M40403 prevents myocardial injury induced by acute hyperglycaemia in perfused rat heart
M40403 prevents myocardial injury induced by acute hyperglycaemia in perfused rat heart
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DOI：
10.1016/j.ejphar.2004.06.037
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发表时间：
2004-08-16
影响因子：
5
通讯作者：
D'Amico, M
中科院分区：
文献类型：
--
作者：
Di Filippo, C;Cuzzocrea, S;D'Amico, M
M40403是一种低分子量、合成的含锰双环己基吡啶超氧化物歧化酶模拟物(SODm)，可去除超氧阴离子(O-.(2)-)，而不干扰其他已知参与心血管变化的活性物种(如一氧化氮[NO]和过氧亚硝酸根[ONOO-])。因此，M40403是一种重要的药理学工具，可以用来分析O-2(-)在高糖心脏灌流引起的心血管功能和生化改变中的作用。高糖心脏灌流引起重要的心血管变化，特征是QT间期延长，冠脉灌注压(CPP)增加，脂质过氧化，MnSOD活性下降和DNA损伤。M40403(1~10 mg/L)可显著降低心血管改变的各项指标。此外，通过心脏组织的免疫组织化学分析，高糖灌流诱导了显著的硝基酪氨酸的形成和多(二磷酸腺苷[ADP]-核糖)合成酶(PARS)的激活。M40403减少了硝基酪氨酸和PARS的染色程度。这些结果清楚地表明，O-2(-)在高浓度葡萄糖心脏灌流引起的心血管功能和生化改变的发生中起关键作用。因此，合成的超氧化物歧化酶，如M40403，为治疗各种心血管疾病提供了一种新的治疗方法，这些自由基被认为发挥了作用。(C)2004爱思唯尔B.V.保留所有权利。
M40403 is a low-molecular-weight, synthetic manganese-containing biscyclohexylpyridine superoxide dismutase mimetic (SODm) that removes superoxide anions (O-.(2)-) without interfering with other reactive species known to be involved in cardiovascular alterations (e.g. nitric oxide [NO] and peroxynitrite [ONOO-]). As such, M40403 represents an important pharmacological tool to dissect the roles of O-2(-) in functional and biochemical cardiovascular alterations induced by perfusion of high glucose concentrations into the heart.Perfusion of a high glucose concentration of glucose into the heart elicited important cardiovascular alterations characterized by QT interval prolongation, increase in coronary perfusion pressure (CPP), lipid peroxidation, decrease in MnSOD activity and DNA damage. All parameters of cardiovascular alteration were attenuated by M40403 (1-10 mg/l). Furthermore, perfusion of a high of glucose concentration induced a significant formation of nitrotyrosine as well as an activation of poly(adenosine diphosphate [ADP]-ribose) synthetase (PARS), as determined by immunohistochemical analysis of heart tissue. The extent of staining for nitrotyrosine and PARS was reduced by M40403.These results clearly indicate that O-2(-) plays a critical role in the development of the functional and biochemical cardiovascular alterations induced by perfusion of a high concentration of glucose into the heart. Therefore, synthetic enzymes of SOD, such as M40403, offer a novel therapeutic approach for the management of various cardiovascular diseases where these radicals have been postulated to play a role. (C) 2004 Elsevier B.V. All rights reserved.