多柔比星诱发急性心脏毒性的早期标志物及其形成机制

M.V. Denysova, N. Strutynska, Y. Korkach, L. Mys, O.M. Magomedov, R. Strutynskyi, V. F. Sagach
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引用次数: 0

摘要

心律失常和充血性心力衰竭是中毒性心肌病的最大风险,也是多柔比星(主要的高活性抗癌药物)的临床限制性副作用。早期诊断心肌病和及时发现化疗引起的心功能不全仍然是一个重要的医学问题。我们的研究旨在通过评估心电图变化和生化指标,确定成年大鼠急性多柔比星诱发心脏毒性的早期症状。急性心脏毒性是通过短期腹腔注射总剂量为 15 毫克/千克的多柔比星来模拟的。实验第 5 天,研究了对照组和实验组大鼠心电图波形的视觉波动、主齿和间期的持续时间和振幅以及心率,以确定心脏毒性的早期心电图征兆。最明显的心电图变化是实验组大鼠的 QT 间期延长一倍,ST 段明显抬高。在离体主动脉环的实验中,我们证实了多柔比星诱导的血管松弛和收缩机制的破坏。给动物服用多柔比星后,血管制备对乙酰胆碱(0.1 μmol/l)的内皮依赖性松弛比对照组少 47%。大鼠在去甲肾上腺素(10 μmol/l)影响下的血管环收缩比对照组低 59%。服用多柔比星后,在心血管紊乱的背景下出现了氧化应激。因此,二烯共轭物和丙二醛的含量分别增加了 4 倍和 2.5 倍。与此同时,在离体的心脏线粒体中,诱导型 NO 合酶的活性增加了 3.7 倍,而组成型 NO 合酶的活性则显著抑制了 4.8 倍。作为损害标志的急性期生化指标,即丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)和肌酸磷酸激酶心肌部分(CPK MB)的含量分别增加了 2.2 倍、1.4 倍和 1.5 倍。因此,多柔比星的急性心脏毒性作用会导致心脏左心室收缩-舒张功能及其传导性、自动性和收缩性发生变化,并在诱导型 NO 合成活性增加和组成型 NO 合成活性降低的背景下,导致主动脉离体制备的松弛和收缩功能受损,同时伴有氧化应激和心肌损伤生化标志物含量增加。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
EARLY MARKERS OF ACUTE DOXORUBICIN-INDUCED CARDIOTOXICITY AND MECHANISMS OF ITS DEVELOPMENT
Arrhythmias and congestive heart failure, which pose the greatest risk of toxic cardiomyopathy, are the clinically limiting side effects of doxorubicin, the main highly active anticancer agent. The difficulty of early diagnosis of cardiomyopathy and timely detection of cardiac dysfunction associated with chemotherapy remains a significant medical problem. The aim of our study was to identify early signs of acute doxorubicin-induced cardiotoxicity in adult rats by assessing ECG changes and biochemical parameters. Acute cardiotoxicity was modelled by short-term intraperitoneal injection of doxorubicin at a total dose of 15 mg/kg. On the 5th day of the experiment, visual fluctuations of electrocardiogram (ECG) waveforms, duration and amplitude of the main teeth and intervals, as well as heart rate (HR) in the control and experimental groups of rats were studied to determine early ECG signs of cardiotoxicity. The most significant ECG changes were a doubling of the QT interval duration and significant ST-segment elevation in the rats of the experimental group. In experiments on isolated aortic rings, we demonstrated doxorubicin-induced disruption of both vascular relaxation and contraction mechanisms. The endothelium-dependent relaxation of vascular preparations of animals after administration of doxorubicin to acetylcholine (0.1 μmol/l) was 47% less than in the control group. The vascular ring contractions in rats under the influence of norepinephrine (10 μmol/l) were 59% lower than in control rats. After doxorubicin administration, oxidative stress developed against the background of cardiovascular disorders. Thus, the content of diene conjugates and malondialdehyde increased by 4 and 2.5 times, respectively. At the same time, in isolated cardiac mitochondria, the activity of inducible NO synthase increased 3.7-fold with a simultaneous significant 4.8-fold inhibition of constitutive NO synthase. An increase in the content of acute-phase biochemical parameters that are markers of damage, namely alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatine phosphokinase myocardial fraction (CPK MB) by 2.2, 1.4 and 1.5 times, respectively, was detected. Thus, the acute cardiotoxic effect of doxorubicin results in changes in the systolic-diastolic function of the left ventricle of the heart and its conduction, automaticity and contractility, as well as impaired relaxation and contraction of isolated preparations of the aorta against the background of increased activity of inducible and decreased constitutive NO synthesis, accompanied by oxidative stress and increased content of biochemical markers of myocardial damage.
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