Skip to main content
SpringerLink
Log in

Probucol treatment reverses antioxidant and functional deficit in diabetic cardiomyopathy

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Earlier we reported that probucol treatment subsequent to the induction of diabetes can prevent diabetes-associated changes in myocardial antioxidants as well as function at 8 weeks. In this study, we examined the efficacy of probucol in the reversal of diabetes induced myocardial changes. Rats were made diabetic with a single injection of streptozotocin (65 mg/kg, i.v.). After 4 weeks of induction of diabetes, a group of animals was treated on alternate days with probucol (10 mg/kg i.p.), a known lipid lowering agent with antioxidant properties. At 8 weeks, there was a significant drop in the left ventricle (LVSP) and aortic systolic pressures (ASP) in the diabetic group. Hearts from these animals showed an increase in the thiobarbituric acid reacting substances (TBARS), indicating increased lipid peroxidation. This was accompanied by a decrease in the myocardial antioxidant enzymes activities, superoxide dismutase (SOD) and glutathione peroxidase (GSHPx). Myocardial catalase activity in the diabetic group was higher. In the diabetic + probucol group both LVSP and ASP showed significant recovery. This was also accompanied by an improvement in SOD and GSHPx activities and there was further increase in the catalase activity. Levels of the TBARS were decreased in this group. These data provide evidence that diabetic cardiomyopathy is associated with an antioxidant deficit which can be reversed with probucol treatment. Improved cardiac function with probucol may be due to the recovery of antioxidants in the heart.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kannel WB: Role of diabetes in cardiac disease. In: S. Zoneraich, (ed.) Diabetes and the Heart, Charles C. Thomas, Springfield, Illinois pp 97–120

  2. Rubler S, Dlugash J, Yuceoglu UZ, Kumral T, Branwood AW, Grishman A: New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 30: 595–602, 1972

    Google Scholar 

  3. Regan TJ, Lyons MM, Ahmed S, Levinson GE, Oldewurtel HA, Ahman M, Haider B: Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest 60: 885–893, 1977

    Google Scholar 

  4. Dhalla NS, Pierce GN, Innes IR, Beamish RE: Pathogenesis of cardiac dysfunction in diabetes mellitus. Can J Cardiol 1: 263–284, 1985

    Google Scholar 

  5. Fein FS, Sonnenblick EH: Diabetic cardiomyopathy. Prog Cardiovasc Dis H 27: 255–270, 1985

    Google Scholar 

  6. Wohaieb SA, Godin DV: Alterations in free radical tissue defense mechanisms in streptozotocin induced diabetes in the rat: Effects of insulin treatment. Diabetes 36: 1014–1018, 1987

    Google Scholar 

  7. Kaul N, Siveski-Iliskovic N, Thomas TP, Hill M, Khaper N, Singal PK: Probucol improves antioxidant activity and modulates development of diabetic cardiomyopathy. Nutrition. In Press, 1995

  8. Simmons KJ Defence against free radicals has therapeutic implications. J Amer Med Assoc 251: 2187–2192, 1984

    Google Scholar 

  9. Halliwell G, Gutteridge JMC: Lipid peroxidation, oxygen radicals, cell damage and antioxidant therapy. Lancet 1: 1396–1397, 1984

    Google Scholar 

  10. Kaul N, Siveski-Iliskovic N, Hill M, Slezak J, Singal PK: Free radicals in the heart. J Pharmacol Toxicol Meth 30: 55–63, 1993

    Google Scholar 

  11. Parthasarathy S, Young SG, Witztum TL, Pittman RC, Steinberg D: Probucol inhibits oxidative modification of low density lipoproteins. J Clin Invest 77: 641–644, 1986

    Google Scholar 

  12. Carew TE, Schwenke DC, Steinberg D: Antiatherogenic effect of Probucol unrelated to its hypocholesterolemic effect. Proc Natl Acad Sci, USA 84: 7725–7729, 1984

