Document Type : Original Article

Authors

1 Ph.D., Associate Professor, Colorectal research center, Shiraz University of medical sciences, Shiraz, Iran

2 M.D., Assistant Professor, Neurology Department, Faculty of Medicine, Shiraz University of medical sciences, Shiraz, Iran

Abstract

Introduction: Cardiac Na+ channels are responsible for the excitation of the cardiac cells. Hyperglycemia is the chief symptom of diabetes and several other complications. Although many studies have been conducted on diabetic cardiomyopathy, the role of high glucose on sodium current has not been completely clarified. In the present study, the authors investigated the role of high glucose concentration on human cardiac sodium channels current in transfected HEK293 cells.
Methods: The authors evaluatedglucose effects on sodium current using the whole-cell patch-clamp technique.
Results: The data indicated that Na+ current was significantly modified with an overnight exposure to high glucose. For steady-state activation, high glucose-induced insignificant hyperpolarizing shifted the V1/2. Steady-state inactivation shifted to more negative potentials with glucose exposure (p < 0.001).
Conclusions: Data suggested that the glucose effect on two forms of sodium channel gates (activation and inactivation) raises the possibility of metabolic modulations of sodium channel activity. A hyperpolarized shift of activation and inactivation is supposed to enhance cardiac cell excitability.

Keywords

  1. Wu L, Shryock JC, Song Y, et al. Antiarrhythmic effects of ranolazine in
    a guinea pig in vitro model of long-QT syndrome. J Pharmacol Exp Ther 2004; 310:599-605.
  2. A I UndrovinasL BelardinelliN A UndrovinasH N Sabbah. Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current. J Cardiovasc Electrophysiol 2006;17(1):169-S177.
  3. A Burashnikov , J M Di DiegoA C ZygmuntL BelardinelliC Antzelevitch.. Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation 2007;116:1449-57.
  4. Dobrev D, Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet 2010; 375:1212-23.
  5. Wasserstrom J A,  Sharma R,  O'Toole M J,  Zheng J,  Kelly J E,  Shryock J,  Belardinelli L,  Aistrup G L. Ranolazine antagonizes the effects of increased late sodium current on intracellular calcium cycling in rat isolated intact heart. J Pharmacol Exp Ther 2009; 331:382-91.
  6. Undrovinas N A, Maltsev V A,  Belardinelli L,  Sabbah H N,   Undrovinas A. Late sodium current contributes to diastolic cell ca2+ accumulation in chronic heart failure. J
    Physiol Sci 2010;60:245-57.
  7. S SossallaB KallmeyerS WagnerM MazurU MaurerK Toischer, et al. Altered Na(+) currents in atrial fibrillation effects of ranolazine on arrhythmias and contractility in human atrial myocardium. J AM Coll Cardiol 2010;55:2330-42.
  8. Rajamani S,  El-Bizri N,  Shryock J C,  Makielski J C,  Belardinelli L. Use-Dependent Block of Cardiac Late Na+ Current by Ranolazine. Heart Rhythm 2009; 6: 1625–1631.
  9. Bilginoglu A, Kandilci HB, Turan B. Intracellular levels of Na(+) and TTX-sensitive Na(+) channel current in diabetic rat ventricular cardiomyocytes. Cardiovasc Toxicol 2013;13:138-47.
  10. Bracken N K,  Woodall A J,  Howarth F C,  Singh J. Voltage-dependence of contraction in streptozotocin-induced diabetic myocytes. Mol Cell Biochem 2004; 261:235-43.
  11. Bich-Hoai T T ,  Marin A,  Dinu C,  Banciu D,  Maria-Luiza F,  Ristoiu V. Hypoxia and high glucose activate tetrodotoxin-resistant Na+currents through PKA and PKC. Acta Neurobiol Exp 2010; 70: 351–361.
  12. Stables C L,  Musa H,  Mitra A,  Bhushal S,  Deo M,  Guerrero-Serna G, et al. Reduced Na⁺ current density underlies impaired propagation in the diabetic rabbit ventricle. J Mol Cell Cardiol 2014; 69:24-31.
  13. Lu Z,  Jiang Y-P,  Wu C-Y C,  Ballou
    L M,  Liu S,  Carpenter E S, et al. Increased persistent sodium current due to decreased PI3K signaling contributes to QT prolongation in the diabetic heart. Diabetes 2013; 62:4257-65.
  14. Chen C,  Wang S,  Hu Q,  Zeng L,  Peng H,  Liu C , et al. Voltage-gated sodium channels are modulated by glucose and involved in regulating cellular insulin content of INS-1 cells. Cell Physiol Biochem 2018;45:446-457.
  15. Khazraei H, Akmali M, Mirkhani H. Mechanical effects of ranolazine on normal and diabetic-isolated rat heart. RPS 2021;16:269-277.