、毛细血管内皮之间的紧密连接松解;肺系数和肺通透指数升高;肺组织活性氧及MDA含量增加.提前给予外源性牛磺酸可使肺组织损伤变化减轻.结论:牛磺酸对大鼠LIR后肺损伤有保护作用,其保护机理之一与其抗氧化,保护细胞之间的紧密连接有关.     

缺血预处理对肢体缺血/再灌注大鼠胃粘膜损伤的保护效应

目的：观察肢体缺血再灌注（LI／R）对胃粘膜的损伤作用及缺血预处理对其影响,探讨胃粘膜损伤的机制及缺血预处理（IPC）的作用机理。方法：观察并测定肢体缺血4h再灌注4h后以及应用肢体缺血预处理干预后各组胃粘膜损伤指数,胃结合粘液量;检测胃粘膜中髓过氧化物酶（MPO）、超氧化物歧化酶（SOD）、丙二醛（MDA）、黄嘌呤氧化酶（XOD）含量的变化以及血浆中乳酸脱氢酶（LDH）的含量变化。结果：大鼠LI／R后胃粘膜损伤指数增加;胃结合粘液量较对照组显著下降;胃粘膜中MPO、MDA、XOD的值均较对照组增加,血浆中LDH的含量亦较对照组显著增加,胃粘膜组织中SOD的酶活力下降;IPC组与LIR组对比,胃结合粘液量较LIR组显著增加：胃粘膜损伤指数、胃粘膜中MPO的含量、以及胃粘膜中MDA、XOD、LDH均较LI／R组明显降低;胃粘膜中SOD酶活力增强。结论：LI／R作为应激原可引起胃粘膜损伤,导致应激性溃疡的发生;自由基在肢体缺血再／灌注后继发胃粘膜损伤过程中发挥作用。缺血预处理可减轻肢体缺血再灌注后的胃粘膜损伤,其作用机制可能是通过减少自由基的产生而发挥其保护作用。     

缺血预适应对肢体缺血/再灌注骨骼肌、小肠和肺损伤的影响

目的:观察肢体缺血/再灌注(LI/R)后骨骼肌、小肠、肺功能损伤变化,并探讨缺血预适应(IPC)的保护效应及机制。方法:实验用雄性Wistar大鼠24只,随机分为3组(n=8):对照(Control)组,缺血/再灌注(I/R)组和缺血预适应(IPC+I/R)组。分别测定血浆乳酸脱氢酶(LDH)、肌酸激酶(CK)、活性氧(ROS)、丙二醛(MDA)、动脉血氧分压(PaO2)和二氧化碳分压(PaCO2),测定血浆血栓素B2(TXB2),6-酮-前列腺素F1α(6-keto-PGF1α)的含量以及TXB2/6-keto-PGF1α比值的变化;测定骨骼肌、小肠、肺组织髓过氧化物酶(MPO)含量,肺湿干比(W/D)及小肠组织DAO含量。观察骨骼肌组织的形态学变化。结果:IPC+I/R组血浆LDH、CK、ROS、MDA、TXB2/6-keto-PGF1α比值明显低于I/R组,PaO2较I/R组明显升高。IPC+I/R组肺湿干比(W/D),骨骼肌、肺、小肠组织MPO含量明显低于I/R组,而小肠DAO活性升高。骨骼肌组织病理学改变减轻。结论:缺血预适应减轻了缺血/再灌注后骨骼肌、小肠、肺功能的损伤,其机制可能与降低氧化损伤、改善TXB2/6-keto-PGF1α的平衡关系有关。     

