Abstract
The aim of this study was to investigate the effects of carnosine, a biological antioxidant, on the acute cardiac damage induced by a single dose of adriamycin in rats. The experimental design consisted of four groups: Control (saline, i.p.); carnosine (CAR; 10 mg/kg/day, i.p.); adriamycin (ADR; 16 mg/kg on the 14th day, i.p.); carnosine with adriamycin. Carnosine was given 2 weeks before and following adriamycin treatment. Blood samples were collected for analysis of plasma creatine kinase (CK) and plasma antioxidant enzymes, glutathione peroxidase (GSH-Px), Cu, Zn-superoxide dismutase (SOD), and catalase (CAT). The rats were then sacrificed, and the hearts were autopsied for hemodynamic study, ECG, and histopathological examination. Results showed that adriamycin produced evident cardiac damage revealed by hemodynamic change, histological alterations, decreased plasma antioxidant enzymes activities, and increased lipid peroxidation to the control value. Carnosine treatment led to significant attenuation of adriamycin-induced cardiomyopathy revealed by normalization of the LVDP, ST interval, CK, SOD, GSH-Px, CAT, and lipid peroxidation. An increase in oxidative stress and inactivation of SOD, GSH-Px, CAT by a single dose of adriamycin were prevented when carnosine was given 2 weeks before and on the same day adriamycin treatment was administered.
Similar content being viewed by others
References
Young RC, Ozols RF, Myers CE (1981) The anthracycline antineoplastic drugs. N Engl J Med 305:139–153
Chularojmontri L, Wattanapitayakul SK, Herunsalee A et al (2005) Antioxidative and cardioprotective effects of Phyllanthus urinaria L. on doxorubicin-induced cardiotoxicity. Biol Pharm Bull 28:1165–1171
Zhou GY, Zhao BL, Hou JW, Ma GE, Xin WJ (1999) Protective effects of sodium tanshinone IIA sulphonate against adriamycin-induced lipid peroxidation in mice hearts in vivo and in vitro. Pharmacol Res 40:487–491
Iliskovic N, Singal PK (1997) Lipid lowering: an important factor in preventing adriamycin-induced heart failure. Am J Pathol 150:727–734
Bharadwaj LA, Davies GF, Xavier IJ, Ovsenek N (2002) l-carnosine and verapamil inhibit hypoxia-induced expression of hypoxia inducible factor (HIF-1 alpha) in H9c2 cardiomyoblasts. Pharmacol Res 45:175–181
Kang JH (2007) Protective effects of carnosine and N-acetylcarnosine on salsolinol-mediated Cu, Zn-superoxide dismutase inactivation. Bull Korean Chem Soc 28:1881–1884
Kang JH, Kim KS, Choi SY et al (2002) Protective effects of carnosine, homocarnosine and anserine against peroxyl radical-mediated Cu, Zn-superoxide dismutase modification. Biochim Biophys Acta 1570:89–96
Fitzpatrick D, Amend JF, Squibb RL, Fisher H (1980) Effects of chronic and acute infections on tissue levels of carnosine, anserine and free histidine in rats and chickens. Proc Soc Exp Biol Med 165:404–408
Fisher DE, Amend JF, Strumeyer DH, Fisher H (1978) A role for carnosine and anserine in histamine metabolism of the traumatized rat. Proc Soc Exp Biol Med 158:402–405
Parrillo JE, Parker MM, Natanson C et al (1990) Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 113:227–242
Zaloga GP, Roberts PR, Black KW et al (1997) Carnosine is a novel peptide modulator of intracellular calcium and contractility in cardiac cells. Am J Physiol 272:H462–H468
Lee JW, Miyawaki H, Bobst EV et al (1999) Improved functional recovery of ischemic rat hearts due to singlet oxygen scavengers histidine and carnosine. J Mol Cell Cardiol 31:113–121
Uchida K, Kawakishi S (1994) Identification of oxidized histidine generated at the active site of Cu, Zn-superoxide dismutase exposed to H2O2. Selective generation of 2-oxo-histidine at the histidine 118. J Biol Chem 269:2405–2410
Choi SY, Kwon HY, Kwon OB, Kang JH (1999) Hydrogen peroxide-mediated Cu, Zn-superoxide dismutase fragmentation: protection by carnosine, homocarnosine and anserine. Biochim Biophys Acta 1472:651–657
Jewett SL, Rocklin AM, Ghanevati M, Abel JM, Marach JA (1999) A new look at a time-worn system: oxidation of CuZn-SOD by H2O2. Free Radic Biol Med 26:905–918
Begum G, Cunliffe A, Leveritt M (2005) Physiological role of carnosine in contracting muscle. Int J Sport Nutr Exerc Metab 15:493–514
Hipkiss AR, Preston JE, Himsworth DT et al (1998) Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Ann NY Acad Sci 854:37–53
Dimitrov NV, Hay MB, Siew S et al (1987) Abrogation of adriamycin-induced cardiotoxicity by selenium in rabbits. Am J Pathol 126:376–383
Baykara B, Tekmen I, Pekcetin C et al (2009) The protective effects of carnosine and melatonin in ischemia-reperfusion injury in the rat liver. Acta Histochem 111:42–51
