Journal of Bioenergetics and Biomembranes

, Volume 50, Issue 6, pp 437–445 | Cite as

Pioglitazone provides beneficial effect in metabolic syndrome rats via affecting intracellular Na+ Dyshomeostasis

  • Ayca BilginogluEmail author
  • Makbule Fulya Tutar Selcuk
  • Hilal Nakkas
  • Belma Turan


Metabolic syndrome, is associated impaired blood glucose level, insulin resistance, and dyslipidemia caused by abdominal obesity. Also, it is related with cardiovascular risk accumulation and cardiomyopathy. The hypothesis of this study was to examine the effect of thiazolidinediones such as pioglitazone on intracellular Na+ homeostasis in heart of metabolic syndrome male rats. Abdominal obesity and glucose intolerance had measured as a marker of metabolic syndrome. Intracellular Na+ concentration ([Na+]i) at rest and [Na+]i during pacing with electrical field stimulation were determined in freshly isolated cardiomyocytes. Also, TTX-sensitive Na+- channel current (INa) density and I-V characteristics of these channels were measured to understand [Na+]i homeostasis. We determined the protein levels of Na+/Ca2+ exchanger and Na+-K+ pump to understand the relation between [Na+]i homeostasis. High sucrose intake significantly increased body mass and blood glucose level of the rats in the metabolic syndrome group as compared with control group. There was a decrease in INa density and there were differences in points on activation curve of INa. Basal [Na+]i in metabolic syndrome group significantly increased but there was a significantly decrease in [Na+]i in stimulated cardiomyocytes in metabolic syndrome. Furthermore, pioglitazone induced decreases in the basal [Na+]i and preserved the decrease in INa and [Na+]i in stimulated cardiomyocytes to those of controls. Histologically, metabolic syndrome affected heart and associated tissues together with many other organs. Results of the present study suggest that pioglitazone has significant beneficial effects on metabolic syndrome associated disturbances in the heart via effecting Na+ homeostasis in cardiomyocytes.


Pioglitazone Intracellular sodium Metabolic syndrome Sodium current Sodium homeostasis 



This study was supported by TUBITAK-SBAG-115S827.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest relating to this manuscript.


