Diazoxide protects against doxorubicin-induced cardiotoxicity in the rat

Abstract

AimChemotherapy with doxorubicin is limited by cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. In this study we wanted to investigate if opening of mitochondrial KATP-channels by diazoxide is protective against doxorubicin cardiotoxicity, and if 5-hydroxydecanoate (5-HD), a selective mitochondrial KATP-channel antagonist, abolished any protection by this intervention.MethodsWistar rats were divided into 7 groups (n = 6) and followed for 10 days with 5 intervention groups including the following treatments: (1) Diazoxide and doxorubicin, (2) diazoxide and 5-hydroxydecanoate (5-HD), (3) 5-HD and doxorubicin, (4) diazoxide and saline and (5) 5-HD and saline. On day 1, 3, 5 and 7 the animals received intraperitoneal (i.p.) injections with 10 mg/kg diazoxide and/or 40 mg/kg 5-HD, 30 minutes before i.p. injections with 3.0 mg/kg doxorubicin. One control group received only saline injections and the other control group received saline 30 minutes prior to 3.0 mg/kg doxorubicin. On day 10 the hearts were excised and Langendorff-perfused. Cardiac function was assessed by an intraventricular balloon and biochemical effects by release of hydrogen peroxide (H2O2) and troponin-T (TnT) in effluate from the isolated hearts, and by myocardial content of doxorubicin.ResultsDoxorubicin treatment produced a significant loss in left ventricular developed pressure (LVDP) (p < 0.05) and an increase in both H2O2 and TnT release in effluate (p < 0.05). Diazoxide significantly attenuated the decrease in LVDP (p < 0.05) and abolished the increased release of H2O2 and TnT (p < 0.05). 5-HD abolished the effects of pretreatment with diazoxide, and these effects were not associated with reduced myocardial accumulation of doxorubicin.ConclusionsPretreatment with diazoxide attenuates doxorubicin-induced cardiac dysfunction in the rat, measured by physiological indices and TnT and H2O2 in effluate from isolated hearts. The effect could be mediated by opening of mitochondrial KATP-channels, reduced doxorubicin-associated free radical generation and decreased cardiomyocyte damage. Diazoxide represents a promising protective intervention against doxorubicin-induced acute cardiotoxicity.

Cardiac Analysis of Autologous Transplantation of Cocultured Skeletal Myoblasts and Mesenchymal Cells in a Rat Model Doxorubicin-Induced Cardiotoxicity: Histopathological and Functional Studies

“…Previous studies have shown that chemotherapy by DOX induces cardiovascular alterations by free radical generation and mitochondrial dysfunction, leading to ischemic or idiopathic dilated cardiomyopathy [15,16].…”

Protecting the heart in cancer therapy

“…Clinically available agents such as losartan 72 , fluvastatin 73 , metformin 74 , iloprost 75 , and meloxicam 76 as well as other clinically unavailable ACEIs 69 – 71 have been shown to have cardioprotective results in vivo . Vasodilators 77 – 79 , neuropeptides 81 , and iron salts 80 have also been found to be useful. Finally, given that the pathogenesis of anthracyclines is in part related to increased oxidative stress 100 , several natural antioxidants (e.g.…”

Direct and Off-Target Effects of ATP-Sensitive Potassium Channels Opener Diazoxide

“…In addition to cytoprotective effects well documented in the literature, DZ was shown to represent a promising pharmacological intervention against cytotoxicity of the drugs known to cause severe impairment of mitochondria, such as isoproterenol and doxorubicin [8,66]. Moderation of ROS production ensuing from DZ administration [8,64,66] was shown to be a part of cytoprotective action.…”

“…Moderation of ROS production ensuing from DZ administration [8,64,66] was shown to be a part of cytoprotective action. However, no direct evidence for the involvement of mK ATP channel in cytoprotection was yet obtained in living organism.…”