Diazoxide protects against doxorubicin-induced cardiotoxicity in the rat

BMC Clinical Pharmacology

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;Institute of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, 5021 Bergen, Norway;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  :  860327
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 】

【 参考文献 】

• [1]Hiona A, Lee AS, Nagendran J, Xie X, Connolly AJ, Robbins RC, Wu JC: Pretreatment with angiotensin-converting enzyme inhibitor improves doxorubicin-induced cardiomyopathy via preservation of mitochondrial function. J Thorac Cardiovasc Surg 2011, 142(2):396-403 e393.
• [2]Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L: Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004, 56(2):185-229.
• [3]Robert J: Preclinical assessment of anthracycline cardiotoxicity in laboratory animals: predictiveness and pitfalls. Cell Biol Toxicol 2007, 23(1):27-37.
• [4]Ferreira AL, Matsubara LS, Matsubara BB: Anthracycline-induced cardiotoxicity. Cardiovasc Hematol Agents Med Chem 2008, 6(4):278-281.
• [5]Gan XT, Cook MA, Moffat MP, Karmazyn M: Protective effects against hydrogen peroxide-induced toxicity by activators of the ATP-sensitive potassium channel in isolated rat hearts. J Mol Cell Cardiol 1998, 30(1):33-41.
• [6]Li W, Xu B, Xu J, Wu XL: Procyanidins produce significant attenuation of doxorubicin-induced cardiotoxicity via suppression of oxidative stress. Basic Clin Pharmacol Toxicol 2009, 104(3):192-197.
• [7]Coetzee WA: Multiplicity of effectors of the cardioprotective agent, diazoxide. Pharmacol Therapeut 2013, 140(2):167-175.
• [8]Garlid AO, Jaburek M, Jacobs JP, Garlid KD: Mitochondrial reactive oxygen species: which ROS signals cardioprotection? Am J Physiol Heart Circ Physiol 2013, 305(7):H960-H968.
• [9]Kelishomi RB, Ejtemaeemehr S, Tavangar SM, Rahimian R, Mobarakeh JI, Dehpour AR: Morphine is protective against doxorubicin-induced cardiotoxicity in rat. Toxicology 2008, 243(1–2):96-104.
• [10]McPherson BC, Yao Z: Morphine mimics preconditioning via free radical signals and mitochondrial K(ATP) channels in myocytes. Circulation 2001, 103(2):290-295.
• [11]Barrere-Lemaire S, Combes N, Sportouch-Dukhan C, Richard S, Nargeot J, Piot C: Morphine mimics the antiapoptotic effect of preconditioning via an Ins(1,4,5)P3 signaling pathway in rat ventricular myocytes. Am J Physiol Heart Circ Physiol 2005, 288(1):H83-H88.
• [12]Ahmed LA, El-Maraghy SA: Nicorandil ameliorates mitochondrial dysfunction in doxorubicin-induced heart failure in rats: possible mechanism of cardioprotection. Biochem Pharmacol 2013, 86(9):1301-1310.
• [13]Abdel-Raheem IT, Taye A, Abouzied MM: Cardioprotective effects of nicorandil, a mitochondrial potassium channel opener against doxorubicin-induced cardiotoxicity in rats. Basic Clin Pharmacol Toxicol 2013, 113(3):158-166.
• [14]Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D’Alonzo AJ, Lodge NJ, Smith MA, Grover GJ: Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res 1997, 81(6):1072-1082.
• [15]Hole LD, Larsen TH, Fossan KO, Lime F, Schjott J: A short-time model to study relevant indices of cardiotoxicity of doxorubicin in the rat. Toxicol Mech Meth 2013, 23(6):412-418.
• [16]Gharanei M, Hussain A, Janneh O, Maddock HL: Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore. Toxicol Appl Pharmacol 2013, 268(2):149-156.
