Protection against postischemic myocardial dysfunction in anesthetized rabbits with scavengers of oxygen-derived free radicals: superoxide dismutase plus catalase, N-2-mercaptopropionyl glycine and captopril.

Postischemic myocardial dysfunction in canine myocardium has been reported to be reduced by scavengers of oxygen-derived free radicals. One potential source of oxygen-derived free radicals in canine myocardium is xanthine oxidase, but human and rabbit myocardium either lack or possess very low levels of this enzyme. Therefore, the effects of scavengers of oxygen-derived free radicals on postischemic myocardial dysfunction produced by 15 min of ischemia and 3 h of reperfusion were evaluated in vivo in the rabbit. Superoxide dismutase (SOD) (45,000 U/kg) and catalase (55,000 U/kg) were given into the left atrium 10 min before ischemia, and followed by an additional 45,000 U/kg of SOD and 55,000 U/kg of catalase given over 85 min. This treatment reduced postischemic myocardial dysfunction, as did sulfhydryl-containing free radical scavengers N-2-mercaptopropionyl glycine (4 mg/kg, i.v.) and captopril (3 mg/kg, i.v.) given 5 min before and 60 min after reperfusion. SOD given alone at the same dose was ineffective, as was enalaprilat (0.3 mg/kg, i.v.), an angiotensin-converting enzyme inhibitor that does not scavenge oxygen-derived free radicals. Thus, postischemic myocardial dysfunction was reduced by scavengers of oxygen-derived free radicals in vivo in a species that is deficient in myocardial xanthine oxidase. This suggests that oxygen-derived free radicals derived from a source other than xanthine oxidase play a role in postischemic myocardial dysfunction.     

Captopril: a free radical scavenger.

The use of captopril in heart failure and hypertension is becoming increasingly accepted. Captopril has a sulphydryl group in its molecular structure. We wondered if this might confer free radical scavenging activity on the drug and have investigated this in an in vitro system. Results show that captopril is a free radical scavenger and we suggest that this action might be relevant in its use in heart failure and other vascular diseases.     

Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury

Recanalization and neuroprotection have been mainly targeted for the specific treatment of acute ischemic stroke. Free radicals play a crucial role in brain ischemic injury by exacerbating membrane damage through peroxidation of unsaturated fatty acids of cell membrane, leading to neuronal death and brain edema. Free radicals have been implicated in stroke pathophysiology as pivotal contributors to cell injury. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a novel potent free radical scavenger that has been clinically used to reduce the neuronal damage following ischemic stroke. Edaravone exerts neuroprotective effects by inhibiting endothelial injury and by ameliorating neuronal damage in brain ischemia. Edaravone provides the desirable features of NOS: it increases eNOS (beneficial NOS for rescuing ischemic stroke) and decreases nNOS and iNOS (detrimental NOS). Post- reperfusion brain edema and hemorrhagic events induced by thrombolytic therapy may be reduced by edaravone pretreatment. Increased productions of superoxide and NO in the brain after reperfusion and a concomitant surge in oxygen free radicals with increased NO during recirculation lead to formation of peroxynitrite, a superpotent radical. Edaravone, which inhibits oxidation and enhances NO production derived from increased eNOS expression, may improve and conserve cerebral blood flow without peroxynitrite generation during reperfusion. Clinical experience with edaravone suggests that this drug has a wide therapeutic time window. The combination therapy (a thrombolytic plus edaravone) is likely to target brain edema, reduce stroke death and improve the recovery from neurological deficits in stoke patients.     

T-0162, a novel free radical scavenger, reduces myocardial infarct size in rabbits