    Google Scholar 

  13. Siveski-Iliskovic N, Kaul N, Singal PK: Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy. Circulation. 89: 2829–2835, 1994

    Google Scholar 

  14. Siveski-Iliskovic N, Hill M, Chow D, Singal PK: Probucol protects against adriamycin cardiomyopathy without interfering with its antitumor effect. Circulation 91: 10–15, 1995

    Google Scholar 

  15. Chisolm GM, Morel DW: Lipoprotein oxidation and cytotoxicity: Effect of probucol on streptozotocin treated rats. Am J Cardiol 62: 20B-26B, 1988

    Google Scholar 

  16. Morel DW, Chisolm GM: Antioxidant treatment of diabetic rats inhibits lipoprotein oxidation and cytotoxicity. J Lipid Res 30: 1827–1834, 1989

    Google Scholar 

  17. Matsushita M, Yoshino G, Iwai M: Protective effects of probucol on alloxan diabetes in rats. Diabetes Res Clin Prac 7: 313–316, 1989

    Google Scholar 

  18. Bondar RJL, Mead DC: Evaluation of glucose-6-phosphate dehydrogenase from leuconostoc mesenterioles in the hexokinase method for determining glucose in serum. Clin Chem 20: 586–590, 1974

    Google Scholar 

  19. Marklund SL: Pyrogallol autoxidation. In: R.A. Greenwald, (ed.) Handbook of Methods for Oxygen Radical Research. Boca Raton, Florida: CRC Press, 1985 pp 243–247

    Google Scholar 

  20. Paglia DE, Valentine WN: Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70: 158–247, 1967

    Google Scholar 

  21. Clairborne A: Catalase activity. In: R.A. Greenwald (ed.) Handbook of Methods for Oxygen Radical Research. Boca Raton, Florida: CRC Press, 1979 pp 283–284

    Google Scholar 

  22. Placer ZA, Cushman LL, Johnson BC: Estimation of product of lipid peroxidation (malondialdehyde) in biochemical systems. Anal Biochem 16: 359–365, 1966

    Google Scholar 

  23. Aust SD: Lipid peroxidation. In: R.A. Greenwald (ed.) Handbook of Methods for Oxygen Radical. Boca Raton, Florida: CRC Press, 1985 pp 203–207

    Google Scholar 

  24. Lowry OH, Rosebrough NJ, Farr AL, Randall AJ: Protein measurement with the folin phenol regent. J Biol Chem 193: 265–275, 1951

    Google Scholar 

  25. Regan TJ, Ettinger PO, Khan ME, Jesuani MU, Lyon MM, Oldewurtel HA, Weber M: Altered myocardial function and metabolism in chronic diabetes mellitus without ischemia in dogs. Circ Res 35: 222–237, 1974

    Google Scholar 

  26. Factor SM, Minase T, Sonnenblick E: Clinical and morphological features of human hypertensive diabetic cardiomyopathy. Am Heart J 99: 446–458, 1980

    Google Scholar 

  27. Heyliger CE, Pierce GN, Singal PK, Beamish RE, Dhalla NS: Cardiac alpha and beta adrenergic receptor alterations in diabetic cardiomyopathy. Basic Res Cardiol 77: 610–618, 1982

    Google Scholar 

  28. Pierce GN, Dhalla NS: Mechanism of defect in cardiac myofibrillar function during diabetes. Am J Physiol 248: E170-E175, 1985

    Google Scholar 

  29. Pierce GN, Kutryk MJB, Dhalla NS: Alterations in Ca2+ binding by and composition of the cardiac sarcolemmal membrane in chronic diabetes. Proc Natl J Acad Sci, USA 80: 5412–5416, 1983

    Google Scholar 

  30. Makino N, Dhalla KS, Elimban V, Dhalla NS: Sarcolemmal calcium transport in streptozotocin-induced diabetic cardiomyopathy in rats. Am J Physiol 253: E202-E207, 1983

