亲水性维生素E类似物瑞索非那酯对大鼠心脏缺血再灌注损伤的有益作用。

Beneficial effect of raxofelast, an hydrophilic vitamin E analogue, in the rat heart after ischemia and reperfusion injury.

作者信息

Campo G M, Squadrito F, Campo S, Altavilla D, Quartarone C, Ceccarelli S, Ferlito M, Avenoso A, Squadrito G, Saitta A, Caputi A P

机构信息

Institute of Pharmacology, School of Medicine, Messina, Italy.

出版信息

J Mol Cell Cardiol. 1998 Aug;30(8):1493-503. doi: 10.1006/jmcc.1998.0713.

DOI:10.1006/jmcc.1998.0713

PMID:9737936

Abstract

Several studies report that among the antioxidant agents used to reduce injury after myocardial ischemia/reperfusion, analogues of vitamin E (VE) seem to have a significant efficacy. Raxofelast is a potent antioxidant agent under investigation, structurally related to VE, having an excellent bioavailability and favourable physicochemical properties. We assessed raxofelast in a rat model of myocardial damage induced by 1 h of left coronary artery occlusion followed by 6 h of reperfusion. Myocardial ischemia/reperfusion produced: wide tissue necrosis (50.3+/-10.3%); membrane peroxidation, evaluated by assessing cardiac malondialdehyde (MAL) (87.8+/-15.8 nmol/g tissuev 9.53+/-2.4 nmol/g tissue) and plasma conjugated dienes (CD) (8.73+/-1.86 DeltaABS/mlv 1.61+/-0.45 DeltaABS/ml); endogenous antioxidant wasting [cardiac VE=23.5+/-10.2 nmol/g tissuev 61.4+/-13.4 nmol/g tissue, cardiac reduced glutatione (GSH)=2.15+/-1.23 micromol/g proteinv 7.34+/-0.92 micromol/g protein and cardiac superoxide dismutase (SOD)=8.9+/-4.1 U/mg proteinv 17. 5+/-4.2 U/mg protein]; depressed mean arterial blood pressure (MAP) (61.4+/-5.8 mmHgv 85.3+/-6.2 mmHg); heart rate (HR) (275+/-35 beats/minv 368+/-34 beats/min) and left-ventricular derivative developed force (LV dP/dtmax) (1050+/-187 mmHg/sv 2520+/-194 mmHg/s); and cardiac neutrophil accumulation, evaluated by assessing cardiac myeloperoxidase (MPO) (9.23+/-2.1 U/g tissuev 0.92+/-0.12 U/g tissue). Administration of raxofelast (25, 50 and 100 mg/kg i.p. 5 min after occlusion) limited myocardial necrosis (22.3+/-14.8%P<0. 005, following the highest dose), reduced lipid peroxidation (MAL=43. 5+/-14.7 nmol/g tissueP<0.001 and CD=4.01+/-2.21 DeltaABS/mlP<0.001, following the highest dose), restored the endogenous antioxidants VE (52.8+/-14.2 nmol/g tissueP<0.001, following the highest dose), SOD (14.2+/-2.7 U/mg proteinP<0.001, following the highest dose) and GSH (4.92+/-1.33 micromol/g proteinP<0.005, following the highest dose), improved hemodynamic parameters (MAP=68.1+/-5.3 mmHgP<0.05, HR=317+/-27 beats/minP<0.05, LV dP/dtmax=1427+/-143 mmHg/sP<0.05, following the highest dose) and reduced myocardial neutrophil infiltration (MPO=5.1+/-1.5 U/g tissueP<0.001, following the highest dose). These data suggest that raxofelast could be considered a useful drug to reduce myocardial infarction.

摘要

多项研究报告称，在用于减轻心肌缺血/再灌注损伤的抗氧化剂中，维生素E（VE）类似物似乎具有显著疗效。瑞索非拉斯特是一种正在研究的强效抗氧化剂，其结构与VE相关，具有出色的生物利用度和良好的理化性质。我们在大鼠左冠状动脉闭塞1小时后再灌注6小时诱导的心肌损伤模型中评估了瑞索非拉斯特。心肌缺血/再灌注导致：广泛的组织坏死（50.3±10.3%）；通过评估心脏丙二醛（MAL）（87.8±15.8 nmol/g组织对9.53±2.4 nmol/g组织）和血浆共轭二烯（CD）（8.73±1.86ΔABS/ml对1.61±0.45ΔABS/ml）来评估的膜过氧化；内源性抗氧化剂消耗[心脏VE=23.5±10.2 nmol/g组织对61.4±13.4 nmol/g组织，心脏还原型谷胱甘肽（GSH）=2.15±1.23μmol/g蛋白对7.34±0.92μmol/g蛋白，心脏超氧化物歧化酶（SOD）=8.9±4.1 U/mg蛋白对17.5±4.2 U/mg蛋白]；平均动脉血压（MAP）降低（61.4±5.8 mmHg对85.3±6.2 mmHg）；心率（HR）（275±35次/分钟对368±34次/分钟）和左心室压力变化最大速率（LV dP/dtmax）（1050±187 mmHg/s对2520±194 mmHg/s）；以及通过评估心脏髓过氧化物酶（MPO）（9.23±2.1 U/g组织对0.92±0.12 U/g组织）来评估的心脏中性粒细胞积聚。在闭塞后5分钟腹腔注射瑞索非拉斯特（25、50和100 mg/kg）可限制心肌坏死（最高剂量后为22.3±14.8%，P<0.005），减少脂质过氧化（最高剂量后MAL=43.5±14.7 nmol/g组织，P<0.001；CD=4.01±2.21ΔABS/ml，P<0.001），恢复内源性抗氧化剂VE（最高剂量后为52.8±14.2 nmol/g组织，P<0.001）、SOD（最高剂量后为14.2±2.7 U/mg蛋白，P<0.001）和GSH（最高剂量后为4.92±1.33μmol/g蛋白，P<0.005），改善血流动力学参数（最高剂量后MAP=68.1±5.3 mmHg，P<0.05；HR=317±27次/分钟，P<0.05；LV dP/dtmax=1427±143 mmHg/s，P<0.05），并减少心肌中性粒细胞浸润（最高剂量后MPO=5.1±1.5 U/g组织，P<0.001）。这些数据表明瑞索非拉斯特可被视为一种用于减少心肌梗死的有用药物。