Skip to main content
SpringerLink
Log in

Voltage dependence of the Ca2+ transient in endocardial and epicardial myocytes from the left ventricle of Goto–Kakizaki type 2 diabetic rats

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

Abstract

Diabetes mellitus is a major global health disorder and, currently, over 450 million people have diabetes with 90% suffering from type 2 diabetes. Left untreated, diabetes may lead to cardiovascular diseases which are a leading cause of death in diabetic patients. Calcium is the trigger and regulator of cardiac muscle contraction and derangement in cellular Ca2+ homeostasis, which can result in heart failure and sudden cardiac death. It is of paramount importance to investigate the regional involvement of Ca2+ in diabetes-induced cardiomyopathy. Therefore, the aim of this study was to investigate the voltage dependence of the Ca2+ transients in endocardial (ENDO) and epicardial (EPI) myocytes from the left ventricle of the Goto–Kakizaki (GK) rats, an experimental model of type 2 diabetes mellitus. Simultaneous measurement of L-type Ca2+ currents and Ca2+ transients was performed by whole-cell patch clamp techniques. GK rats displayed significantly increased heart weight, heart weight/body weight ratio, and non-fasting and fasting blood glucose compared to controls (CON). Although the voltage dependence of L-type Ca2+ current was unaltered, the voltage dependence of the Ca2+ transients was reduced to similar extents in EPI–GK and ENDO–GK compared to EPI–CON and ENDO–CON myocytes. TPK L-type Ca2+ current and Ca2+ transient were unaltered. THALF decay of L-type Ca2+ current was unaltered; however, THALF decay of the Ca2+ transient was shortened in ENDO and EPI myocytes from GK compared to CON rat hearts. In conclusion, the amplitude of L-type Ca2+ current was unaltered; however, the voltage dependence of the Ca2+ transient was reduced to similar extents in EPI and ENDO myocytes from GK rats compared to their respective controls, suggesting the possibility of dysfunctional sarcoplasmic reticulum Ca2+ transport in the GK diabetic rat hearts.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ogurtsova K, da Rocha Fernandes JD, Huang Y, Linnenkamp U, Guariguata L, Cho NH, Cavan D, Shaw JE, Makaroff LE (2017) IDF diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 128:40–50. https://doi.org/10.1016/j.diabres.2017.03.024

    Article  PubMed  CAS  Google Scholar 

  2. Julien J (1997) Cardiac complications in non-insulin-dependent diabetes mellitus. J Diabetes Complicat 11:123–130

    Article  PubMed  CAS  Google Scholar 

  3. Fang ZY, Prins JB, Marwick TH (2004) Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 25(4):543–567

    Article  PubMed  CAS  Google Scholar 

  4. Bodi I, Mikala G, Koch SE, Akhter SA, Schwartz A (2005) The L-type calcium channel in the heart: the beat goes on. J Clin Invest 115(12):3306–3317

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415(6868):198–205

    Article  PubMed  CAS  Google Scholar 

  6. Aronsen JM, Louch WE, Sjaastad I (2016) Cardiomyocyte Ca2+ dynamics: clinical perspectives. Scand Cardiovasc J 50(2):65–77

    Article  PubMed  CAS  Google Scholar 

  7. Pereira L, Ruiz-Hurtado G, Rueda A, Mercadier JJ, Benitah JP, Gomez AM (2014) Calcium signaling in diabetic cardiomyocytes. Cell Calcium 56(5):372–380

    Article  PubMed  CAS  Google Scholar 

  8. Benitah JP, Alvarez JL, Gomez AM (2010) L-type Ca(2+) current in ventricular cardiomyocytes. J Mol Cell Cardiol 48(1):26–36

    Article  PubMed  CAS  Google Scholar 

  9. Goto Y, Kakizaki M, Masaki N (1975) Spontaneous diabetes produced by selective breeding of normal Wistar rats. Proc JPN Acad 51:80–85

    Article  Google Scholar 

  10. Chandler MP, Morgan EE, McElfresh TA, Kung TA, Rennison JH, Hoit BD, Young ME (2007) Heart failure progression is accelerated following myocardial infarction in type 2 diabetic rats. Am J Physiol 293(3):H1609–H1616

