Exp Clin Endocrinol Diabetes 2013; 121(08): 441-447
DOI: 10.1055/s-0033-1345168
Article
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Effect of Spironolactone on Cardiovascular Complications Associated with Type-2 Diabetes in Rats

B. M. Patel
1   Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
,
J. Kakadiya
3   Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, India
,
R. K. Goyal
2   Institute of Life Sciences, Ahmedabad University Navarangpura, Ahmedabad, Gujarat, India
,
A. A. Mehta
3   Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, India
› Author Affiliations
Further Information

Publication History

received 25 January 2013
first decision 23 April 2013

accepted 24 April 2013

Publication Date:
11 September 2013 (online)

Abstract

We have studied the effect spironolactone (20 mg/kg/day) on cardiovascular complications in neonatal model of diabetes in rats, induced by administering 90 mg/kg streptozotocin (STZ), i.p. in 2 day old rats. Diabetes was checked after 12 weeks. At the end of 8 weeks of treatment, various biochemical and cardiac parameters were measured. STZ produced hyperglycemia, hyperinsulinemia, dyslipidemia, increased creatinine, cardiac enzyme and C-reactive protein (CRP) levels, worsened hemodynamic parameters, cardiac hypertrophy and oxidative stress. Chronic treatment with spironolactone significantly reduced serum glucose levels but did not alter insulin levels. It also significantly prevented the dyslipidemia and reduced elevated Lactate de-hydrogenase, creatinine kinase, CRP and creatinine levels. Chronic treatment with spironolactone prevented STZ-induced hypertension, tachycardia and elevated rate of pressure development and decay. Spironolactone also produced beneficial effect by preventing cardiac hypertrophy as evident from left ventricular collagen levels, cardiac and left ventricular hypertrophic indices and prevented oxidative stress. In conclusion, our data suggests that spironolactone prevents STZ induced metabolic abnormalities and cardiovascular complications in animal model of type 2 diabetes.

