Durdagi Gulcin, Pehlivan Deniz Yildiz, Oyar Eser Oz, Bahceci Selen Akyol, Ozbek Mustafa
Faculty of Medicine, Department of Physiology, Izmir Katip Celebi University, Izmir, Turkey.
Faculty of Medicine, Department of Histology and Embryology, Izmir Katip Celebi University, Izmir, Turkey.
Cardiovasc Toxicol. 2021 May;21(5):354-364. doi: 10.1007/s12012-020-09625-y. Epub 2021 Jan 3.
The main disadvantage of doxorubicin (DOX) is that it has cardiotoxic side effects. Our aim is to evaluate the cardioprotective effects of adrenomedullin (ADM) and to compare these effects with melatonin (MEL), it's cardioprotective effects are well known. Rats were divided into four groups: Control group (0.9% NaCl solution, intravenously), Doxorubicin group (45 mg/kg DOX, intravenously), Doxorubicin + Melatonin group (DOX + MEL, 10 mg/kg melatonin, intraperitoneally), Doxorubicin + Adrenomedullin group (DOX + ADM, 12 µg/kg adrenomedullin, intraperitoneally). A single dose of DOX was injected to the experimental groups on day 5, and a single dose of 0.9% NaCl solution was injected to the control group through the tail vein. The animals were anesthetized and ECG recordings were obtained on day 8. For the purpose of biochemical and histological analysis, cardiac tissue biopsy was obtained after ECG recordings. Compared to the control group, the DOX group had significantly increased duration of QRS complex, PR interval, QT interval and QTc interval. QRS complex, QT interval and QTc interval were prolonged with the administration of DOX and shortened with the administration of ADM. MEL weakened the toxic effects of DOX on the cardiac tissue and it is shown histologically. DOX increased interleukins (IL-1α, IL-6, IL-18), tumor necrosis factor-α (TNF-α), hypoxia-inducible factor 1-alpha (HIF-1α), malondialdehyde (MDA), nitric oxide (NO), creatine kinase myocardial band (CK-MB), and total oxidant status (TOS) levels in cardiac tissue, while reducing total antioxidant status (TAS), superoxide dismutase (SOD) and catalase (CAT) levels. MEL administration decreased the levels of CK-MB, MDA, IL-1α, IL-6, IL-18, NO, and TNF-α, whereas ADM only decreased IL-1α, IL-18, MDA and TNF-α levels. In summary, these results show that DOX has toxic effects on rat cardiac tissue which is documented histologically, electrocardiographically and biochemically. MEL alleviated histological damage and showed improvement on the several biochemical parameters of cardiac tissue. ADM brought several electrocardiographic and biochemical parameters closer to normal values.
阿霉素（DOX）的主要缺点是具有心脏毒性副作用。我们的目的是评估肾上腺髓质素（ADM）的心脏保护作用，并将这些作用与褪黑素（MEL）的作用进行比较，褪黑素的心脏保护作用是众所周知的。将大鼠分为四组：对照组（静脉注射0.9%氯化钠溶液）、阿霉素组（静脉注射45mg/kg DOX）、阿霉素+褪黑素组（DOX+MEL，腹腔注射10mg/kg褪黑素）、阿霉素+肾上腺髓质素组（DOX+ADM，腹腔注射12μg/kg肾上腺髓质素）。在第5天给实验组注射单剂量的DOX，通过尾静脉给对照组注射单剂量的0.9%氯化钠溶液。在第8天对动物进行麻醉并记录心电图。为了进行生化和组织学分析，在记录心电图后获取心脏组织活检样本。与对照组相比，DOX组的QRS波群时限、PR间期、QT间期和QTc间期显著延长。给予DOX后QRS波群时限、QT间期和QTc间期延长，给予ADM后缩短。组织学显示，MEL减轻了DOX对心脏组织的毒性作用。DOX增加了心脏组织中白细胞介素（IL-1α、IL-6、IL-18）、肿瘤坏死因子-α（TNF-α）、缺氧诱导因子1-α（HIF-1α）、丙二醛（MDA）、一氧化氮（NO）、肌酸激酶同工酶（CK-MB）和总氧化状态（TOS）水平，同时降低了总抗氧化状态（TAS）、超氧化物歧化酶（SOD）和过氧化氢酶（CAT）水平。给予MEL可降低CK-MB、MDA、IL-1α、IL-6、IL-18、NO和TNF-α水平，而给予ADM仅降低IL-1α、IL-18、MDA和TNF-α水平。总之，这些结果表明，DOX对大鼠心脏组织具有毒性作用，这在组织学、心电图和生化方面均有记录。MEL减轻了组织学损伤，并改善了心脏组织的几个生化参数。ADM使几个心电图和生化参数更接近正常值。
