Nicorandil ameliorates mitochondrial dysfunction in doxorubicin-induced heart failure in rats: Possible mechanism of cardioprotection
Nicorandil ameliorates mitochondrial dysfunction in doxorubicin-induced heart failure in rats: Possible mechanism of cardioprotection
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DOI：
10.1016/j.bcp.2013.07.005
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发表时间：
2013-11-01
影响因子：
5.8
通讯作者：
EL-Maraghy, Shohda A.
中科院分区：
文献类型：
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作者：
Ahmed, Lamiaa A.;EL-Maraghy, Shohda A.
尽管阿霉素具有心脏毒性，但在多种癌症的治疗中，它仍然是一种高效的抗肿瘤药物。本研究观察了尼可地尔对阿霉素累积给药引起的大鼠血流动力学改变和线粒体功能障碍的保护作用。多柔比星静脉注射。超过2周，以获得18毫克/公斤的累积剂量。尼可地尔(3 mg/kg/d)口服加或不加阿霉素治疗。在接受末次阿霉素治疗后24小时记录心率和主动脉血流量。然后处死大鼠，快速取出心脏，测定细胞色素c、bcl2、bax和caspase3的表达，并测定caspase-3活性、磷酸肌酸和腺嘌呤核苷酸含量。同时检测线粒体氧化磷酸化能力、肌酸激酶活性和氧化应激标志物，并观察DNA断裂和超微结构变化。尼可地尔能有效缓解阿霉素心脏毒性所致的心率减慢、主动脉血流减慢和线粒体氧化应激状态。尼可地尔还通过恢复线粒体氧化磷酸化能力和肌酸激酶活性来保持磷酸肌酸和腺嘌呤核苷酸的含量。此外，尼可地尔通过抑制细胞凋亡信号通路、DNA片段化和线粒体超微结构改变而提供显著的心脏保护作用。有趣的是，尼可地尔并不干扰阿霉素对实体Ehrlich肿瘤生长的细胞毒作用。综上所述，尼可地尔可有效对抗阿霉素诱导的大鼠心力衰竭，改善血流动力学紊乱、线粒体功能障碍和超微结构改变，但不影响其抗肿瘤活性。(C)2013 Elsevier Inc.保留所有权利。
Despite of its known cardiotoxicity, doxorubicin is still a highly effective anti-neoplastic agent in the treatment of several cancers. In the present study, the cardioprotective effect of nicorandil was investigated on hemodynamic alterations and mitochondrial dysfunction induced by cumulative administration of doxorubicin in rats. Doxorubicin was injected i.p. over 2 weeks to obtain a cumulative dose of 18 mg/kg. Nicorandil (3 mg/kg/day) was given orally with or without doxorubicin treatment. Heart rate and aortic blood flow were recorded 24 h after receiving the last dose of doxorubicin. Rats were then sacrificed and hearts were rapidly excised for estimation of caspase-3 activity, phosphocreatine and adenine nucleotides contents in addition to cytochrome c, Bcl2, Bax and caspase 3 expression. Moreover, mitochondrial oxidative phosphorylation capacity, creatine kinase activity and oxidative stress markers were measured together with the examination of DNA fragmentation and ultrastructural changes. Nicorandil was effective in alleviating the decrement of heart rate and aortic blood flow and the state of mitochondrial oxidative stress induced by doxorubicin cardiotoxicity. Nicorandil also preserved phosphocreatine and adenine nucleotides contents by restoring mitochondrial oxidative phosphorylation capacity and creatine kinase activity. Moreover, nicorandil provided a significant cardioprotection via inhibition of apoptotic signaling pathway, DNA fragmentation and mitochondrial ultrastructural changes. Interestingly, nicorandil did not interfere with cytotoxic effect of doxorubicin against the growth of solid Ehrlich carcinoma. In conclusion, nicorandil was effective against the development of doxorubicin-induced heart failure in rats as indicated by improvement of hemodynamic perturbations, mitochondrial dysfunction and ultrastructural changes without affecting its antitumor activity. (C) 2013 Elsevier Inc. All rights reserved.