 
  • References

  • 1 Goyal BR, Solanki N, Goyal RK et al. Investigation into the cardiac effects of spironolactone in the experimental model of type 1 diabetes. J Cardiovasc Pharmacol 2009; 54: 502-509
  • 2 http://www.who.int/mediacentre/factsheets/fs312/en/index.html accessed on 18th January, 2011
  • 3 Gilbert RE, Jeriuns G, Cooper ME. Diabetes and hypertension: prognostic and therapeutic considerations. Blood Press 1995; 4: 329-338
  • 4 Patel BM, Agarwal SS, Bhadada SV. Perindopril protects against streptozotocin induced hyperglycemic myocardial damage/alterations. Human and Experimental Toxicology 2012; 31: 1138-1149
  • 5 Patel BM, Mehta AA. The choice of antihypertensive agents in diabetes subjects. Diabetes and Vascular Disease Research 2013; [Accepted]
  • 6 Goyal BR, Patel MM, Bhadada SV. Comparative evaluation of spironolactone, atenolol, metoprolol, ramipril and perindopril on diabetes induced cardiovascular complications in type 1 diabetes in rats. International Journal of Diabetes and Metabolism 2011; 19: 11-18
  • 7 Patel BM, Mehta AA. Aldosterone And Angiotensin: Role In Diabetes And Cardiovascular Diseases. European Journal of Pharmacology 2012; 697: 1-12
  • 8 Stier Jr CT, Chander PN, Rocha R. Aldosterone as a mediator in cardiovascular injury. Cardiol Rev 2002; 10: 97-107
  • 9 Jandeleit-Dahm KA, Tikellis C, Reid CM et al. Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes. J Hypertens 2005; 23: 463-473
  • 10 Barbato JC, Rashid S, Mulrow PJ et al. Mechanisms for Aldosterone and Spironolactone-Induced Positive Inotropic Actions in the Rat Heart. Hypertension 2004; 44: 751
  • 11 Nehme JA, Lacolley P, Labat C et al. Spironolactone improves carotid artery fibrosis and distensibility in rat post-ischaemic heart failure. J Mol Cell Cardiol 2005; 39: 511-519
  • 12 Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med 1999; 341: 709-717
  • 13 Tsutamoto T, Wada A, Maeda K et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol 2001; 37: 1228-1233
  • 14 Goyal BR, Mehta AA. Beneficial role of spironolactone, telmisartan and their combination on isoproterenol induced cardiac hypertrophy. Acta Cardiologica January 2012; 67: 203-211
  • 15 Goyal BR, Mesariya P, Goyal RK et al. Effect of telmisartan on cardiovascular complications associated with STZ-diabetic rats. Mol Cell Biochem 2008; 314: 123-131
  • 16 Goyal BR, Parmar K, Goyal RK et al. Beneficial role of telmisartan on cardiovascular complications associated with STZ-induced type-2 diabetic rats. Pharmacol Rep 2011; 63: 956-966
  • 17 Beutler E, Duron O, Kelly B. Reduced glutathione estimation. J Lab Clin Med 1963; 61: 882
  • 18 Misra HP, Frodvich I. The role of superoxide anion autoxidation of epinephrine and a simple method for superoxide dismutase. J Biol Chem 1984; 247: 3170-3175
  • 19 Aeibi H, Bergmeyer H. Methods in enzymatic analysis. 2nd edition. New York: Academic Press; 1974
  • 20 Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissue by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351-358
  • 21 Portha B, Picon L, Rosselin G. Chemical diabetes in the adult rats as the spontaneous evolution of neonatal diabetes. Diabetologia 1979; 17: 371-377
  • 22 Bochud M, Nussberger J, Bovet P et al. Plasma Aldosterone Is Independently Associated With the Metabolic Syndrome. Hypertension 2006; 48: 239-245
  • 23 Epstein M, Buckalew V, Martinez FM et al. Anti-proteinuric efficacy of eplerenone, enalapril, and eplerenone/enalapril combination therapy in diabetic hypertensives with microalbuminuria. Am J Hypertens 2002; 15: 24A Abstract OR-54
  • 24 Goyal B, Mehta A. Diabetic cardiomyopathy: Pathophysiological mechanisms and cardiac dysfuntion. Hum Exp Toxicol 2012; [Epub ahead of print]
  • 25 Hitomi H, Kiyomoto H, Nishiyama A et al. Aldosterone Suppresses Insulin Signaling Via the Downregulation of Insulin Receptor Substrate-1 in Vascular Smooth Muscle Cells. Hypertension 2007; 50: 750-755
  • 26 Corbould A. Effects of Spironolactone on Glucose Transport and lnterleukin-6 Secretion in Adipose Cells of Women. Horm Metab Res 2007; 39: 915-918
  • 27 Kopprasch S, Pietzsch J, Ansurudeen I et al. Prediabetic and diabetic in vivo modification of circulating low-density lipoprotein attenuates its stimulatory effect on adrenal aldosterone and cortisol secretion. J Endocrinol 2009; 200: 45-52
  • 28 Ostergren J. Renin-angiotensin-system blockade in the prevention of diabetes. Diabetes Res Clin Pract 2007; 76: S13-S21
  • 29 Maliukova NG. Effect of hyperlipidemia on the activity of renin-angiotensin-aldosterone system in patients with chronic cardiac insufficiency. Lik Sprava 2004; 5-6: 29-32
  • 30 Gökmen O, Senöz S, Gülekli B et al. Comparison of four different treatment regimes in hirsutism related to polycystic ovary syndrome. Gynecol Endocrinol 1996; 10: 249-255
  • 31 Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285: 2481-2485