    Google Scholar 

  31. Penparkgul S, Fein F, Sonnenblick Eh, Scheuer J: Depressed cardiac sarcoplasmic reticular function from diabetic rats. J Mol Cell Cardiol 13: 303–309, 1981

    Google Scholar 

  32. Ganguly PK, Pierce GN, Dhalla KS, Dhalla NS: Defective sarcoplasmic reticulum calcium transport in diabetic cardiomyopathy. Am J Physiol 244: E528-E535, 1983

    Google Scholar 

  33. Kobayashi A, Yamashete T, Kaneko M, Nishiyama T, Hayashi H, Yamazaki N: Effects of verapamil on experimental cardiomyopathy in the Syrian hamster. JACC 10: 1128–1134, 1987

    Google Scholar 

  34. Gupta M, Singal PK: Time course of structure, function, and metabolic changes due to an exogenous source of oxygen metabolites in rat heart. Can J Physiol Pharmacol 67: 1549–1559, 1989

    Google Scholar 

  35. Guarnieri C, Flamigni F, Caldarera CM: Role of oxygen in cellular damage induced by reoxygenation of hypoxic heart. J Mol Cell Cardiol 12: 797–808, 1980

    Google Scholar 

  36. Hodgson EK, Fridovich I: The interaction of bovine erythrocyte superoxide dismutase with hydrogen peroxide: Chemiluminescence and peroxidation. Biochemistry 14: 5399–5303, 1975

    Google Scholar 

  37. Searle AJ, Willson RL: Glutathione peroxide: Effect of superoxide, hydroxyl and bromine free radicals on enzyme activity. Int J Radiat Biol 37: 213–217, 1980

    Google Scholar 

  38. Giuliano D, Acampara R, D'Onofrio P: Medical hypothesis: cardiovascular complications of diabetes mellitus-from glucose to insulin and back. Diabetic Metabol 20: 445–453, 1994

    Google Scholar 

  39. Marshall RN: Pharmacology and toxicology of probucol. Artery 10: 7–21, 1982

    Google Scholar 

  40. Drash AL, Rudert WA, Borquaye S, Wang R, Lieberman I: Effect of probucol on development of diabetes mellitus in BB rats. Am J Cardiol 62: 27B-30B, 1988

    Google Scholar 

  41. O'Brien K, Nagano Y, Gown A, Kita T, Chait A: Probucol treatment affects the cellular composition but not antioxidized low density lipoprotein immunoreactivity of plaque from Watanabe heritable hyperlipedimic rabbits. Arteriosclerosis and Thrombosis 11: 751–759, 1991

    Google Scholar 

  42. Litwin SE, Raya TE, Anderson PG, Daugherty S, Goldman S: Abnormal cardiac function in the streptozotocin-diabetic rat. J Clin Invest 86: 481–488, 1990

    Google Scholar 

  43. Schwartz CJ: Introduction — The Probucol Experience: A review of the past and a look at the future. Am J Cardiol 62: 1B-5B, 1988

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. St. Boniface General Hospital Research Centre, Division of Cardiovascular Sciences, Winnipeg, Canada

    N. Kaul, N. Siveski-Iliskovic, M. Hill, N. Khaper, C. Seneviratne & P. K. Singal

  2. Department of Physiology, University of Manitoba, St. Boniface General Hospital Research Centre, Winnipeg, Canada

    N. Kaul, N. Siveski-Iliskovic, M. Hill, N. Khaper, C. Seneviratne & P. K. Singal

Authors
  1. N. Kaul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Siveski-Iliskovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. Khaper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Seneviratne
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. K. Singal
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaul, N., Siveski-Iliskovic, N., Hill, M. et al. Probucol treatment reverses antioxidant and functional deficit in diabetic cardiomyopathy. Mol Cell Biochem 160, 283–288 (1996). https://doi.org/10.1007/BF00240060

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00240060

Key words

Search

Navigation