缺血预适应对大鼠肢体缺血/再灌注后小肠细胞凋亡的影响

目的：观察大鼠肢体缺血再灌注后小肠粘膜自由基及钙含量改变与细胞凋亡情况．以及缺血预适应对其变化的影响。方法：将雄性Wistar大鼠18只,随机分为对照（Control）组,缺血／再灌注（I／R）组和缺血预适应（IPC＋I／R）组,分别测定血浆和小肠组织超氧化物歧化酶（SOD）、黄嘌呤氧化酶（XOD）、丙二醛（MDA）的含量,小肠组织钙及线粒体钙含量;小肠组织的Bel-2和Bax蛋白的表达水平;检测小肠细胞凋亡情况。结果：肢体I／R后血浆和小肠粘膜SOD减少而XOD和MDA增加;小肠组织钙及线粒体钙含量增多;Bel-2蛋白表迭和Bax表达增多,但Bel-2／Bax比值降低;凋亡细胞增多。IPC减轻了I／R后引起的XOD、MDA含量的升高,并且增加了SOD的含量;减轻了组织和线粒体钙超载;Bel-2的表达则明显升高而Bax表达较I／R组明显减少,Bel-2／Bax比值升高;凋亡细胞减少。结论：肢体IR引起小肠粘膜自由基的增多,钙超栽,凋亡细胞增多;IPC可能通过减少自由基的产生及钙超载,抑制细胞凋亡而对肢体I／R继发的小肠功能损伤起保护作用。     

大鼠肢体缺血/再灌注后肝脏iNOS表达的变化及其意义

目的:探讨肢体缺血/再灌注(I/R)致肝损伤时肝组织iNOS表达的变化及其意义.方法:夹闭大鼠双侧股动脉根部4 h、开放2～24 h,制备肢体I/R模型.RT-PCR检测肝组织iNOSmRNA表达的改变,免疫组化染色法观察iNOS蛋白及过氧亚硝基阴离子(ONOO-)的生成与分布,比色法测定肝组织MDA含量及SOD活性;对肢体I-R大鼠用氨基胍抑制iNOS活性后,观察其肝组织的病理学变化.结果:肢体I-R后,肝组织iNOS mRNA的表达水平较对照组显著上调(P＜0.05),肝组织内出现大量iNOS及ONOO-阳性肝细胞,肝组织MDA含量升高及SOD活性降低均与对照组有显著性差异(P＜0.01).应用氨基胍抑制iNOS活性,使肢体I-R所致肝组织病变减轻.结论:肢体I/R后,肝组织iNOSmRNA及蛋白表达显著上调,所诱生的高浓度NO参与介导了肢体I/R引发的肝脏损伤.     

肢体缺血预处理减轻大鼠海马缺血/再灌注损伤

目的:探讨肢体缺血预处理(LIP)对大鼠全脑缺血/再灌注损伤的影响.方法: 36只大鼠椎动脉凝闭后随机分为假手术(Control)组、脑缺血组、肢体缺血组、LIP 0 d组(LIP后即刻行脑缺血)、LIP 1 d组(LIP后1 d行脑缺血)和LIP 2 d组(LIP后2 d行脑缺血).重复夹闭大鼠双侧股动脉3次(每次10 min,间隔10 min)作为LIP,夹闭颈总动脉进行全脑缺血8 min后再灌注.硫堇染色观察海马CA1区组织学分级及锥体神经元密度以判断海马损伤程度.结果:脑缺血组海马CA1区锥体神经元损伤严重,与Control组比较,组织学分级明显升高,神经元密度明显降低(P<0.01).LIP 0 d组海马CA1区神经元损伤较脑缺血组明显减轻,组织学分级明显降低,神经元密度明显升高(P<0.01).而LIP 1 d组和LIP 2 d组大鼠海马CA1区锥体细胞缺失较多,仍有明显的组织损伤.结论:LIP可减轻随后立即发生的脑缺血/再灌注损伤,但对间隔1 d后的脑缺血/再灌注损伤无显著对抗作用.     

肢体缺血预处理减少大鼠全脑缺血再灌注诱导的海马CA1区锥体神经元凋亡

探探讨肢体缺血预处理(limb ischemic preconditioning,LIP)对大鼠全脑缺血再灌注后海马CA1区锥体细胞凋亡的影响。46只大鼠椎动脉凝闭后分为假手术组、肢体缺血组、脑缺血组、LIP组。重复夹闭大鼠双侧股动脉3次(每次10min,间隔10min)作为LIP,之后立即夹闭双侧颈总动脉进行全脑缺血8min后再灌注。DNA凝胶电泳、TUNEL和吖啶橙/溴乙锭(AO/EB)双染技术从生化和形态学方面观察海马神经元凋亡的情况。凝胶电泳显示,脑缺血组出现了凋亡特征性DNA梯状条带,而LIP组无上述条带出现。与脑缺血组比较,LIP可明显减少海马CAI区TUNEL阳性神经元数(17.8±5.8vs 69.8±12,P<0.01)。AO/EB染色也显示LIP可明显减少脑缺血再灌注引起的神经元凋亡。以上结果提示,LIP可抑制脑缺血再灌注后海马神经元的凋亡,进而减轻脑缺血再灌注损伤,提供脑保护作用。     

