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Horm Metab Res 2015; 47(02): 97-106
DOI: 10.1055/s-0034-1385855
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Antiapoptotic and Antioxidant Effects of Carvedilol and Vitamin E Protect Against Diabetic Nephropathy and Cardiomyopathy in Diabetic Wistar Albino Rats

M. H. Abdel-Raheem
1   Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
,
S. U. Salim
1   Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
,
E. Mosad
2   Clinical Pathology Department (Immunohistochemistry Lab), South Egypt Cancer Institute, Assiut University, Assiut, Egypt
,
A. Al-Rifaay
3   Pathology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
,
H. S. Salama
1   Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
,
H. Hasan-Ali
4   Cardiovascular Medicine Department, Faculty of Medicine, Assiut University, Assiut, Egypt
› Author Affiliations
Further Information

Publication History

received 12 March 2014

accepted 07 July 2014

Publication Date:
08 August 2014 (online)

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Abstract

Carvedilol is a novel β-adrenoreceptor blocker, with antioxidant properties inhibiting lipid peroxidation and preventing the depletion of endogenous antioxidants. Moreover, carvedilol was reported to enhance the expression of Bcl-2 gene, which has antioxidant and antiapoptotic effects. There are few researches testing the protective effect of carvedilol on the development of diabetic cardiomyopathy and nephropathy. In this study, we induced diabetes mellitus in male Wistar albino rats. We investigated carvedilol, as well as vitamin E, administrated in healthy and diabetic rats for 6 weeks to compare their effects on biochemical parameters and the expression of Bcl-2 protein in both myocardial and renal tissues by immunohistochemistry. The study showed that the diabetic rats not only had renal dysfunction and more myocardial damage, but also showed lower expression of Bcl-2 protein. Carvedilol and vitamin E treatments were associated with better renal function and less myocardial damage, lower blood glucose, and lipid peroxidation, higher antioxidant capacity, better serum lipids, and higher expression of Bcl-2 protein in diabetic rats. These results indicate that carvedilol and vitamin E treatments partly protect against myocardial and renal damage probably via their antioxidant and antiapoptotic properties in diabetic rats.

