Diazoxide protects against doxorubicin-induced cardiotoxicity in the rat

BMC Pharmacology and Toxicology

Jan Schjøtt²  Fredrik Limé¹  Kjell Ove Fossan¹  Terje Hjalmar Larsen³  Lisa Drange Hole¹ 

[1]Section of Clinical Pharmacology, Laboratory of Clinical Biochemistry, Haukeland University Hospital, 5021 Bergen, Norway

[2]Institute of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, 5021 Bergen, Norway

[3]Department of Heart Disease, Haukeland University Hospital, 5021 Bergen, Norway

关键词: Diazoxide;    Ex vivo;    Cardiotoxicity;    5-hydroxydecanoate;    Rat;    Heart;    Doxorubicinol;    Hydrogenperoxide;    Troponin T;    Doxorubicin;   

Others  :  848367
DOI  :  10.1186/2050-6511-15-28

 received in 2014-01-29, accepted in 2014-05-21,  发布年份 2014

【 摘 要 】

Aim

Chemotherapy 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 K_ATP-channels by diazoxide is protective against doxorubicin cardiotoxicity, and if 5-hydroxydecanoate (5-HD), a selective mitochondrial K_ATP-channel antagonist, abolished any protection by this intervention.

Methods

Wistar 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.

Results

Doxorubicin 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.

Conclusions

Pretreatment 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 K_ATP-channels, reduced doxorubicin-associated free radical generation and decreased cardiomyocyte damage. Diazoxide represents a promising protective intervention against doxorubicin-induced acute cardiotoxicity.

【 授权许可】

   
2014 Hole et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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