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

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.