1. We investigated the effects of 1-(3-tert-butyl-2-hydroxy-5-methoxyphenyl)-3-(3-pyridylmethyl)urea hydrochloride (T-0162), a novel low-molecular weight free radical scavenger, on the generation of superoxide anions and hydroxyl radicals in vitro and in vivo and on myocardial infarct (MI) size in an in vivo model of MI in rabbits. 2. It was found that T-0162 scavenged both superoxide anions and hydroxyl radicals in a concentration-dependent manner in vitro. 3. In an in vivo rabbit model with 30 min coronary occlusion and 30min reperfusion, T-0162 scavenged hydroxyl radicals generated in the myocardium during reperfusion. 4. Anaesthetized open-chest Japanese white male rabbits were subjected to 30 min coronary occlusion and 48 h reperfusion. The control group (n = 10) was infused with 10% lecithin solution for 220 min from 10 min before occlusion to 180 min after reperfusion. The pretreatment group (n = 10) was infused with T-0162 dissolved in 10% lecithin solution for 220 min from 10 min before occlusion to 180 min after reperfusion at a rate of 400 microg/kg per min. The post-treatment group (n = 10) was injected with an i.v. bolus of 10 mg/kg T-0162 and was then infused with 400 microg/kg per min T-0162 for 190 min from 10 min before reperfusion to 180 min after reperfusion. After 48 h reperfusion, infarct size was measured histologically and expressed as a percentage of area at risk (AAR). 5. There was no significant difference in haemodynamic parameters among the three groups throughout the experimental period. The per cent infarct size of the AAR in the T-0162 groups (24.8+/-4.3 and 30.5+/-3.9% for pre- and posttreatment groups, respectively) was significantly reduced compared with control (44.7+/-4.1%; P<0.05). There was no significant difference in the AAR among the three groups. 6. In conclusion, T-0162 reduces MI size through the inhibition of reperfusion injury.     

Gliclazide: a general free radical scavenger.

Free radical mechanisms have been implicated in diabetic microangiopathy. Agents that scavenge free radicals may be beneficial. We assessed the scavenging ability of two sulphonylureas, gliclazide and glibenclamide, in vitro. The assay which employs o-dianisidine sensitised by riboflavin can be used to distinguish between superoxide scavengers and general scavengers. The former species lead to an augmentation while the latter has an inhibitory effect. The drugs were added in final concentrations of 0.5, 1.0, 2.5 and 5.0 micrograms/ml. The percentage inhibition (mean +/- S.D.) for each concentration of gliclazide respectively was 11.0 +/- 2.5%, 20.8 +/- 2.9%, 31.4 +/- 2.2% and 47.2 +/- 0.8%. Glibenclamide had no scavenging effects. The results demonstrate that gliclazide is a powerful general free radical scavenger in vitro. We postulate that this scavenging quality of gliclazide may be important in diabetes.     

Improvement of postischemic dopaminergic dysfunction by edaravone, a free radical scavenger

Effects of a free radical scavenger, edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), on ischemia/reperfusion-induced dysfunctions of rat striatal dopaminergic neurons were examined using in vivo brain microdialysis. During transient forebrain ischemia, dopamine levels in dialysates were elevated 140-fold above controls but rapidly recovered after reperfusion. The increase in dopamine levels induced by high K+ stimulation after reperfusion was far smaller than that of the controls. Pretreatment with edaravone but not post-treatment dose-dependently improved the response to high K+ but not the massive dopamine increase during ischemia. These results suggest that free radicals produced during ischemia play more important roles in ischemia/reperfusion-induced dysfunctions of dopaminergic neurons.     

自由基清除剂依达拉奉对H_2O_2损伤的PC12细胞释放谷氨酸的影响

目的:探讨H_2O_2对PC12细胞谷氨酸(GLU)释放的影响及依达拉奉的阻断作用。方法:用H_2O_2处理体外培养的PC12细胞建立细胞损伤模型,并加入不同剂量的依达拉奉(10~(-3),10~(-4),10~(-5),10~(-6), 10~(-7)mol·L~(-1)),显微镜下观察PC12细胞形态,MTT法检测活细胞存活率,GLU试剂盒测定细胞培养液中GLU的含量。结果:H_2O_2处理24 h后,细胞形态发生明显改变,胞体变小、突起缩回。MTT吸光值减小,活细胞数减少。GLU释放含量明显增加。依达拉奉组细胞形态明显改善,MTT吸光值显著增加, GLU释放含量明显降低。结论:在H_2O_2的作用下,PC12细胞GLU释放增加,加入依达拉奉后PC12细胞的GLU释放量减少。     

氨乙基异硫脲对在体家兔缺血/再灌流心肌损伤及自由基生成的影响(英文)

