The Effects of Valsartan on Cardiac Function and Pro-Oxidative Parameters in the Streptozotocin-Induced Diabetic Rat Heart

Open access


Diabetes mellitus is a major risk factor for cardiovascular diseases, while cardiovascular diseases are a leading cause of morbidity and mortality worldwide. The renin-angiotensin- aldosterone system controls renal, cardiovascular, adrenal function and regulates fluid and electrolyte balance as well as blood pressure. Because of his role, inhibition of reninangiotensin- aldosteron system is another therapy approach that reduces the risk of diabetes and cardiovascular disease. In this study, our goal was to evaluate effect of valsartan,as inhibitor of angiotensin II receptor type 1, on cardiac tissue and function, with focus on cardiodynamic and oxidative stress. The present study was carried out on 20 adult male Wistar albino rats (8 week old and with body masses of 180- 200 g). Rats were divided randomly into 2 groups (10 animals per group). Healthy animals treated with 1 μM of valsartan and streptozotocin-induced diabetic animals perfused with 1 μM of valsartan 4 weeks after the induction of diabetes. Our results demonstrated that acute application of valsartan has different effect on cardiodynamics in rat heart of diabetic and healthy animals but did not improve cardiac function in hyperglycemia- induced changes. A challenge for further investigations are studies with chronic or acute administration, alone or in combination with other angiotensin-converting-enzyme inhibitor in various models of diabetes.

1. Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocr Rev 2003;24(3): 261-271

2. Vranic A, Simovic S, Ristic P, Nikolic T, Stojic I, Srejovic I et al. The acute effects of different spironolactone doses oncardiac function in streptozotocin-induced diabetic rats. Can J Physiol Pharmacol 2017; 95: 1343-1350

3. Nguyen Dinh Cat A, Jaisser F. Extrarenal effects of aldosterone. Curr Opin Nephrol Hypertens 2012; 21: 147-156

4. Nguyen Dinh Cat A, Montezano AC, Burger D, Touyz RM. Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal 2013; 19: 1110-1120

5. Nguyen Dinh Cat A, Touyz RM. Cell signaling of angiotensin II on vasculartone: novel mechanisms. Curr Hypertens Rep 2011; 13: 122-128

6. Kintscher U, Marx N, Martus P, Stoppelhaar M, Schimkus J, Schneider A et al. Effect ofhigh-dose valsartan on inflammatory and lipid parameters in patients with Type 2 diabetes and hypertension. Diabetes Res Clin Pract 2010; 89: 209-215

7. Ristic P, Srejovic I, Nikolic T, Stojic I, Ristic D, Zivkovic V et al. The effects of zofenopril on cardiac function and pro-oxidative parameters in the streptozotocin-induced diabetic rat heart. Mol Cell Biochem 2017; 426: 183-193

8. Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, Hua TA et al. Effect ofnateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 2010; 362: 1463-1476

9. Kjeldsen SE, Julius S, Mancia G, McInnes GT, Hua T, Weber MA et al. Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients. the VALUE trial J Hypertens 2006;24: 1405-1412

10. Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel BH et al. Ramipril and the development of diabetes. JAMA 2001; 286: 1882-1885

11. Scheen AJ. Prevention of type 2 diabetes mellitus through inhibition of the renin-angiotensin system. Drugs 2004; 64: 2537-2565

12. Weber MA, Julius S, Kjeldsen SE, Brunner HR, Ekman S, Hansson L. Blood pressure dependent and independent effects of antihypertensive treatment onclinical events in the VALUE Trial Lancet 2004;363: 2049-2051

13. Hollenberg NK, Parving HH, Viberti G, Remuzzi G, Ritter S, Zelenkofske S et al. Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus. J Hypertens 2007; 25: 1921-1926

14. Chabrashvili T, Kitiyakara C, Blau J, Karber A, Aslam S, Welch WJ et al. Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression. Am J Physiol Regul Integr Comp Physiol 2003; 285: 117-124

15. Hornig B, Landmesser U, Kohler C, Ahlersmann D, Spiekermann S, Christoph A et al. Comparative effect of ACE inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation 2001; 103: 799-805

16. Kim HJ, Han SJ, Kim DJ, Jang HC, Lim S, Choi SH et al. Effects of valsartan andamlodipine on oxidative stress in type 2 diabetic patients with hypertension: arandomized, multicenter study. Korean J Intern Med 2017; 32: 497-504