Effect of aminoguanidine on ischemia-reperfusion induced myocardial injury in rats

Myocardial ischemia-reperfusion (MI/R) has been implicated in the induction of inducible nitric oxide synthase (iNOS) that leads to increase production of nitric oxide (NO). Recently, excessive production of NO has been involved in causing myocardial injury. In our in vivo model, we examined the effects of aminoguanidine (AMG), a known iNOS inhibitor, on percentage infarct size in anaesthetized rats. A total of 14 rats were equally divided into two groups (n = 7 in each group). To produce myocardial necrosis, the left main coronary artery was occluded for 30 min, followed by 120 min of reperfusion, in anesthetized rats. AMG (200 mg kg⁻¹) was given intravenously 10 min before occlusion. The volume of infarct size and the risk zone were determined by planimentry of each tracing and multiplying by the slice thickness. Infarct size was normalized by expressing it as a percentage of the area at risk. Hemodynamic parameters were measured via the left carotid artery. Compared to MI/R group, whereas AMG administration elevated mean arterial blood pressure, statistically reduced the myocardial infarct size (21± 1 and 14± 4%, respectively) and infract size/risk zone (53± 3 and 37± 5%, respectively) in rat model of ischemia-reperfusion. In conclusion, this study indicates that iNOS inhibitor, AMG, show reduction in NO’s side effect in I/R injury.     

Protein kinase C is involved in cardioprotective effects of ischemic preconditioning on infarct size and ventricular arrhythmia in rats in vivo

Protein kinase C (PKC) has been known to play an important role in ischemic preconditioning (IP). This study was designed to examine whether the translocation of PKC is associated with the cardioprotective effects of IP in vivo on infarct size and ventricular arrhythmias in a rat model.Using anesthetized rats, heart rate, systolic blood pressure, infarct size and ventricular arrhythmias during 45 min of coronary occlusion were measured. PKC activity was assayed in both the cytosolic and cell membrane fraction . Brief 3-min periods of ischemia followed by 10 min of reperfusion were used to precondition the myocardium. Calphostin C was used to inhibit PKC.Infarct size was significantly reduced by IP (68.1 (2.5)%, mean (S.E.) vs. 45.2 (3.4)%, p < 0.01). The reduction in infarct size by IP was abolished by pretreatment with calphostin C. The total number of ventricular premature complex (VPC) during 45 min of coronary occlusion was reduced by IP (1474 (169) beats/45 min vs. 256 (82) beats/45 min, p < 0.05). The reduction the total number of VPC induced by IP was abolished by the administration of calphostin C before the episode of brief ischemia. The same tendency was observed in the duration of ventricular tachycardia and the incidence of ventricular fibrillation. PKC activity in the cell membrane fraction transiently increased immediately after IP (100 vs. 142%, p < 0.01) and returned to baseline 15 min after IP. Pretreatment with calphostin C prevented the translocation of PKC.The translocation of PKC plays an important role in the cardioprotective effect of IP on infarct size and ventricular arrhythmias in anesthetized rats.     

心肌缺血预适应循环血中微囊泡对大鼠心肌I/R损伤的作用

目的：研究心肌缺血预适应（IPC）大鼠循环血中微囊泡（MVs）对大鼠在体心肌缺血/再灌注（I/R）损伤的作用及相关机制。方法：反复短暂结扎/松开大鼠冠状动脉左前降支建立大鼠IPC模型,自腹主动脉取血,超速离心法分离循环血中的IPC-MVs,并对其进行流式鉴定。建立在体大鼠心肌I/R模型,股静脉注射IPC-MVs 7 mg/kg。HE染色观察心肌形态学变化,TTC染色检测心肌梗死范围,TUNEL染色检测心肌细胞凋亡率。比色法测定血清乳酸脱氢酶（LDH）活力,分光光度法测定心肌组织caspase 3活力,Western blot法检测心肌组织Bcl-2、Bax蛋白表达水平。结果：流式细胞术检测IPC-MVs浓度为4380±745个/μl。与I/R组比较,IPC-MVs能够减轻I/R大鼠心肌组织损伤,缩小心肌梗死范围（P<0.01）,减少心肌细胞凋亡数量（P<0.01）,明显降低血清LDH活力（P<0.01）,降低心肌组织caspase 3活力（P<0.01）,升高Bcl-2蛋白表达（P<0.01）,降低Bax蛋白表达（P<0.01）,升高Bcl-2/Bax比值（P<0.01）。结论：IPC-MVs显著减轻大鼠在体心肌I/R损伤,通过上调心肌组织中Bcl-2的蛋白表达,下调Bax的蛋白表达,升高Bcl-2/Bax比值,降低caspase 3活力而发挥心肌保护作用。     