Key words

thiobarbaturic acid - Bcl-2 - total antioxidant status
 

  • References

  • 1 Haidara MA, Yassin HZ, Rateb M, Ammar H, Zorkani MA. Role of oxidative stress in development of cardiovascular complications in diabetes mellitus. Curr Vasc Pharmacol 2006; 4: 215-227
    CrossrefPubMedGoogle Scholar
  • 2 Stark G. Functional consequences of oxidative membrane damage. J Membr Biol 2005; 205: 1-16
    CrossrefPubMedGoogle Scholar
  • 3 Eno CO, Zhao G, Olberding KE, Li C. The Bcl-2 proteins Noxa and Bcl-xL co-ordinately regulate oxidative stress-induced apoptosis. Biochem J 2012; 444: 69-78
    CrossrefPubMedGoogle Scholar
  • 4 Hashemzadeh M, Movahed MR, Russu WA, Soroush L, Hill DN. Novel design and synthesis of modified structure of carvedilol. Recent Pat Cardiovasc Drug Discov 2011; 6: 175-179
    PubMedGoogle Scholar
  • 5 Pereira GC, Silva AM, Diogo CV, Carvalho FS, Monteiro P, Oliveira PJ. Drug-induced cardiac mitochondrial toxicity and protection: from doxorubicin to carvedilol. Curr Pharm Des 2011; 17: 2113-2129
    CrossrefPubMedGoogle Scholar
  • 6 Huang H, Shan J, Pan X-H, Wang H-P, Qian L-B, Xia Q. Carvedilol improved diabetic rat cardiac function depending on antioxidant ability. Diabetes Res Clin Pract 2007; 75: 7-13
    CrossrefPubMedGoogle Scholar
  • 7 Cameron NE, Cotter MA, Low PA. Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. Am J Physiol 1991; 261 (1 Pt 1) E1-E8
    PubMedGoogle Scholar
  • 8 Thayer WS. Serum lipid peroxides in rats treated chronically with adriamycin. Biochem Pharmacol 1984; 33: 2259-2263
    CrossrefPubMedGoogle Scholar
  • 9 Miller NJ, Rice-Evans C, Davies MJ, Gopinathan V, Milner A. A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. Clin Sci 1993; 84: 407-412
    PubMedGoogle Scholar
  • 10 Rodrigues MA, Rodrigues JL, Martins NM, Barbosa F, Curti C, Santos NA, Santos AC. Carvedilol protects against cisplatin-induced oxidative stress, redox state unbalance and apoptosis in rat kidney mitochondria. Chem-Biol Interact 2011; 189: 45-51
    PubMedGoogle Scholar
  • 11 Jang JH, Surh YJ. Potentiation of cellular antioxidant capacity by Bcl-2: implications for its antiapoptotic function. Biochem Pharmacol 2003; 66: 1371-1379
    CrossrefPubMedGoogle Scholar
  • 12 Halliwell B, Gutteridge JM. Lipid peroxidation, oxygen radicals, cell damage, and antioxidant therapy. Lancet 1984; 1 (8391) 1396-1397
    PubMedGoogle Scholar
  • 13 Hunt JV, Smith CC, Wolff SP. Autoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modification by glucose. Diabetes 1990; 39: 1420-1424
    CrossrefPubMedGoogle Scholar
  • 14 Del Rio D, Stewart AJ, Pellegrini N. A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr Metab Cardiovasc Diseases 2005; 15: 316-328
    PubMedGoogle Scholar
  • 15 Yoshida M, Kimura H, Kyuki K, Ito M. Effect of combined vitamin E and insulin administration on renal damage in diabetic rats fed a high cholesterol diet. Biol Pharmaceut Bull 2005; 28: 2080-2086
    CrossrefPubMedGoogle Scholar
  • 16 Dallak MM, Mikhailidis DP, Haidara MA, Bin-Jaliah IM, Tork OM, Rateb MA, Yassin HZ, Al-Refaie ZA, Ibrahim IM, Elawa SM, Rashed LA, Afifi NA. Oxidative stress as a common mediator for apoptosis induced-cardiac damage in diabetic rats. Open Cardiovasc Med J 2008; 2: 70-78
    CrossrefPubMedGoogle Scholar
  • 17 Haidara MA, Mikhailidis DP, Rateb MA, Ahmed ZA, Yassin HZ, Ibrahim IM, Rashed LA. Evaluation of the effect of oxidative stress and vitamin E supplementation on renal function in rats with streptozotocin-induced Type 1 diabetes. J Diabetes Complications 2009; 23: 130-136
    CrossrefPubMedGoogle Scholar
  • 18 Vessby J, Basu S, Mohsen R, Berne C, Vessby B. Oxidative stress and antioxidant status in type 1 diabetes mellitus. J Intern Med 2002; 251: 69-76
    CrossrefPubMedGoogle Scholar
  • 19 Gerhardinger C, Brown LF, Roy S, Mizutani M, Zucker CL, Lorenzi M. Expression of vascular endothelial growth factor in the human retina and in nonproliferative diabetic retinopathy. Am J Pathol 1998; 152: 1453-1462
    PubMedGoogle Scholar
  • 20 Galkowska H, Olszewsk WL, Wojewodzka U, Mijal J, Filipiuk E. Expression of apoptosis- and cell cycle-related proteins in epidermis of venous leg and diabetic foot ulcers. Surgery 2003; 134: 213-220
    CrossrefPubMedGoogle Scholar
  • 21 El-Bahr SM. Curcumin regulates gene expression of insulin like growth factor, B-cell CLL/lymphoma 2 and antioxidant enzymes in streptozotocin induced diabetic rats. BMC Complement Alternat Med 2013; 13: 368
    CrossrefPubMedGoogle Scholar
  • 22 Malfitano C, Alba Loureiro TC, Rodrigues B, Sirvente R, Salemi VM, Rabechi NB, Lacchini S, Curi R, Irigoyen MC. Hyperglycaemia protects the heart after myocardial infarction: aspects of programmed cell survival and cell death. Eur J Heart Failure 2010; 12: 659-667
    CrossrefPubMedGoogle Scholar
  • 23 Hasnan J, Yusof MI, Damitri TD, Faridah AR, Adenan AS, Norbaini TH. Relationship between apoptotic markers (Bax and Bcl-2) and biochemical markers in type 2 diabetes mellitus. Singapore Med J 2010; 51: 50-55
    PubMedGoogle Scholar