    CAS  Google Scholar 

  11. El Omar MM, Yang ZK, Phillips AO, Shah AM (2004) Cardiac dysfunction in the Goto-Kakizaki rat. A model of type II diabetes mellitus. Basic Res Cardiol 99(2):133–141

    Article  PubMed  Google Scholar 

  12. Crisostomo J, Rodrigues L, Matafome P, Amaral C, Nunes E, Louro T, Monteiro P, Seica R (2010) Beneficial effects of dietary restriction in type 2 diabetic rats: the role of adipokines on inflammation and insulin resistance. Br J Nutr 104(1):76–82

    Article  PubMed  CAS  Google Scholar 

  13. Witte K, Jacke K, Stahrenberg R, Arlt G, Reitenbach I, Schilling L, Lemmer B (2002) Dysfunction of soluble guanylyl cyclase in aorta and kidney of Goto-Kakizaki rats: influence of age and diabetic state. Nitric Oxide 6(1):85–95

    Article  PubMed  CAS  Google Scholar 

  14. Vahtola E, Louhelainen M, Forsten H, Merasto S, Raivio J, Kaheinen P, Kyto V, Tikkanen I, Levijoki J, Mervaala E (2010) Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat. Cardiovasc Diabetol 9:5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Picatoste B, Ramirez E, Caro-Vadillo A, Iborra C, Ares-Carrasco S, Egido J, Tunon J, Lorenzo O (2013) Sitagliptin reduces cardiac apoptosis, hypertrophy and fibrosis primarily by insulin-dependent mechanisms in experimental type-II diabetes. Potential roles of GLP-1 isoforms. PLoS ONE 8(10):e78330

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Korkmaz-Icoz S, Lehner A, Li S, Vater A, Radovits T, Hegedus P, Ruppert M, Brlecic P, Zorn M, Karck M, Szabo G (2015) Mild type 2 diabetes mellitus reduces the susceptibility of the heart to ischemia/reperfusion injury: identification of underlying gene expression changes. J Diabetes Res 2015:396414. https://doi.org/10.1155/2015/396414

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Gronholm T, Cheng ZJ, Palojoki E, Eriksson A, Backlund T, Vuolteenaho O, Finckenberg P, Laine M, Mervaala E, Tikkanen I (2005) Vasopeptidase inhibition has beneficial cardiac effects in spontaneously diabetic Goto-Kakizaki rats. Eur J Pharmacol 519(3):267–276

    Article  PubMed  CAS  Google Scholar 

  18. Devanathan S, Nemanich ST, Kovacs A, Fettig N, Gropler RJ, Shoghi KI (2013) Genomic and metabolic disposition of non-obese type 2 diabetic rats to increased myocardial fatty acid metabolism. PLoS ONE 8(10):e78477

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Yu X, Zhang Q, Cui W, Zeng Z, Yang W, Zhang C, Zhao H, Gao W, Wang X, Luo D (2014) Low molecular weight fucoidan alleviates cardiac dysfunction in diabetic Goto-Kakizaki rats by reducing oxidative stress and cardiomyocyte apoptosis. J Diabetes Res 2014:420929. https://doi.org/10.1155/2014/420929

    Article  PubMed  PubMed Central  Google Scholar 

  20. Darmellah A, Baetz D, Prunier F, Tamareille S, Rucker-Martin C, Feuvray D (2007) Enhanced activity of the myocardial Na(+)/H (+) exchanger contributes to left ventricular hypertrophy in the Goto-Kakizaki rat model of type 2 diabetes: critical role of Akt. Diabetologia 50(6):1335–1344

    Article  PubMed  CAS  Google Scholar 

  21. Cheng ZJ, Vaskonen T, Tikkanen I, Nurminen K, Ruskoaho H, Vapaatalo H, Muller D, Park JK, Luft FC, Mervaala EM (2001) Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto-Kakizaki rats. Hypertension 37(2 Part 2):433–439

    Article  PubMed  CAS  Google Scholar 

  22. Liepinsh E, Vilskersts R, Zvejniece L, Svalbe B, Skapare E, Kuka J, Cirule H, Grinberga S, Kalvinsh I, Dambrova M (2009) Protective effects of mildronate in an experimental model of type 2 diabetes in Goto-Kakizaki rats. Br J Pharmacol 157(8):1549–1556