Myocardial energy metabolism in ischemic preconditioning and cardioplegia: A metabolic control analysis

For both, cardioplegia (CP) and ischemic preconditioning (IP), increased ischemic tolerance with reduction in infarct size is well documented. These cardioprotective effects are related to a limitation of high energy phosphate (HEP) depletion. As CP and IP have to be assumed to act by different mechanisms, their effects on myocardial HEP metabolism cannot be assumed to be identical. Therefore, a systematic analysis of myocardial HEP metabolism for both procedures and their combination was performed, addressing the question whether there are different effects on myocardial HEP metabolism by IP and CP. In this study, metabolic control analysis was used to analyze the regulation of HEP metabolism. In open chest pigs subjected to 45 min LAD occlusion (index ischemia), CP and IP preserved myocardial ATP (control (C) 0.14 ± 0.05 μmol/g wwt; CP: 0.95 ± 0.14, IP: 0.61 ± 0.12; p<0.05 C vs. CP and IP) and reduced myocardial necrosis (infarct size IA/RA: C: 90.0 ± 3.0%; CP: 0.0 ± 0.0% but patchy necroses; IP: 5.05 ± 2.1%; p<0.05 C vs. CP and IP). The effects on HEP metabolism, however, were different: CP acted predominantly by slowing down the breakdown of phosphocreatine (PCr) during early phases of ischemia (C: ΔPCr 0–2 min: 5.24 ± 0.32 μmol/g wwt; CP: ΔPCr 0–2 min: 3.38 ± 0.23 μmol/g wwt, p<0.05 vs. C), leaving ATP breakdown during later stages unaffected (C: ΔATP 5–45 min: 1.77 ± 0.11 μmol/g wwt CP: ΔATP 5–45 min: 1.59 ± 0.28 μmol/g wwt, n.s. vs. C). In contrast to CP, in IP PCr breakdown was even increased (IP: ΔPCr 0–2 min: 7.06 ± 0.34 μmol/g wwt, p<0.05 vs. C), but ATP depletion greatly attenuated (IP: ΔATP 5–45 min: 0.48 ± 0.10 μmol/g wwt, p<0.05 vs. C and CP). Combining IP and CP yielded an additive effect with slowing down the breakdown of both PCr (IP+CP: ΔPCr 0–2 min: 5.09± 0.35 μmol/g wwt, p<0.05 vs. C and IP) and ATP (IP+CP: ΔATP 5–45 min: 0.56 ± 0.48 μmol/g wwt, p<0.05 vs. C and CP), resulting in a higher ATP content at the end of index ischemia (1.86 ± 0.46 μmol/g wwt, p<0.05 vs. C, CP and IP). Compared to IP, combining IP+CP achieved also a further reduction in infarct size (IA/RA: 0.0 ± 0.0%, p<0.05 vs IP) and—compared to CP—a disappearance of the patchy necroses. {The concept of major differences in myocardial HEP metabolism during CP and IP is further supported at a molecular level by metabolic control analysis. CP but not IP slowed down the CK reaction velocity at high PCr levels. In contrast to CP exerting a continuous decline in vATPase for any given ATP level, in IP myocardium ATPase reaction velocity was even increased at higher ATP contents, whereas a marked decrease in ATPase reaction velocity was found if ATP levels decreased. The equilibrium of the CK-reaction remained unchanged following CP, whereas IP induced a changing CK equilibrium, which was the more shifted towards PCr the more myocardial HEP content decreased. The data demonstrate different effects of CP and IP on myocardial HEP metabolism, i.e. PCr and ATP breakdown as well as the apparent equilibrium of the creatine kinase (CK)-reaction. For these reasons the combination of the two protective interventions has an additive effect. (Mol Cell Biochem 278: 222–232, 2005)     