17. Jung KH, Chu K, Lee ST, Kim SJ, Song EC, Kim EH et al. Blockade of AT1 receptorreduces apoptosis, inflammation, and oxidative stressin normotensive rats with intracerebral hemorrhage. J Pharmacol Exp Ther 2007;322: 1051-1058

18. Navalkar S, Parthasarathy S, Santanam N, Khan BV. Irbesartan, an angiotensin type 1 receptor inhibitor, regulatesmarkers of inflammation in patients with premature atherosclerosis. J Am Coll Cardiol 2001; 37: 440- 444

19. Shmiedr R, Hilgers KF, Schlaich MP, Shmidt BMW. Renin- angiotensin system and cardiovascular risk, Lancet 2007; 369(9568): 1208-1219

20. Yang ZH, Peng XD. Effects of valsartan on diabetic cardiomyopathy in rats with type 2 diabetes mellitus. Chin Med J 2010; 123: 3640-3643

21. Tesch GH, Allen TJ. Rodent models of streptozotocininduced diabetic nephropathy. Nephrology 2007; 12: 261-266

22. Auclair C, Voisin E. Nitroblue tetrazolium reduction. In: Greenwald RA (ed) CRC handbook of methods for oxygen radical research. Boca Raton CRC Press, 1985: 123-132

23. Green LC, Wagnwr DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite and (15 N) nitrate in biological fluids. Anal Biochem 1985;126: 131-138

24. Pick E, Keisari Y. A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture. J Immunol Methods 1980; 38: 161-170

25. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351-358

26. Goyal SN, Reddy NM, Patil KR, Nakhate KT, Ojha S, Patil CR et al. Challenges and issues with streptozotocininduced diabetes-A clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics. Chem Biol Interact 2016; 244: 49-63

27. Chan P, Wong KL, Liu IM, Tzeng TF, Yang TL et al. Antihyperglycemic action of angiotensin II receptor antagonist, valsartan, in streptozotocin-induced diabetic rats. J Hypertens 2003; 21; 761-769

28. Criscione L, De Gasparo M, Buhlmayer P, Whitebread S, Ramjoue HP, Wood J. Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. Br J Pharmacol 1993; 110: 7617-7671

29. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363: 2022-2031

30. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362: 759-766

31. Ward ML, Crossman DJ. Mechanisms underlying the impaired contractility of diabetic cardiomyopathy. World J Cardiol 2014; 6: 577-584

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

33. Seeger H, Lippert C, Wallwiener D, Mueck AO. Valsartan and candesartan can inhibit deteriorating effects of angiotensin II on coronary endothelial function. J Renin Angiotensin Aldosterone Syst 2001; 2: 141-143

34. Khanna S, Singh GB, Khullar M. Nitric oxide synthases and diabetic cardiomyopathy. Nitric Oxide 2014; 1: 29-34

35. Janssen S, Pokreisz P, Schoonjans L, Pellens M, Vermeersch P, Tjwa M et al. Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circ Res 2004; 94: 1256-1262

36. Ichinose F, Bloch KD, Wu JC, Hataishi R, Aretz HT, Picard MH et al. Pressure overload-induced LV hy pertrophy and dysfunction in mice are exacerbated by congenital NOS3 deficiency. Am J Physiol Heart Circ Physiol 2004; 286: H1070-H1075

37. Scherrer-Crosbie M, Ullrich R, Bloch KD, Nakajima H, Nasseri B, Aretz HT et al. Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation 2001; 104: 1286-1291

38. Nagareddy PR, Xia Z, McNeill JH, MacLeod KM. Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes. Am J Physiol Heart Circ Physiol. 2005; 289: H2144-H2152

39. West MB, Ramana KV, Kaiserova K, Sirvastava SK, Bhatngar A. L-Arginin prevents metabolic effects of high glucose in diabetic mice. FEBS let. 2008; 582: 2609-2614

40. Iglarz M, Touyz RM, Viel EC, Amiri F, Schiffrin EL. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction with the reninangiotensin system. Am J Hypertens. 2004; 17: 597-603.

Serbian Journal of Experimental and Clinical Research

The Journal of Faculty of Medical Sciences, University of Kragujevac

Journal Information

CiteScore 2018: 0.13

SCImago Journal Rank (SJR) 2018: 0.118
Source Normalized Impact per Paper (SNIP) 2018: 0.079


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 71 71 10
PDF Downloads 60 60 5