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Yang H, Nyby MD, Ao Y, Chen A, Adelson DW, Smutko V, Wijesuriya J, Go VL, Tuck ML (2011) Role of brainstem thyrotropin-releasing hormone-triggered sympathetic overactivation in cardiovascular mortality in type 2 diabetic Goto-Kakizaki rats. Hypertens Res 35:157–165

    Article  PubMed  CAS  Google Scholar 

  24. Alameddine A, Fajloun Z, Bourreau J, Gauquelin-Koch G, Yuan M, Gauguier D, Derbre S, Ayer A, Custaud MA (2015) The cardiovascular effects of salidroside in the Goto-Kakizaki diabetic rat model. J Physiol Pharmacol 66(2):249–257

    PubMed  CAS  Google Scholar 

  25. Desrois M, Lan C, Movassat J, Bernard M (2017) Reduced up-regulation of the nitric oxide pathway and impaired endothelial and smooth muscle functions in the female type 2 diabetic Goto-Kakizaki rat heart. Nutr Metab 14:6. https://doi.org/10.1186/s12986-016-0157-z. eCollection:6-0157

    Article  CAS  Google Scholar 

  26. Desrois M, Clarke K, Lan C, Dalmasso C, Cole M, Portha B, Cozzone PJ, Bernard M (2010) Upregulation of eNOS and unchanged energy metabolism in increased susceptibility of the aging type 2 diabetic GK rat heart to ischemic injury. Am J Physiol 299(5):H1679–H1686

    CAS  Google Scholar 

  27. Salem KA, Qureshi MA, Sydorenko V, Parekh K, Jayaprakash P, Iqbal T, Singh J, Oz M, Adrian TE, Howarth FC (2013) Effects of exercise training on excitation-contraction coupling and related mRNA expression in hearts of Goto-Kakizaki type 2 diabetic rats. Mol Cell Biochem 380(1–2):83–96

    Article  PubMed  CAS  Google Scholar 

  28. Howarth FC, Qureshi MA (2008) Myofilament sensitivity to Ca2+ in ventricular myocytes from the Goto-Kakizaki diabetic rat. Mol Cell Biochem 315(1–2):69–74

    Article  PubMed  CAS  Google Scholar 

  29. Lou Q, Fedorov VV, Glukhov AV, Moazami N, Fast VG, Efimov IR (2011) Transmural heterogeneity and remodeling of ventricular excitation-contraction coupling in human heart failure. Circulation 123(17):1881–1890

    Article  PubMed  PubMed Central  Google Scholar 

  30. Glukhov AV, Fedorov VV, Lou Q, Ravikumar VK, Kalish PW, Schuessler RB, Moazami N, Efimov IR (2010) Transmural dispersion of repolarization in failing and nonfailing human ventricle. Circ Res 106(5):981–991

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Campbell SG, Haynes P, Kelsey SW, Nava KE, Campbell KS (2013) Altered ventricular torsion and transmural patterns of myocyte relaxation precede heart failure in aging F344 rats. Am J Physiol 305(5):H676–H686

    CAS  Google Scholar 

  32. Smail MM, Qureshi MA, Shmygol A, Oz M, Singh J, Sydorenko V, Arabi A, Howarth FC, Al Kury L (2016) Regional effects of streptozotocin-induced diabetes on shortening and calcium transport in epicardial and endocardial myocytes from rat left ventricle. Physiol Rep 4(22):e13034

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Kristiansen SB, Lofgren B, Stottrup NB, Khatir D, Nielsen-Kudsk JE, Nielsen TT, Botker HE, Flyvbjerg A (2004) Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes. Diabetologia 47(10):1716–1721

    Article  PubMed  CAS  Google Scholar 

  34. Chung CS, Campbell KS (2013) Temperature and transmural region influence functional measurements in unloaded left ventricular cardiomyocytes. Physiol Rep 1(6):e00158

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Howarth FC, Levi AJ (1998) Internal free magnesium modulates the voltage dependence of contraction and Ca transient in rabbit ventricular myocytes. Pflügers Arch 435(5):687–698

    Article  PubMed  CAS  Google Scholar 

  36. D’Souza A, Howarth FC, Yanni J, Dobryznski H, Boyett MR, Adeghate E, Bidasee KR, Singh J (2011) Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat. Exp Physiol 96(9):875–888