  • 24 Cipollone F, Chiarelli F, Iezzi A, Fazia ML, Cuccurullo C, Pini B, De Cesare D, Torello M, Tumini S, Cuccurullo F, Mezzetti A. Relationship between reduced BCL-2 expression in circulating mononuclear cells and early nephropathy in type 1 diabetes. Int J Immunopathol Pharmacol 2005; 18: 625-635
    PubMedGoogle Scholar
  • 25 Budni P, Pedrosa RC, Dalmarco EM, Dalmarco JB, Frode TS, Wilhelm Filho D. Carvedilol enhances the antioxidant effect of vitamins E and C in chronic Chagas heart disease. Arqui Brasil Cardiol 2013; 101: 304-310
    PubMedGoogle Scholar
  • 26 Dandona P, Ghanim H, Brooks DP. Antioxidant activity of carvedilol in cardiovascular disease. J Hyperten 2007; 25: 731-741
    CrossrefPubMedGoogle Scholar
  • 27 Botti H, Batthyany C, Trostchansky A, Radi R, Freeman BA, Rubbo H. Peroxynitrite-mediated alpha-tocopherol oxidation in low-density lipoprotein: a mechanistic approach. Free Rad Biol Med 2004; 36: 152-162
    CrossrefPubMedGoogle Scholar
  • 28 Lopez BL, Christopher TA, Yue TL, Ruffolo R, Feuerstein GZ, Ma XL. Carvedilol, a new beta-adrenoreceptor blocker antihypertensive drug, protects against free-radical-induced endothelial dysfunction. Pharmacology 1995; 51: 165-173
    CrossrefPubMedGoogle Scholar
  • 29 Yue TL, McKenna PJ, Lysko PG, Gu JL, Lysko KA, Ruffolo Jr RR, Feuerstein GZ. SB 211475, a metabolite of carvedilol, a novel antihypertensive agent, is a potent antioxidant. Eur J Pharmacol 1994; 251: 237-243
    CrossrefPubMedGoogle Scholar
  • 30 Watanabe K, Arozal W, Sari F, Arumugam S, Thandavarayan RA, Suzuki K, Kodama M. The role of carvedilol in the treatment of dilated and anthracyclines-induced cardiomyopathy. Pharmaceuticals 2011; 4: 770-781
    CrossrefPubMedGoogle Scholar
  • 31 Schwarz ER, Kersting PH, Reffelmann T, Meven DA, Al-Dashti R, Skobel EC, Klosterhalfen B, Hanrath P. Cardioprotection by Carvedilol: antiapoptosis is independent of beta-adrenoceptor blockage in the rat heart. J Cardiovasc Pharmacol Therap 2003; 8: 207-215
    PubMedGoogle Scholar
  • 32 Zeng H, Liu X, Zhao H. Effects of carvedilol on cardiomyocyte apoptosis and gene expression in vivo after ischemia-reperfusion in rats. J Huazhong Univ Sci Technol Med Sci 2003; 23: 127-130
    CrossrefPubMedGoogle Scholar
  • 33 Kumar S, Vasudeva N, Sharma S. GC-MS analysis and screening of antidiabetic, antioxidant and hypolipidemic potential of Cinnamomum tamala oil in streptozotocin induced diabetes mellitus in rats. Cardiovasc Diabetol 2012; 11: 95
    CrossrefPubMedGoogle Scholar
  • 34 Sarkhail P, Rahmanipour S, Fadyevatan S, Mohammadirad A, Dehghan G, Amin G, Shafiee A, Abdollahi M. Antidiabetic effect of Phlomis anisodonta: effects on hepatic cells lipid peroxidation and antioxidant enzymes in experimental diabetes. Pharmacol Res 2007; 56: 261-266
    CrossrefPubMedGoogle Scholar
  • 35 Yousif MH, Benter IF, Akhtar S. Inhibition of calcium/calmodulin-dependent protein kinase II normalizes diabetes-induced abnormal vascular reactivity in the rat perfused mesenteric vascular bed. Auton Autacoid Pharmacol 2003; 23: 27-33
    CrossrefPubMedGoogle Scholar
  • 36 Erickson JR, He BJ, Grumbach IM, Anderson ME. CaMKII in the cardiovascular system: sensing redox states. Physiol Rev 2011; 91: 889-915
    CrossrefPubMedGoogle Scholar
  • 37 Cabassi A, Coghi P, Govoni P, Barouhiel E, Speroni E, Cavazzini S, Cantoni AM, Scandroglio R, Fiaccadori E. Sympathetic modulation by carvedilol and losartan reduces angiotensin II-mediated lipolysis in subcutaneous and visceral fat. J Clin Endocr Metab 2005; 90: 2888-2897
    CrossrefPubMedGoogle Scholar
  • 38 Farvid MS, Jalali M, Siassi F, Hosseini M. Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes. Diabetes Care 2005; 28: 2458-2464
    CrossrefPubMedGoogle Scholar
  • 39 Muruganandan S, Gupta S, Kataria M, Lal J, Gupta PK. Mangiferin protects the streptozotocin-induced oxidative damage to cardiac and renal tissues in rats. Toxicology 2002; 176: 165-173
    CrossrefPubMedGoogle Scholar
  • 40 Li B, Tan Y, Sun W, Fu Y, Miao L, Cai L. The role of zinc in the prevention of diabetic cardiomyopathy and nephropathy. Toxicol Mech Meth 2013; 23: 27-33
    CrossrefPubMedGoogle Scholar
  • 41 Ramprasath T, Kumar PH, Puhari SS, Murugan PS, Vasudevan V, Selvam GS. L-Arginine ameliorates cardiac left ventricular oxidative stress by upregulating eNOS and Nrf2 target genes in alloxan-induced hyperglycemic rats. Biochem Biophys Res Commun 2012; 428: 389-394
    CrossrefPubMedGoogle Scholar
  • 42 Suanarunsawat T, Devakul Na Ayutthaya W, Songsak T, Thirawarapan S, Poungshompoo S. Antioxidant Activity and Lipid-Lowering Effect of Essential Oils Extracted from Ocimum sanctum L. Leaves in Rats Fed with a High Cholesterol Diet. J Clin Biochem Nutr 2010; 46: 52-59
    PubMedGoogle Scholar
  • 43 Ozkaya D, Naziroglu M, Armagan A, Demirel A, Koroglu BK, Colakoglu N, Kukner A, Sonmez TT. Dietary vitamin C and E modulates oxidative stress induced-kidney and lens injury in diabetic aged male rats through modulating glucose homeostasis and antioxidant systems. Cell Biochem Funct 2011; 29: 287-293
    CrossrefPubMedGoogle Scholar