抗心肌缺血再灌注损伤药物的研究进展

八十年代以来 ,随着冠状动脉溶栓术、经皮腔内冠状动脉成形术 (ＰＴＣＡ)、冠状动脉内扩张术、冠状动脉旁路术等技术的推广应用 ,心肌再灌注损伤 (ｍｙｏｃａｒ ｄｉａｌｒｅｐｅｒｆｕｓｉｏｎｉｎｊｕｒｙ ;ＭＲＩ)已越来越受到广大基础和临床工作者的重视 ,探索防治心肌缺血再灌注损伤的药物已成为当今医学科学研究的热点之一。1　抗氧自由基药物动物实验和临床应用自由基 (ＯＦＲ)清除剂超氧化物歧化酶 (ＳＯＤ)和过氧化氢酶 (ＣＡＴ) ,使心肌收缩力及心功能有明显改善。含疏基化合物的特点是含疏基 ,提供氢原子 ,使ＯＦＲ变成不活泼的…     

一氧化氮与心肌缺血—再灌注损伤

血管内皮细胞合成和释放的一氧化氮（ＮＯ）在心血管系统中具有重要的舒张血管，抗粒细胞，血小板粘附和聚集作用。在心肌缺血－再灌注过程中，ＮＯ既有减轻再灌注损伤，又有介导灌注损伤的双重作用。调节体内Ｌ－精氨酸，ＮＯ合成途径，可望为心肌缺血－再灌注损伤的预防和治疗提供新的方法。     

心肌缺血再灌注损伤研究进展

急性心肌梗死是主要的致死致残原因,再灌注治疗是其标准的治疗方案,然而再灌注治疗伴随着再灌注损伤,再灌注损伤的机理目前还未完全清楚,分子、细胞、组织上的改变均与参与再灌注损伤,本文就心肌缺血再灌注损伤的研究进展作一综述。     

心肌缺血再灌注损伤研究进展

八十年代以来 ,随着冠状动脉溶栓术、经皮冠状动脉成形术 (ＰＴＣＡ)、冠状动脉内扩张术、冠状动脉旁路术等技术的推广应用 ,心肌再灌注损伤 (ｍｙｏｃａｒｄｉａｌｒｅｐｅｒｆｕｓｉｏｎｉｎｊｕｒｙ ;ＭＲＩ)已越来越受到广大基础和临床工作者的重视。心肌缺血再灌注损伤具有多因素复杂的机制 ,概括起来 ,包括以下几点 :1　自由基与心肌缺血再灌注损伤大量研究表明 ,心肌缺血再灌注时 ,氧自由基含量明显增加。1.1　心肌缺血再灌注时 ,氧自由基生成增多 :(1)次黄嘌呤 黄嘌呤氧化酶系统。在心肌缺血时 ,能量消耗 ,细胞内三磷酸腺苷 (ＡＴＰ…     

心肌缺血再灌注损伤研究进展

正心肌缺血本质是心肌的氧供需求平衡失调,缺血心肌可呈现功能、形态及代谢等方面的损伤[1,2],减少心肌缺血后损伤的最有效办法就是恢复组织灌注。但是,目前遇到的问题是缺血心肌在恢复血液再灌注后,出现了心律失常、心肌能量代谢障碍、心肌细胞超微结构的变化及微血管内皮细胞(VEC)损伤和功能障碍等一系列的功能、结构、代谢及心肌细胞电生理特性等各个方面的损伤进一步加重的现象,即心肌缺血/再灌     

一氧化氮在心肌缺血再灌注损伤中的作用

90年代以来,人们对一氧化氮(ＮｉｔｒｉｃＯｘｉｄｅ,ＮＯ)在心肌缺血再灌注过程中的作用进行了大量研究,结论不甚一致,争论的焦点集中在以下两个方面:1在心肌缺血再灌注过程中,ＮＯ的产生是增加还是减少?2ＮＯ是参与了心肌缺血再灌注损伤,还是减轻心肌缺血再灌注损伤。本文对近年来有关ＮＯ与心肌缺血再灌注损伤的实验进行了分析和总结,旨在澄清ＮＯ在心肌缺血再灌注过程中的作用。一、ＮＯ的产生与心肌缺血再灌注　心肌缺血再灌注过程中ＮＯ的产生量,不同的实验有不同的结论。Ｔｓａｏ等[1]在猫局部心肌缺血90ｍｉｎ后再灌注实验中,发现再…     