在家兔心脏冠状动脉结扎缺血/再灌流的损伤型模上,采用电子自旋共振(ESR)技术,直接测定整体家兔心肌缺血/再灌流早期自由基信号。自由基清除剂2-β-氨乙基异硫脲(AET)1.7 mg/kg,结扎前15 miniv,能使缺血30 min/再灌流2 min时,缺血心肌中自由基总浓度(10.6±4.1 nmol/g)明显低于对照组(18.0±2.1 nmol/g),而维拉帕米不能明显降低自由基生成量。AET还能减少再灌流期间脂质过氧化产物丙二醛生成量,降低血浆中CK,LDH的含量,改善ECG变化,从而使心肌梗塞的范围由对照组的31±4％降至12±2％。此外,AET可消除致死性室颤的发生。实验结果提示,自由基在缺血/再灌流损伤发生中起重要作用。AET对缩小心肌梗塞范围,消除室颤的发生具有良好的作用,因此可能是一类防治急性心肌梗塞及溶栓治疗或心脏手术后再灌流引起心律失常的有应用价值的新药。     

The specific free radical scavenger edaravone suppresses bleomycin-induced acute pulmonary injury in rabbits

1. Intratracheal instillation of bleomycin induces a condition in rabbits that serves as a useful model of human pulmonary fibrosis. Bleomycin-induced production of reactive oxygen species leads to acute lung inflammation and induction of apoptosis, which is followed by pulmonary fibrosis at a later chronic stage. In the present study, we tested whether edaravone, a free radical scavenger, would suppress bleomycin-induced acute pulmonary inflammation. 2. Rabbits were divided into three groups (n = 10 in each): (i) a bleomycin-treated group, which received intratracheal instillation of 2 mg/kg bleomycin; (ii) a bleomycin + edaravone group, which received a 10 day regimen of daily intravenous injections of edaravone (3 mg/kg per day) beginning 3 days before bleomycin instillation; and (iii) a saline control group. Rabbits were killed for analysis 7 days after bleomycin administration. 3. In lung tissues from the bleomycin-treated group, marked infiltration of inflammatory cells, consisting mainly of lymphocytes, neutrophils and eosinophils, was observed. In addition, significantly increased numbers of TUNEL-positive (apoptotic) and transforming growth factor-beta-positive cells were seen. All these effects were significantly attenuated by treatment with edaravone. 4. The findings of the present study suggest that edaravone may be useful in the prevention of acute lung injury resulting from the production of reactive oxygen species.     

黄芩苷对羟自由基诱发心肌损伤的保护作用

目的:研究黄芩苷(baicalin,Bai)对羟自由基诱导大鼠心肌损伤的保护作用。方法:体外羟自由基发生系诱导心肌脂质过氧化,无机磷法测定心肌三磷酸腺苷(ATP)酶活性,分光光度法检测脂质过氧化物(MDA)含量、线粒体膨胀度和细胞色素氧化酶活性。结果:在羟自由基作用下心肌细胞膜中MDA含量明显升高,ATP酶活性显著降低,且ATP酶活性与MDA含量间呈显著负相关;线粒体膨胀明显,细胞色素氧化酶活性下降。Bai可降低保护羟自由基引起的心肌细胞膜MDA含量的升高和提高ATP酶活性;降低线粒体膨胀程度,恢复细胞色素氧化酶活性。结论:Bai可能通过清除氧自由基,抑制MDA的生成实现其保护心肌的功能。     

Targeting reperfusion injury in acute myocardial infarction: a review of reperfusion injury pharmacotherapy

Introduction: Acute myocardial infarction (AMI) (secondary to lethal ischemia–reperfusion [IR]) contributes to much of the mortality and morbidity from ischemic heart disease. Currently, the treatment for AMI is early reperfusion; however, this itself contributes to the final myocardial infarct size, in the form of what has been termed ‘lethal reperfusion injury’. Over the last few decades, the discovery of the phenomena of ischemic preconditioning and postconditioning, as well as remote preconditioning and remote postconditioning, along with significant advances in our understanding of the cardioprotective pathways underlying these phenomena, have provided the possibility of successful mechanical and pharmacological interventions against reperfusion injury.