  1. Albarado-Iban A, Avelino-Cruz JE, Velasco M, Torres-Ja’come J, Hiriart M (2013) Metabolic syndrome remodels electrical activity of the sinoatrial node and produces arrhythmias in rats. PLOS ONE 8:e76534. CrossRefGoogle Scholar
  2. Anzawa R, Bernard M, Tamareille S, Baetz D, Confort-Gouny S, Gascard JP, Cozzone P, Feuvray D (2006) Intracellular sodium increase and susceptibility to ischaemia in hearts from type 2 diabetic db/db mice. Diabetologia 49:598–606. CrossRefGoogle Scholar
  3. Ayaz M, Can B, Ozdemir S, Turan B (2002) Protective effect of selenium treatment on diabetes-induced myocardial structural alterations. Biol Trace Elem Res 89:215–226. CrossRefGoogle Scholar
  4. Bell DS (2003) Heart failure: the frequent, forgotten, and often fatal complication of diabetes. Diabetes Care 26:2433–2441. CrossRefGoogle Scholar
  5. Bers DM (2001) Excitation-contraction coupling and cardiac contractile force. 2nd ed. Dordrecht/Boston. Kluwer Academic Publishers, LondonCrossRefGoogle Scholar
  6. Bers DM, Eisner DA, Valdivia HH (2003) Sarcoplasmic reticulum Ca2+ and heart failure: roles of diastolic leak and Ca2+ transport. Circ Res 93(6):487–490. CrossRefGoogle Scholar
  7. Bilginoglu A, Kandilci HB, Turan B (2013) Intracellular levels of Na+ and TTX-sensitive Na+ channel current in diabetic rat ventricular cardiomyocytes. Cardiovasc Toxicol 13:138–147. CrossRefGoogle Scholar
  8. Blaschke F, Spanheimer R, Khan M, Law RE (2006) Vascular effects of TZDs: new implications. Vasc Pharmacol 45:3–18. CrossRefGoogle Scholar
  9. Cross HR, Radda GK, Clarke K (1995) The role of Na+/K+ ATPase activity during low flow ischemia in preventing myocardial injury: a 31P, 23Na and 87Rb NMR spectroscopic study. Magn Reson Med 34:673–685. CrossRefGoogle Scholar
  10. Davidoff AJ, Mason MM, Davidson MB, Carmody MW, Hintz KK, Wold LE, Podolin DA, Ren J (2004) Sucrose-induced cardiomyocytes dysfunction is both preventable and reversible with clinically relevant treatments. Am J Physiol Endocrinol Metab 286:E718–E724. CrossRefGoogle Scholar
  11. Despa S, Bers DM (2013) Na+ transport in the normal and failing heart—remember the balance. J Mol Cell Cardiol 61:2–10. CrossRefGoogle Scholar
  12. Despa S, Islam MA, Pogwizd SM, Bers DM (2002) Intracellular [Na+]i and Na+-pump rate in rat and rabbit ventricular myocytes. J Physiol 539:133–143. CrossRefGoogle Scholar
  13. Dormandy J, Charbonnel B, Eckland D, Erdmann E, Massi-Benedetti M, Moules IK et al (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the proactive study (prospective pioglitazone clinical trial in macrovascular events): a randomised controlled trial. Lancet 366:1279–1289. CrossRefGoogle Scholar
  14. Dutta K, Podolin DA, Davidson MB, Davidoff AJ (2001) Cardiomyocyte dysfunction in sucrose-fed rats is associated with insulin resistance. Diabetes 50:1186–1192. CrossRefGoogle Scholar
  15. Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, Montori VM (2007) Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 49:403–414. CrossRefGoogle Scholar
  16. Girman CJ, Rhodes T, Mercuri M, Pyorala K, Kjekshus J, Pedersen TR et al (2004) The metabolic syndrome and risk of major coronary events in the Scandinavian simvastatin survival study (4S) and the air force/Texas coronary atherosclerosis prevention study (AFCAPS/TexCAPS). Am J Cardiol 93:136–141. CrossRefGoogle Scholar
  17. Hansen PS, Clarke RJ, Buhagiar KA, Hamilton E, Garcia A, White C, Rasmussen HH (2007) Alloxan-induced diabetes reduces sarcolemmal Na+-K+ pump function in rabbit ventricular myocytes. Am J Physiol Cell Physiol 292:C1070–C1077. CrossRefGoogle Scholar
  18. Hattori Y, Matsuda N, Kimura J, Ishitani T, Tamada A, Gando S, Kemmotsu O, Kanno M (2000) Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload. J Physiol 527:85–94. CrossRefGoogle Scholar
  19. Howarth FC, Qureshi A, Adeghate E (2004) Contraction and intracellular free Ca2+ concentrations in ventricular myocytes from rats receiving sucrose-enriched diets. Int J Diabetes Metab 12:5–9 Google Scholar
  20. Hsieh SD, Muto T, Tsuji H, Arase Y, Murase T (2010) Clustering of other metabolic risk factors in subjects with metabolic syndrome. Metabolism 59:697–702. CrossRefGoogle Scholar
  21. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716. CrossRefGoogle Scholar