一氧化氮在心肌缺血再灌注损伤中的作用

1987年Palmer等确认一氧化氮(nitric oxide,NO)即为内皮衍生舒张因子(endothelium-derivedrelaxing factor,EDRF)的实验揭开了生物学研究的一个崭新的领域。它由内皮细胞产生,介导血管内皮依赖性舒张,对控制局部血流有重要作用。最近有实验显示在心肌缺血再灌注过程中也存在血管内皮严重受损,表现为内皮依赖性舒张受限。现就此问题作一综述。     

心肌缺血再灌注损伤的研究进展

<正>心肌组织缺血时,尽早恢复血供是最重要的治疗手段,然而当缺血的心肌组织再次恢复血流灌注时,心肌的组织结构、能量代谢、电生理及心功能反而会产生更加严重,甚至不可逆的损伤,这种损伤被称为缺血再灌注损伤(ischemia reperfusion injury,IRI)。IRI的主要机制包括氧化应激反应、钙超载、炎症损伤及线粒体膜通透性转换孔(mitochondrial permeablity transition pore,mP TP)开放等~([1])。这些机制在缺     

心肌缺血再灌注损伤的研究进展

心肌缺血再灌注(I/R)损伤会导致心律失常、心肌顿抑、微血管阻塞等,严重影响病人心功能及预后。因此,探索如何减少心肌I/R损伤具有重要的临床意义。综述缺血再灌注损伤发病机制及干预方法,以期为临床缺血性心脏病血运重建后引起I/R损伤的防治提供参考。     

心肌缺血再灌注损伤防治研究进展

通过溶栓、冠脉动脉(冠脉)搭桥以及冠脉介入是治疗急性心肌梗死的有效方法。但在改善心肌血供的同时可能加重单纯心肌缺血所造成的损伤，即所谓的再灌注损伤。采取措施防治心肌缺血再灌注损伤对促进心肌细胞存活具有重要意义。很多研究结果表明药物因子对心肌缺血再灌注损伤具有防治作用，其中包括自由基清除剂、钙通道阻滞剂、中性粒细胞抑制     

一氧化氮与肺缺血再灌注损伤的研究进展

一氧化氮（nitricoxide，NO）是一种活性很强的自由基，具有广泛的生物学活性。多项研究提示NO在急性肺缺血／再灌注（ischemia／reperfusion，I／R）损伤中具有重要作用。本文重点描述有关一氧化氮在肺I／R损伤中作用的研究进展。     

New progress in roles of nitric oxide during hepatic ischemia reperfusion injury

Hepatic ischemia reperfusion injury(HIRI) is a clinical condition which may lead to cellular injury and organ dysfunction. The role of nitric oxide(NO) in HIRI is complicated and inconclusive. NO produced by endothelial nitric oxide synthase(e NOS) activation plays a protective role during early HIRI. But e NOS overexpression and the resulting excessive NO bioavailability can aggravate liver injury. NO induced by inducible nitric oxide synthase(i NOS) may have either a protective or a deleterious effect during the early phase of HIRI, but it may protect the liver during late HIRI. Here, we reviewed the latest findings on the role of NO during HIRI:(1) NO exerts a protective effect against HIRI by increasing NO bioavailability, downregulating p53 gene expression, decreasing inflammatory chemokines, reducing ROS via inhibiting the mitochondrial respiratory chain, activating s GCGTP-c GMP signal pathway to reduce liver cell apoptosis, and regulating hepatic immune functions;(2) e NOS protects against HIRI by increasing NO levels, several e NOS/NO signal pathways(such as Akt-e NOS/NO, AMPK-e NOS/NO and HIF-1α-e NOS/NO) participating in the anti-HIRI process, and inhibiting over-expression of e NOS also protects against HIRI; and(3) the inhibition of i NOS prevents HIRI. Thus, the adverse effects of NO should be avoided, but its positive effect in the clinical treatment of diseases associated with HIRI should be recognized.     

