Effect of oxidative stress on ventricular arrhythmia in rabbits with adriamycin-induced cardiomyopathy

Abstract

The purpose of the present study was to examine the effects of oxidative stress on ventricular arrhythmias in rabbits with adriamycin-induced cardiomyopathy and the relationship between oxidative stress and ventricular arrhythmia. Forty Japanese white rabbits were randomly divided into four groups (n=10 in each): control group, metoprolol (a selective β1 receptor blocker) group, carvedilol (a nonselective β blocker/α-1 blocker) group and adriamycin group. Models of adriamycin-induced cardiomyopathy were established by intravenously injecting adriamycin hydrochloride (1 mg/kg) to rabbits via the auri-edge vein twice a week for 8 weeks in the adriamycin, metoprolol and carvedilol groups. Rabbits in the control group were given equal volume of saline through the auri-edge vein. Rabbits in the metoprolol and carvedilol groups were then intragastrically administrated metoprolol (5 mg/kg/d) and carvedilol (5 mg/kg/d) respectively for 2 months, while those in the adriamycin and control groups were treated with equal volume of saline in the same manner as in the metroprolol and carvedilol groups. Left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) were measured by echocardiography. Plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), malondialdehyde (MAD) and superoxide dismutase (SOD) were detected. The left ventricular wedge preparations were perfused with Tyrode’s solution. The transmural electrocardiogram, transmural action potentials from epicardium (Epi) and endocardium (Endo), transmural repolarization dispersion (TDR) were recorded, and the incidences of triggered activity and ventricular arrhythmias were obtained at rapid cycle lengths. The results showed that TDR and the serum MDA and NT-proBNP levels were increased, and LVEF and the serum SOD level decreased in the adriamycin group compared with the control group. The incidences of triggered activity and ventricular arrhythmia were significantly higher in the adriamycin group than those in the control group (P<0.05). In the carvedilol group as compared with the adriamycin group, the serum SOD level and the LVEF were substantially increased; the TDR, and the serum MDA and NT-proBNP levels were significantly decreased; the incidences of triggered activity and ventricular arrhythmia were obviously reduced (P<0.05). There were no significant differences in the levels of MDA and SOD, LVEF, TDR and the incidences of triggered activity and ventricular arrhythmia between the adriamycin group and the metoprolol group. It was concluded that carvedilol may inhibit triggered activity and ventricular arrhythmias in rabbit with adriamycin-induced cardiomyopathy, which is related to the decrease in oxygen free radials.

Keywords

heart failure / carvedilol / oxidative stress / adriamycin / ventricular arrhythmias / delayed afterdepolarizations

References

[1] ChatterjeeK., ZhangJ., HonboN., et al.. Doxorubicin cardiomyopathy. Cardiology, 2010, 115(2): 155-162

[2] LudkeA.R., Al-ShudiefatA.A., DhingraS., et al.. Singal PKA concise description of cardioprotective strategies in doxorubicin-induced cardiotoxicity. Can J Physiol Pharmacol, 2009, 87(10): 756-763

[3] ChaiswingL., ColeM.P., St ClairD.K., et al.. Oxidative damage precedes nitrative damage in adriamycin-induced cardiac mitochondrial injury. Toxicol Pathol, 2004, 32(5): 536-547

[4] GiordanoF.J.. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest, 2005, 115(3): 500-508

[5] HareJ.M.. Oxidative stress and apoptosis in heart failure progression. Circ Res, 2001, 89(3): 198-200

[6] BoucekR.J., MiracleA.Jr, AndersonM., et al.. Persistent effects of doxorubicin on cardiac gene expression. J Mol Cell Cardiol, 1999, 31(8): 1435-1446

[7] LuC., AraiM., MisaoY., et al.. Autologous bone marrow cell transplantation improves left ventricular function in rabbit hearts with cardiomyopathy via myocardial regeneration-unrelated mechanisms. Heart Vessels, 2006, 21(3): 180-187

[8] EldemerdashE.. Evidences for prevention of nitroglycerin tolerance by carvedilol. Pharmacol Res, 2006, 53(4): 380-385

[9] YanG.X., JoshiA., GuoD., et al.. Phase 2 reentry as a trigger to initiate ventricular fibrillation during early acute myocardial ischemia. Circulation, 2004, 110(9): 1036-1041

[10] YanG.X., RialsS.J., WuY., et al.. Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization. Am J Physiol Heart Circ Physiol, 2001, 281: H1968-H1975

[11] TakemuraG., FujiwaraH.. Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis, 2007, 49(5): 330-352

[12] SwainS.M., WhaleyF.S., EwerM.S.. Congestive heart failure in patients treated with doxorubicin. Cancer, 2003, 97(11): 2869-2879

[13] KumarD., LouH., SingalP.K.. Oxidative stress and apoptosis in heart dysfunction. Herz, 2002, 27(7): 662-668

[14] LiuN., YuR., RuanY., et al.. Protective effect of carvedilol on abnormality of L-type calcium current induced by oxygen free radical in cardiomyocytes. J Huazhong Univ Sci Technol [Med Sci], 2004, 24(5): 433-436

[15] XiangP., DengH.Y., LiK., et al.. Dexrazoxane protects against doxorubicin-induced cardiomyopathy: upregulation of Akt and Erk phosphorylation in a rat model. Cancer Chemother Pharmacol, 2009, 63(2): 343-349

[16] ZipesD.P., WellensH.J.. Sudden Cardiac Death. Circulation, 1998, 98: 2334-2351

[17] AzizE.F., JavedF., PratapB., et al.. Strategies for the prevention and treatment of sudden cardiac death. Open Access Emerg Med, 2010, 2: 99-114

[18] TerentyevD., GyörkeI., BelevychA.E., et al.. Redox modification of ryanodine receptors contributes to sarcoplasmic reticulum Ca2+ leak in chronic heart failure. Circ Res, 2008, 103(12): 1466-1472

[19] BlayneyL.M., LaiF.A.. Ryanodine receptor-mediated arrhythmias and sudden cardiac death. Pharmacol Ther, 2009, 123(2): 151-177

[20] DuanD.D.. A leakage leads to failure: roles of sarcoplasmic reticulum Ca2+ leak via RyR2 in heart failure progression. Hypertension, 2010, 55(4): 849-851

[21] SantosD.L., MorenoA.J., LeinoR.L., et al.. Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy. Toxicol Appl Pharmacol, 2002, 185(3): 218-227

[22] ZhouQ., XiaoJ., JiangD., et al.. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. Nat Med, 2011, 17(8): 1003-1009

[23] ZengH., LiuX., ZhaoH.. Effects of carvedilol on cardiomyocyte apoptosis and gene expression in vivo after ischemia-reperfusion in rat. J Huazhong Univ Sci Technolog Med Sci, 2003, 23(2): 127-130

[24] MochizukiM., YanoM., OdaT., et al.. Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure. J Am Coll Cardiol, 2007, 49(16): 1722-1732