  22. Lambert R, Srodulski S, Peng X, Margulies KB, Despa F, Despa S (2015) Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+–glucose cotransport. Am Heart Assoc 4:e002183. Google Scholar
  23. Louch WE, Hougen K, Mørk HK, Swift F, Aronsen JM, Sjaastad I, Reims HM, Roald B, Andersson KB, Christensen G, Sejersted OM (2010) Sodium accumulation promotes diastolic dysfunction in end-stage heart failure following Serca2 knockout. J Physiol 588:465–478. CrossRefGoogle Scholar
  24. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kihida K (2001) PPAR-gamma ligands increase expression and plasma concentrations of adiponectin, an adipocyte-derived protein. Diabetes 50:2094–2099. CrossRefGoogle Scholar
  25. Nagai Y, Ichihara A, Nakano D, Kimura S, Pelisch N, Fujisawa Y, Hitomi H, Hosomi N, Kiyomoto H, Kohno M, Ito H, Nishiyama A (2009) Possible contribution of the non-proteolytic activation of prorenin to the development of insulin resistance in fructose-fed rats. Exp Physiol 94:1016–1023. CrossRefGoogle Scholar
  26. Okatan EN, Durak AT, Turan B (2016) Electrophysiological basis of metabolic-syndrome-induced cardiac dysfunction. Can J Physiol Pharmacol 94(10):1064–1073. CrossRefGoogle Scholar
  27. Panchal SK, Poudyal H, Iyer A, Nazer R, Alam A, Diwan V et al (2011) High-carbohydrate high-fat diet-induced metabolic syndrome and cardiovascular remodeling in rats. J Cardiovasc Pharmacol 57:51–64. CrossRefGoogle Scholar
  28. Pieske B, Maier LS, Piacentino V III, Weisser J, Hasenfuss G, Houser S (2002) Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium. Circulation 106:447–453. CrossRefGoogle Scholar
  29. Reaven G (2002) Metabolic syndrome pathophysiology and implications for management of cardiovascular disease. Circulation 106:286–288. CrossRefGoogle Scholar
  30. Ronchi C, Torre E, Rizzetto R, Bernardi J, Rocchetti M, Zaza A (2017) Late sodium current and intracellular ionic homeostasis in acute ischemia. Basic Res Cardiol 112:12. CrossRefGoogle Scholar
  31. Ruiz-Ramirez A, Chavez-Salgado M, Peneda-Flores JA, Zapata E, Masso F, El-Hafidi M (2011) High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria. Am J Physiol Endocrinol Metab 301:E1198–E1207. CrossRefGoogle Scholar
  32. Scamps F, Vassort G (1994) Effect of extracellular ATP on the Na+ current in rat ventricular myocytes. Circ Res 74:710–717. CrossRefGoogle Scholar
  33. Schaffer SW, Ballard-Croft C, Boerth S, Allo SN (1997) Mechanisms underlying depressed Na+/Ca2+ exchanger activity in the diabetic heart. Cardiovasc Res 34:129–136.
  34. Soria A, D’Alessandro ME, Lombardo YB (2001) Duration of feeding on a sucrose-rich diet determines metabolic and morphological changes in rat adipocytes. J Appl Physiol 91:2109–2116. CrossRefGoogle Scholar
  35. Sugishita K, Su Z, Li F, Philipson KD, Barry WH (2001) Gender influences [Ca2+]i during metabolic inhibition in myocytes overexpressing the Na+-Ca2+ exchanger. Circulation 104:2101–2106. CrossRefGoogle Scholar
  36. Van Emous JG, Nederhoff MGJ, Ruigrok TJC, Van Echteld CJA (1997) The role of the Na+ channel in the accumulation of intracellular Na+ during myocardial ischemia: consequences for post-ischemic recovery. J Mo Cell Cardiol 29:85–96. CrossRefGoogle Scholar
  37. Vasanji Z, Cantor EJ, Juric D, Moyen M, Netticadan T (2006) Alterations in cardiac contractile performance and sarcoplasmic reticulum function in sucrose-fed rats is associated with insulin resistance. Am J Physiol Cell Physiol 291:C772–C780. CrossRefGoogle Scholar
  38. Weber CR, Piacentino V 3rd, Houser SR, Bers DM (2003) Dynamic regulation of sodium/calcium exchange function in human heart failure. Circulation 108:2224–2229.
  39. Winer N, Sowers JR (2004) Epidemiology of diabetes. J Clin Pharmacol 44:397–405. CrossRefGoogle Scholar
  40. Wold LE, Dutta K, Mason MM, Ren J, Cala SE, Schwanke ML et al (2005) Impaired SERCA function contributes to cardiomyocytes dysfunction in insulin resistant rats. J Mol Cell Cardiol 39:297–307. CrossRefGoogle Scholar
  41. Yki-Järvinen H (2004) Drug therapy: thiazolidinediones. N Engl J Med 351:1106–1118. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biophysics, Faculty of MedicineAnkara Yıldırım Beyazıt UniversityAnkaraTurkey
  2. 2.Department of Biophysics, Faculty of MedicineAnkara UniversityAnkaraTurkey
  3. 3.Department of Histology and Embriyology, Faculty of MedicineAnkara Yıldırım Beyazıt UniversityAnkaraTurkey

Personalised recommendations