一氧化氮合酶在N-乙酰半胱氨酸调控大鼠心肌冷缺血-再灌注损伤中的变化

目的:观察一氧化氮合酶(NOS)在N-乙酰半胱氨酸(NAC)调控大鼠心肌冷缺血-再灌注损伤中的变化。方法:将健康雄性Lewis大鼠60只随机分为3组。(1)对照组:摘取供心前30 min,经供体大鼠下腔静脉注射生理盐水0.5 mL;(2)供体预处理组:摘取供心前30 min,经供体大鼠下腔静脉注射NAC300 mg/kg,受体大鼠不作预处理;(3)受体预处理组:移植前30 min,经受体大鼠下腔静脉注射NAC300 mg/kg,供体大鼠不作预处理。将冷藏于4℃HTK液18 h的供心移植至受体大鼠腹腔,建立同种异体心脏移植模型。于再灌注24 h后取供心采用免疫组化方法检测诱导型一氧化氮合酶/内皮型一氧化氮合酶(iNOS/eNOS)蛋白表达水平,以免疫组化评分(IHS)表示。采用Real time-PCR法检测iNOS/eNOS mRNA表达。结果:与对照组相比,供、受体预处理组的iNOS蛋白表达降低,IHS评分分别为3.00±0.15、1.50±0.22、1.63±0.26,P<0.05;而eNOS蛋白表达升高,IHS评分分别为2.00±0.21,3.60±0.16,3.40±0.26,P<0.05。与对照组相比,受体预处理组iNOS mRNA表达降低(0.43±0.17对1.00±0.41,P<0.05),供体预处理组eNOS mRNA表达升高(3.06±1.47对1.00±0.65,P<0.05)。结论:NOS参与了NAC预处理减轻移植大鼠心肌缺血-再灌注损伤的过程。     

Nitric oxide in myocardial ischemia/reperfusion injury

Administration of nitric oxide (NO), NO donors or drugs that enhance NO release (statins, calcium antagonists, ACE-inhibitors, dexamethasone) prior to ischemia protects the myocardium against ischemia/reperfusion injury. While this exogenous administration of NO prior to ischemia can initiate a preconditioning-like phenomenon, endogenous NO-synthase (NOS)-derived NO is not involved in triggering or mediating the early phase of ischemic preconditioning's protection, but does play a pivotal role for initiating and mediating the delayed phase of ischemic preconditioning's protection. The present review now summarizes the importance of endogenous and exogenous NO when given at the time of reperfusion for vascular and myocardial function and morphological outcome following ischemia/reperfusion. Given the inconsistency of the published data, potential confounding factors that might affect experimental results on the role of NO in myocardial ischemia/reperfusion were identified, such as (1) the lack of characterization of the involved NOS isoforms in myocardial ischemia/reperfusion injury in different animal species, (2) the lack of direct measurements of myocardial NO concentration and/or NOS activity to assure sufficient NOS inhibition, (3) the lack of consideration of nonenzymatic NO production as a potential source of NO, and (4) the absence of plasma or blood components in in vitro studies influencing NO delivery and metabolism. Future research on the importance of NO in ischemia/reperfusion injury will have to focus more precisely on the identification and standardization of potential confounding experimental factors that influence synthesis, transport, and interaction of NO with various targets in blood and tissue.     

Preconditioning by inhaled nitric oxide prevents hyperoxic and ischemia/reperfusion injury in rat lungs

Since the generation of nitric oxide (NO) is an essential step in the trigger phase of ischemic preconditioning, short-term inhalation of NO before ischemia should ameliorate ischemia/reperfusion (I/R) injury of the lung. We tested this hypothesis in high oxygen (>99%) ventilated rats in order to additionally evaluate compatibility of NO and exposure to hyperoxia. Male adult Sprague-Dawley rats inhaled NO (15 ppm, 10 min) before the left lung hilum was clamped for 1 h, and the reperfusion phase was observed for 4 h (NO group). Animals in the I/R group underwent the same treatment, but without NO inhalation. A third group without I/R served as time-matched controls. Animals in the I/R group showed severe I/R injury in terms of arterial pO2 (apO2), which was reduced to 22% of surgical controls (SCs) at time point 30 min reperfusion, and increased endothelial permeability (Evans blue procedure). The pretreatment with NO attenuated these effects. The pO2 after 4 h reperfusion was still 3.0-fold higher in the NO group compared to I/R. In contrast, the I/R- and hyperoxia-induced invasion of leukocytes, as determined by measuring myeloperoxidase (MPO) activity, was not affected by NO. These data were correlated with the activity of major cellular signaling pathways by measuring the phosphorylation at activating and inhibitory sites of extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, protein kinase B (AKT), and glycogen synthase kinase 3beta (GSK-3beta), and by determination of cGMP in plasma and lung tissue. Inhalation of NO partly prevented the loss of activation by I/R and hyperoxic ventilation of ERK, JNK, and AKT, and it reduced the I/R-induced activation of GSK-3beta. The level of cGMP in plasma and lung tissue was increased in the NO group after 4 h reperfusion. In conclusion, application of inhaled NO in the preconditioning mode prevented I/R injury in the rat lung without interfering effects of hyperoxic ventilation. The effects of NO on cellular signaling pathways resemble mechanisms of ischemic preconditioning, but further studies have to evaluate the physiological relevance of these results.     