  • 32 Pradhan A, Manson J, Rifai N et al. C-reactive protein, interleukin-6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286: 327-334
  • 33 Gilbert KC, Brown NJ. Aldosterone and inflammation. Curr Opin Endocrinol Diabetes Obes 2010; 17: 199-204
  • 34 Syngle A, Vohra K, Kaur L et al. Effect of spironolactone on endothelial dysfunction in rheumatoid arthritis. Scan J Rheum 2009; 38: 15-22
  • 35 Satoh M, Nakamura M, Akatsu T et al. C-reactive protein co-expresses with tumor necrosis factor-α in the myocardium in human dilated cardiomyopathy. This article is not included in your organization’s subscription. However, you may be able to access this article under your organization’s agreement with Elsevier. Eur J Heart Fail 2005; 7: 748-754
  • 36 Godfrey V, Farquharson CA, Macdonald JE et al. Effect of spironolactone on C-reactive protein levels in patients with heart disease. Int J Cardiol 2007; 117: 282-284
  • 37 Huang E, Kuo W, Chen Y et al. Homocysteine and other biochemical parameters in Type 2 diabetes mellitus with different diabetic duration or diabetic retinopathy. Clinica himica Acta 2006; 366: 293-298
  • 38 Hagar HH. Folic acid and vitamin B12 supplementation attenuates isoprenaline-induced myocardial infarction in experimental hyperhomocysteinemic rats. Pharmacol Res 2002; 46: 213-219
  • 39 Bedrak E, Hammer R, Goldberg S. Plasma enzymes in relation to aldosterone administration and acclimatization in rats. J Appl Physiol 1967; 22: 297-300
  • 40 Mizushige K, Yao L, Noma T et al. Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model. Circulation 2000; 101: 899-907
  • 41 Zannad F, Dousset B, Alla F. Treatment of Congestive Heart Failure; Interfering the Aldosterone-Cardiac Extracellular Matrix Relationship. Hypertension 2001; 38: 1227
  • 42 Guarda E, Myers P, Brilla C et al. Endothelial cell induced modulation of cardiac fibroblast collagen metabolism. Cardiovasc Res 1993; 27: 1004-1008
  • 43 Delcayre C, Silvestre JS. Review. Aldosterone and the heart: towards a physiological function?. Cardiovasc Res 1999; 43: 7-12
  • 44 Mill JG, Milanez Mda C, de Resende MM et al. Spironolactone prevents cardiac collagen proliferation after myocardial infarction in rats. Clin Exp Pharmacol Physiol 2003; 30: 739-744
  • 45 Lacolley P, Safar ME, Lucet B et al. Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats. J Am Coll Cardiol 2001; 37: 662-667
  • 46 Nagata K, Obata K, Xu J et al. Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Failure in Low-Aldosterone Hypertensive Rats. Hypertension 2006; 47: 656
  • 47 Grossman E, Shemesh J, Shamiss A et al. Left Ventricular Mass in Diabetes. Arch Int Med 1992; 152: 5
  • 48 Okoshi MP, Yan X, Okoshi K et al. Aldosterone directly stimulates cardiac myocyte hypertrophy. J Card Fail 2004; 10: 511-518
  • 49 Takeda Y, Yoneda T, Demura M et al. Cardiac aldosterone production in genetically hypertensive rats. Hypertension 2000; 36: 495-500
  • 50 Tsukashita M, Marui A, Nishina T et al. Spironolactone alleviates late cardiac remodeling after left ventricular restoration surgery. J Thorac Cardiovasc Surg 2008; 136: 58-64
  • 51 Bunag RD, Tomita T, Saski S. Streptozocin diabetic rats are hypertensive despite reduced hypothalamic responsiveness. Hypertension 1982; 4: 556-565
  • 52 Baum M. Insulin stimulates volume absorption in the rabbit proximal convoluted tubule. J Clin Invest 1987; 79: 1104-1109
  • 53 Wang W. Chronic administration of aldosterone depresses baroreceptor reflex function in the dog. Hypertension 1994; 24: 571-575
  • 54 Hoffmann J, Grimm W, Menz V et al. Heart rate variability and baroreflex sensitivity in idiopathic dilated cardiomyopathy. Heart 2000; 83: 531-538
  • 55 Zhang Y, Liu J, Wang Y et al. Intervention of spironolactone on heart rate variability and its circardian rhythm in patients with heart failure. J Chin Clin Med 2006; 1: 264-267
  • 56 Zhang M, Xu YJ, Saini HK et al. Pentoxifylline attenuates cardiac dysfunction and reduces TNF-α level in ischemic-reperfused heart. Am J Physiol Heart Circ Physiol 2005; 289: H832-H839
  • 57 Quinkler M, Zehnder D, Eardley KS et al. Increased expression of mineralocorticoid effector mechanisms in kidney biopsies of patients with heavy proteinuria. Circulation 2005; 112: 1435-1443
  • 58 Han S, Kim C, Kim H et al. Spironolactone Prevents Diabetic Nephropathy through an Anti-Inflammatory Mechanism in Type 2 Diabetic Rats. J Am Soc Nephrol 2006; 17: 1362-1372
  • 59 Siwik D, Fagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 2001; 280: C53-C60
  • 60 Haffner SM, Agil A, Mykkanen L et al. Plasma oxidizability in subjects with normal glucose tolerance and NIDDM. Diabetes Care 1995; 18: 646-653
  • 61 Zhao W, Ahokas RA, Weber KT et al. II-induced cardiac molecular and cellular events: role of aldosterone. Am J Physiol Heart Circ Physiol 2006; 291: H336-H343