• [17]Akai K, Wang Y, Sato K, Sekiguchi N, Sugimura A, Kumagai T, Komaru T, Kanatsuka H, Shirato K: Vasodilatory effect of nicorandil on coronary arterial microvessels: its dependency on vessel size and the involvement of the ATP-sensitive potassium channels. J Cardiovasc Pharmacol 1995, 26(4):541-547.
• [18]Feng J, Li H, Rosenkranz ER: Diazoxide protects the rabbit heart following cardioplegic ischemia. Mol Cell Biochem 2002, 233(1–2):133-138.
• [19]Deng Q, Scicli AG, Lawton C, Silverman NA: Coronary flow reserve after ischemia and reperfusion of the isolated heart. Divergent results with crystalloid versus blood perfusion. J Thorac Cardiovasc Surg 1995, 109(3):466-472.
• [20]Hanley PJ, Daut J: K(ATP) channels and preconditioning: a re-examination of the role of mitochondrial K(ATP) channels and an overview of alternative mechanisms. J Mol Cell Cardiol 2005, 39(1):17-50.
• [21]Feng RH, Zhang JC, Li XQ, Sun HL, Liu B, Zhao YZ, Tang XD, Li J: Attenuation of cardiac ischemia/reperfusion injury by transient low hydroperoxide pretreatment in rat. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi =Chinese J Appl Physiol 2013, 29(3):247-250.
• [22]Valen G, Starkopf J, Takeshima S, Kullisaar T, Vihalemm T, Kengsepp AT, Lowbeer C, Vaage J, Zilmer M: Preconditioning with hydrogen peroxide (H2O2) or ischemia in H2O2-induced cardiac dysfunction. Free Radic Res 1998, 29(3):235-245.
• [23]Essick EE, Wilson RM, Pimentel DR, Shimano M, Baid S, Ouchi N, Sam F: Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes. PloS one 2013, 8(7):e68697.
• [24]Chennuru A, Saleem MT: Antioxidant, lipid lowering, and membrane stabilization effect of sesamol against doxorubicin-induced cardiomyopathy in experimental rats. BioMed Res Int 2013, 2013:934239.
• [25]Fouad AA, Albuali WH, Al-Mulhim AS, Jresat I: Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity. Environ Toxicol Pharmacol 2013, 36(2):347-357.
• [26]Garlid KD, Dos Santos P, Xie ZJ, Costa AD, Paucek P: Mitochondrial potassium transport: the role of the mitochondrial ATP-sensitive K(+) channel in cardiac function and cardioprotection. Biochim Biophys Acta 2003, 1606(1–3):1-21.
• [27]Gross GJ, Peart JN: KATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol 2003, 285(3):H921-H930.
• [28]Lim KH, Javadov SA, Das M, Clarke SJ, Suleiman MS, Halestrap AP: The effects of ischaemic preconditioning, diazoxide and 5-hydroxydecanoate on rat heart mitochondrial volume and respiration. J Physiol 2002, 545(Pt 3):961-974.
• [29]Hanley PJ, Mickel M, Loffler M, Brandt U, Daut J: K(ATP) channel-independent targets of diazoxide and 5-hydroxydecanoate in the heart. J Physiol 2002, 542(Pt 3):735-741.
• [30]Suzuki M, Saito T, Sato T, Tamagawa M, Miki T, Seino S, Nakaya H: Cardioprotective effect of diazoxide is mediated by activation of sarcolemmal but not mitochondrial ATP-sensitive potassium channels in mice. Circulation 2003, 107(5):682-685.
• [31]Hausenloy D, Wynne A, Duchen M, Yellon D: Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation 2004, 109(14):1714-1717.
• [32]Hanley PJ, Drose S, Brandt U, Lareau RA, Banerjee AL, Srivastava DK, Banaszak LJ, Barycki JJ, Van Veldhoven PP, Daut J: 5-Hydroxydecanoate is metabolised in mitochondria and creates a rate-limiting bottleneck for beta-oxidation of fatty acids. J Physiol 2005, 562(Pt 2):307-318.
• [33]Das M, Parker JE, Halestrap AP: Matrix volume measurements challenge the existence of diazoxide/glibencamide-sensitive KATP channels in rat mitochondria. J Physiol 2003, 547(Pt 3):893-902.