Areas covered: This review summarizes the evidence from clinical trials evaluating pharmacological agents as adjuncts to standard reperfusion therapy for ST-elevation AMI.

Expert opinion: Reperfusion injury pharmacotherapy has moved from bench to bedside, with clinical evaluation and ongoing clinical trials providing us with valuable insights into the shortcomings of current research in establishing successful treatments for reducing reperfusion injury. There is a need to address some key issues that may be leading to lack of translation of cardioprotection seen in basic models to the clinical setting. These issues are discussed in the Expert opinion section.     

Targeting reperfusion injury in acute myocardial infarction: a review of reperfusion injury pharmacotherapy

INTRODUCTION: Acute myocardial infarction (AMI) (secondary to lethal ischemia-reperfusion [IR]) contributes to much of the mortality and morbidity from ischemic heart disease. Currently, the treatment for AMI is early reperfusion; however, this itself contributes to the final myocardial infarct size, in the form of what has been termed 'lethal reperfusion injury'. Over the last few decades, the discovery of the phenomena of ischemic preconditioning and postconditioning, as well as remote preconditioning and remote postconditioning, along with significant advances in our understanding of the cardioprotective pathways underlying these phenomena, have provided the possibility of successful mechanical and pharmacological interventions against reperfusion injury. AREAS COVERED: This review summarizes the evidence from clinical trials evaluating pharmacological agents as adjuncts to standard reperfusion therapy for ST-elevation AMI. EXPERT OPINION: Reperfusion injury pharmacotherapy has moved from bench to bedside, with clinical evaluation and ongoing clinical trials providing us with valuable insights into the shortcomings of current research in establishing successful treatments for reducing reperfusion injury. There is a need to address some key issues that may be leading to lack of translation of cardioprotection seen in basic models to the clinical setting. These issues are discussed in the Expert opinion section.     

Effect of N-2-mercaptopropionylglycine in limiting myocardial reperfusion injury following 90 minutes of ischemia in dogs

Present study was designed to examine the effectiveness of N-2-mercaptopropionyl glycine (MPG) on oxygen free radical (OFR) mediated reperfusion injury. Twenty dogs underwent 90 min of left anterior descending (LAD) coronary artery occlusion followed by 4 h of reperfusion. In control animals (n = 12), 115 ml of saline was infused through left atrium at the onset of reperfusion whereas treated animals (n = 8) received loading dose of MPG (40 mg/kg) infused through left atrium for 1 h followed by maintenance dose (25 mg/kg) for remaining 3 hours. Percentage area of necrosis vis-a-vis area at risk and percentage necrosis in left ventricular mass in MPG treated animals was significantly lower in comparison to control animals. Reperfusion in control group increased the lipid peroxidation and lowered glutathione (GSH) and superoxide dismutase (SOD) activity. MPG treatment significantly lowered the lipid peroxidation whereas GSH and SOD levels in necrotic zone were higher than in control. The above results suggest that MPG can offer a significant cardioprotection against oxidative stress in canine model.     

Further evidence of the antiulcer activity of IAC, a novel free radical scavenger

It has been proposed that free radicals, reactive oxygen species (ROS) and reactive nitrogen species play a critical role in gastric mucosal damage. It is well known that the exposure of gastric mucosa to damaging factors such as stress and nonsteroidal anti-inflammatory drugs produces acute ulcers that are mainly mediated by ROS. The aim of the present study was to investigate the gastroprotective properties of bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate (IAC), a novel nonpeptidyl low-molecular-weight radical scavenger, in two different models of gastric ulcer in rats caused by ROS. IAC was orally administered at the doses of 50 and 100 mg/kg before gastric ulceration induced by indomethacin and water immersion and restraint stress. The number and severity of gastric lesions, following macroscopic inspection of the mucosa, were evaluated and expressed as an ulcer score. Oral administration of IAC dosed at 50 and 100 mg/kg was able to significantly prevent gastric ulceration induced by indomethacin and by stress. The gastroprotective effect of IAC on gastric mucosa could be attributed to its intrinsic antioxidant activity, suggesting it as a novel antiulcer agent.