Non-ischemic myocardial preconditioning

The reduction of infarct size produced by brief ischemic episodes prior to a sustained occlusion of a coronary artery, called ischemic preconditioning, is a well known phenomenon that occurs in several species, but its mechanism is still under investigation. Recent reports support the idea that this protection can also be obtained by non-ischemic maneuvers like distention of the left ventricle and metabolic stimulation of myocardial cells. The features of non-ischemic preconditioning (temporal limitation, second window, tolerance development, remote preconditioning and efficiency of the protection), as opposed to those of ischemic preconditioning, are still to be determined. Neither is it known if non-ischemic preconditioning occurs in humans. From a physiological point of view the protective effect of an increase in metabolic rate of the heart means a constant feed-back mechanism in the myocardial cell that counteracts the presumptive damage consequent to the increase in metabolism. Therefore, in the presence of a sudden coronary occlusion the metabolic rate of the heart immediately before the occlusion would have a dual role of increasing the degree of ischemia and of protecting against it.     

Equal reduction in infarct size by ethylisopropyl-amiloride pretreatment and ischemic preconditioning in the in situ rabbit heart

Inhibition of Na⁺/H⁺ exchange with amiloride analogues has been shown to provide functional protection during ischemia and reperfusion and to reduce infarct size in isolated rat hearts. In rat hearts, treatment with ethylisopropyl-amiloride (EIPA, a selective Na⁺/H⁺ exchange inhibitor) was additive to the protection afforded by ischemic preconditioning. In addition, such compounds have been demonstrated to reduce infarct size in in situ rabbit hearts. The aim of the present study was to determine to what extent preischemic treatment with EIPA could reduce infarct size in an in situ rabbit model of regional ischemia and reperfusion. We also wished to determine if this effect was additive to the infarct reducing effect of ischemic preconditioning. Anaesthetized, open chest rabbits, were subjected to 45 min of regional ischemia and 150 min of reperfusion. The risk zone was determined by fluorescent particles and infarct size was determined by TTC staining. Four groups were investigated: control, ischemic preconditioned (IP) (5 min of ischemia followed by 10 min reperfusion), EIPA (0.65 mg/kg iv given preischemically) and EIPA + IP. The main results expressed as percent infarction of the risk zone ± S.E.M. for the different groups were: control 59.2 ± 3.3% (n = 6), IP 16.3 ± 2.1% (n = 6) (p < 0.001 vs. control), EIPA 16.9 ± 4.1% (n = 5) (p < 0.001 vs. control), EIPA + IP 22.5 ± 9.5% (n = 6) (p < 0.001 vs. control). In conclusion: EIPA, when administered prior to ischemia, caused a reduction in infarct size in the in situ rabbit heart which was similar to that seen with ischemic preconditioning, however, the effect was not additive to ischemic preconditioning.     

Invasive surgery reduces infarct size and preserves cardiac function in a porcine model of myocardial infarction

Reperfusion injury following myocardial infarction (MI) increases infarct size (IS) and deteriorates cardiac function. Cardioprotective strategies in large animal MI models often failed in clinical trials, suggesting translational failure. Experimentally, MI is induced artificially and the effect of the experimental procedures may influence outcome and thus clinical applicability. The aim of this study was to investigate if invasive surgery, as in the common open chest MI model affects IS and cardiac function. Twenty female landrace pigs were subjected to MI by transluminal balloon occlusion. In 10 of 20 pigs, balloon occlusion was preceded by invasive surgery (medial sternotomy). After 72 hrs, pigs were subjected to echocardiography and Evans blue/triphenyl tetrazoliumchloride double staining to determine IS and area at risk. Quantification of IS showed a significant IS reduction in the open chest group compared to the closed chest group (IS versus area at risk: 50.9 ± 5.4% versus 69.9 ± 3.4%, P = 0.007). End systolic LV volume and LV ejection fraction measured by echocardiography at follow‐up differed significantly between both groups (51 ± 5 ml versus 65 ± 3 ml, P = 0.033; 47.5 ± 2.6% versus 38.8 ± 1.2%, P = 0.005). The inflammatory response in the damaged myocardium did not differ between groups. This study indicates that invasive surgery reduces IS and preserves cardiac function in a porcine MI model. Future studies need to elucidate the effect of infarct induction technique on the efficacy of pharmacological therapies in large animal cardioprotection studies.