Activation of ATP-sensitive potassium channels prevents doxorubicin-induced mitochondrial dysfunction in the heart and impaired vascular responses in rats

M.V. Denysova, N. Strutynska, L. Mys, Y. Korkach, V. F. Sagach, R. Strutynskyi
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Abstract

One of the side effects of the anticancer drug doxorubicin is its mitotoxicity. At the same time, a sufficient number of functioning mitochondria is required for normal energy supply to the heart. The system of ATP-sensitive potassium channels (KATP -channels) of cytoplasmic and mitochondrial membranes is considered to be the central metabolic sensor of energy supply, and their opening triggers mechanisms of protection against cell damage and death under the influence of pathological factors. The aim of our study was to investigate the effect of KATP-channel opener flocalin on doxorubicin-induced mitochondrial dysfunction in the heart, impaired vascular contraction-relaxation function, and oxidative stress. Acute cardiotoxicity was modelled by short-term intraperitoneal injection of doxorubicin in a total dose of 15 mg/kg. To prevent damage, animals were administered flocalin at a dose of 2.5 mg/kg for 5 consecutive days. It was found that the rate of formation of superoxide anion (•O2 - ) and hydroxyl radical (•OH) in the heart mitochondria significantly increased after administration of doxorubicin by 10.5 and 3.4 times, respectively, and the level of H2O2 increased by 5.3 times. When rats were administered flocalin against the background of doxorubicin, oxidative stress indicators were significantly reduced, namely, the rate of •O2 - and •ON generation was 4 and 1.6 times lower, respectively, and the H2O2 levels were 4.6 times lower. Under conditions of impaired redox status in the rat heart after doxorubicin administration, mitochondrial permeability transition pore opening was activated: the amplitude of spontaneous swelling doubled, and Ca2+-induced swelling increased 1.5-fold. The use of flocalin reduced the amplitude of mitochondrial swelling in calcium-free medium by 84.6%, and under the conditions of action inducer of mPTP opening calcium, this index was restored to control values. Endothelium-dependent relaxation of aorta preparations of doxorubicin-treated animals to acetylcholine (0.1 μmol/l) was 47% less than in the control group. Contractions of aortic rings in these animals under the influence of norepinephrine (10 μmol/l) were reduced by 59% compared to control rats. When flocalin, a KATP-channel opener, was injected into rats, the contractile responses of isolated rat aortic rings were restored almost to the values of control animals, while the endothelium-dependent vasodilator effects of acetylcholine (0.1 μmol/l) under the influence of flocalin were restored by 69% compared with animals injected with doxorubicin. Thus, the opening of KATP-channels by flocalin prevents doxorubicininduced mitochondrial dysfunction in the heart, reduces oxidative stress and prevents vascular contractionrelaxation disorders.
激活 ATP 敏感钾通道可预防多柔比星诱发的大鼠心脏线粒体功能障碍和血管反应受损
抗癌药物多柔比星的副作用之一是有丝分裂毒性。与此同时,心脏的正常能量供应需要足够数量的线粒体。细胞质和线粒体膜上的 ATP 敏感钾通道(KATP 通道)系统被认为是能量供应的核心代谢传感器,在病理因素的影响下,它们的开放会触发细胞损伤和死亡的保护机制。我们的研究旨在探讨 KATP 通道开放剂氟卡林对多柔比星诱导的心脏线粒体功能障碍、血管收缩-舒张功能受损和氧化应激的影响。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。为防止损伤,连续5天给动物注射2.5毫克/千克剂量的氟钙素。研究发现,给大鼠服用多柔比星后,心脏线粒体中超氧化物阴离子(-O2-)和羟自由基(-OH)的形成率显著增加,分别增加了 10.5 倍和 3.4 倍,H2O2 的水平增加了 5.3 倍。在多柔比星的背景下给大鼠服用氟钙素,氧化应激指标明显降低,即-O2-和-ON的生成率分别降低了4倍和1.6倍,H2O2水平降低了4.6倍。在多柔比星用药后大鼠心脏氧化还原状态受损的条件下,线粒体通透性转换孔开放被激活:自发肿胀的幅度增加了一倍,Ca2+诱导的肿胀增加了1.5倍。在无钙介质中使用氟卡林可使线粒体肿胀幅度降低 84.6%,而在 mPTP 开放钙作用诱导剂的条件下,该指数可恢复到控制值。多柔比星处理动物的主动脉制备对乙酰胆碱(0.1 μmol/l)的内皮依赖性松弛比对照组少 47%。与对照组相比,这些动物在去甲肾上腺素(10 μmol/l)影响下的主动脉环收缩减少了 59%。给大鼠注射氟卡林(一种 KATP 通道开启剂)后,离体大鼠主动脉环的收缩反应几乎恢复到对照组动物的值,而在氟卡林的影响下,乙酰胆碱(0.1 μmol/l)对内皮依赖性血管扩张作用比注射多柔比星的动物恢复了 69%。因此,氟卡林对 KATP 通道的开放可防止多柔比星诱导的心脏线粒体功能障碍,减少氧化应激,防止血管收缩舒张失调。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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