Selective modulation of endogenous nitric oxide formation in ischemia/reperfusion injury in isolated rat hearts

The role of nitric oxide (NO) in ischemia/reperfusion injury is controversial. We tested the role of inducible NOS (iNOS) in the ischemia/reperfusion injury in isolated rat hearts using the selective iNOS inhibitor S-methylisothiourea sulfate (SMT) and the non-selective NOS inhibitor N^G-nitro-L-arginine methyl ester (L-NAME). After 15 min of stabilization in Langendorff mode, hearts were perfused either with normal Krebs-Henseleit buffer, buffer containing 100 μM L-NAME, 0.5 μM SMT or 50 μM SMT for 5 min and were subjected to 25 min of ischemia followed by 30 min of reperfusion. Left ventricular developed pressure (LVDP) and total coronary flow (CF) were recorded continuously. After ischemia/reperfusion, a marked expression of iNOS protein was demonstrated by Western blotting, while virtually no iNOS protein was present in hearts without ischemia/reperfusion. Regional myocardial blood flow (RMBF) was measured with colored microspheres. Coronary vasoactive concentration of L-NAME and SMT depressed myocardial function as shown by decreased LVDP, dP/dt_max and coronary .ow before ischemia. After ischemia the recovery of the total CF was impaired in L-NAME and 50 μM SMT pretreated hearts which was related to homogenous RMBF decrease in the right and left ventricle compared to that in control group. Low concentration SMT (0.5 μM) showed no coronary vasoactive effects before ischemia and attenuated ischemia/reperfusion injury indicated by lower ischemic contracture at 25 min of ischemia and reduced CK and LDH release during reperfusion. Thus, NOS inhibition did not affect blood flow distribution in rat hearts either in the pre-ischemic or reperfusion period. Selective iNOS inhibition reduced ischemic injury by reducing ischemic contracture and CK as well as LDH release during reperfusion. Received: 20 March 2002, Returned for 1. revision: 8 April 2002, 1. Revision received: 14 August 2002, Returned for 2. revision: 5 September 2002, 2. Revision received: 3 February 2003, Accepted: 18 February 2003, Published online: 16 April 2003     

Attenuation of myocardial ischemia/reperfusion injury in mice with myocyte-specific overexpression of endothelial nitric oxide synthase

OBJECTIVE: The role of nitric oxide (NO) in myocardial ischemia/reperfusion injury remains controversial as both NO donors and NO synthase (NOS) inhibitors have shown to be protective. We generated transgenic (TG) mice that overexpress endothelial NOS (eNOS) exclusively in cardiac myocytes to determine the effects of high cardiac NO levels on ischemia/reperfusion injury and cellular Ca(2+) homeostasis. Wild-type (WT) mice served as controls. METHODS: Hearts were perfused in vitro and subjected to 20 min of total no-flow ischemia and 30 min of reperfusion (n=5 per group). Left ventricular function, cGMP levels and intracellular Ca(2+) transients (Ca(2+)(i)) were determined. RESULTS: Left ventricular pressure was reduced (maximum, -33%) and basal cardiac cGMP was increased (twofold) in TG hearts, and the changes were reversed by NOS blockade with N(G)-nitro-L-arginine methyl ester (L-NAME). Relative to baseline, recovery of reperfusion contractile function was significantly better in hearts from TG (98%) than WT (51%) mice, and L-NAME abolished this effect. Heart rate and coronary perfusion pressure were not different between groups. Systolic and diastolic Ca(2+)(i) concentrations were similar in WT and TG hearts, but Ca(2+)(i) overload during early reperfusion tended to be less in TG hearts. Kinetic analysis of pressure curves and Ca(2+)(i) transients revealed a faster left ventricular diastolic relaxation and abbreviated aequorin light signals in TG hearts at baseline and during reperfusion. CONCLUSIONS: High levels of NO/cGMP strongly protect against ischemia/reperfusion injury, the protection is largely independent of changes in Ca(2+)(i) modulation, but relates to reduced preischemic performance. Myocyte-specific NO augmentation may aid in studies of the (patho)physiological roles of cardiac-derived NO.