Lee YT, Hsu CC, Lin MH, Liu KS, Yin MC (2005) Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol 513:145–150
Mikami K, Otaka M, Watanabe D et al (2006) Zinc L-carnosine protects against mucosal injury in portal hypertensive gastropathy through induction of heat shock protein 72. J Gastroenterol Hepatol 21:1669–1674
Saad SY, Najjar TA, Arafah MM (2006) Cardioprotective effects of subcutaneous ebselen against daunorubicin-induced cardiomyopathy in rats. Basic Clin Pharmacol Toxicol 99:412–417
Jain SK (1988) Evidence for membrane lipid peroxidation during the in vivo aging of human erythrocytes. Biochim Biophys Acta 937:205–210
Stocks J, Dormandy TL (1971) The autoxidation of human red cell lipids induced by hydrogen peroxide. Br J Haematol 20:95–111
Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–169
Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500
Beers RF Jr, Sizer IW (1952) A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem 195:133–140
Li L, Takemura G, Li Y et al (2006) Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy. Circulation 113:535–543
Roberts PR, Zaloga GP (2000) Cardiovascular effects of carnosine. Biochemistry (Mosc) 65:856–861
Venkatesan N (1998) Curcumin attenuation of acute adriamycin myocardial toxicity in rats. Br J Pharmacol 124:425–427
Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC (2005) Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation 111:1601–1610
le Marec H, Spinelli W, Rosen MR (1986) The effects of doxorubicin on ventricular tachycardia. Circulation 74:881–889
Jabr RI, Cole WC (1993) Alterations in electrical activity and membrane currents induced by intracellular oxygen-derived free radical stress in guinea pig ventricular myocytes. Circ Res 72:1229–1244
Pacher P, Liaudet L, Bai P et al (2002) Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure. J Pharmacol Exp Ther 300:862–867
Saad SY, Najjar TA, Al-Rikabi AC (2001) The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats. Pharmacol Res 43:211–218
Timioglu O, Kutsal S, Ozkur M et al (1999) The effect of EGb 761 on the doxorubicin cardiomyopathy. Res Commun Mol Pathol Pharmacol 106:181–192
Herman EH, Zhang J, Rifai N et al (2001) The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity. Cancer Chemother Pharmacol 48:297–304
Mostafa AM, Nagi MN, Al Rikabi AC, Al-Shabanah OA, El-Kashef HA (1999) Protective effect of aminoguanidine against cardiovascular toxicity of chronic doxorubicin treatment in rats. Res Commun Mol Pathol Pharmacol 106:193–202
Halliwell B (1991) Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Am J Med 91:14S–22S
Daosukho C, Chen Y, Noel T et al (2007) Phenylbutyrate, a histone deacetylase inhibitor, protects against adriamycin-induced cardiac injury. Free Radic Biol Med 42:1818–1825
Mukherjee S, Banerjee SK, Maulik M et al (2003) Protection against acute adriamycin-induced cardiotoxicity by garlic: role of endogenous antioxidants and inhibition of TNF-alpha expression. BMC Pharmacol 3:16
Li T, Danelisen I, Bello-Klein A, Singal PK (2000) Effects of probucol on changes of antioxidant enzymes in adriamycin-induced cardiomyopathy in rats. Cardiovasc Res 46:523–530
Hartman PE, Hartman Z, Ault KT (1990) Scavenging of singlet molecular oxygen by imidazole compounds: high and sustained activities of carboxy terminal histidine dipeptides and exceptional activity of imidazole-4-acetic acid. Photochem Photobiol 51:59–66
Harman D (1991) The aging process: major risk factor for disease and death. Proc Natl Acad Sci USA 88:5360–5363
Sharonov BP, Govorova N, Lyzlova SN (1990) Carnosine as a potential scavenger of oxidants generated by stimulated neutrophils. Biochem Int 21:61–68
Hartman PE (1986) Interception of toxic agents/mutagens/carcinogens: some of nature’s novel strategies. Basic Life Sci 39:169–179
Fontana M, Pinnen F, Lucente G, Pecci L (2002) Prevention of peroxynitrite-dependent damage by carnosine and related sulphonamido pseudodipeptides. Cell Mol Life Sci 59:546–551
Nagasawa T, Yonekura T, Nishizawa N, Kitts DD (2001) In vitro and in vivo inhibition of muscle lipid and protein oxidation by carnosine. Mol Cell Biochem 225:29–34
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dursun, N., Taşkın, E. & Öztürk, F. Protection Against Adriamycin-Induced Cardiomyopathy by Carnosine in Rats: Role of Endogenous Antioxidants. Biol Trace Elem Res 143, 412–424 (2011). https://doi.org/10.1007/s12011-010-8875-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-010-8875-y