    Article  PubMed  Google Scholar 

  37. Bryant SM, Shipsey SJ, Hart G (1999) Normal regional distribution of membrane current density in rat left ventricle is altered in catecholamine-induced hypertrophy. Cardiovasc Res 42(2):391–401

    Article  PubMed  CAS  Google Scholar 

  38. Volk T, Ehmke H (2002) Conservation of L-type Ca2+ current characteristics in endo- and epicardial myocytes from rat left ventricle with pressure-induced hypertrophy. Pflügers Arch 443(3):399–404

    Article  PubMed  CAS  Google Scholar 

  39. Pereira L, Matthes J, Schuster I, Valdivia HH, Herzig S, Richard S, Gomez AM (2006) Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice. Diabetes 55(3):608–615

    Article  PubMed  CAS  Google Scholar 

  40. Howarth FC, Qureshi MA, Hassan Z, Al Kury LT, Isaev D, Parekh K, Yammahi SR, Oz M, Adrian TE, Adeghate E (2011) Changing pattern of gene expression is associated with ventricular myocyte dysfunction and altered mechanisms of Ca2+ signalling in young type 2 Zucker diabetic fatty rat heart. Exp Physiol 96(3):325–337

    Article  PubMed  CAS  Google Scholar 

  41. 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(Pt 1):85–94

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Sheikh AQ, Hurley JR, Huang W, Taghian T, Kogan A, Cho H, Wang Y, Narmoneva DA (2012) Diabetes alters intracellular calcium transients in cardiac endothelial cells. PLoS ONE 7(5):e36840

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Misra T, Gilchrist JS, Russell JC, Pierce GN (1999) Cardiac myofibrillar and sarcoplasmic reticulum function are not depressed in insulin-resistant JCR:LA-cp rats. Am J Physiol 276(6 Pt 2):H1811–H1817

    PubMed  CAS  Google Scholar 

  44. Abe T, Ohga Y, Tabayashi N, Kobayashi S, Sakata S, Misawa H, Tsuji T, Kohzuki H, Suga H, Taniguchi S, Takaki M (2002) Left ventricular diastolic dysfunction in type 2 diabetes mellitus model rats. Am J Physiol 282(1):H138–H148

    CAS  Google Scholar 

  45. Belke DD, Swanson EA, Dillmann WH (2004) Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart. Diabetes 53(12):3201–3208

    Article  PubMed  CAS  Google Scholar 

  46. D’Souza A, Howarth FC, Yanni J, Dobrzynski H, Boyett MR, Adeghate E, Bidasee KR, Singh J (2014) Chronic effects of mild hyperglycaemia on left ventricle transcriptional profile and structural remodelling in the spontaneously type 2 diabetic Goto-Kakizaki rat. Heart Fail Rev 19(1):65–74

    Article  PubMed  CAS  Google Scholar 

  47. Dhalla NS, Liu X, Panagia V, Takeda N (1998) Subcellular remodeling and heart dysfunction in chronic diabetes [editorial]. Cardiovasc Res 40(2):239–247

    Article  PubMed  CAS  Google Scholar 

  48. Dhalla NS, Rangi S, Zieroth S, Xu YJ (2012) Alterations in sarcoplasmic reticulum and mitochondrial functions in diabetic cardiomyopathy. Exp Clin Cardiol 17(3):115–120

    PubMed  PubMed Central  CAS  Google Scholar 

  49. Vinch CS, Aurigemma GP, Simon HU, Hill JC, Tighe DA, Meyer TE (2005) Analysis of left ventricular systolic function using midwall mechanics in patients > 60 years of age with hypertensive heart disease and heart failure. Am J Cardiol 96(9):1299–1303

    Article  PubMed  Google Scholar 

  50. Cazorla O, Lacampagne A (2011) Regional variation in myofilament length-dependent activation. Pflügers Arch 462(1):15–28

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work has been supported by a grant from the College of Medicine & Health Sciences, United Arab Emirates University, Al Ain; Sheikh Hamdan Bin Rashid Al Maktoum Award, Dubai; Zayed University, Abu Dhabi; and funding from the Al Ain Equestrian, Shooting and Golf Club.

Author information

Authors and Affiliations

  1. Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi, UAE

    Lina Al Kury

  2. Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine

    Vadym Sydorenko

  3. Department of Physiology, College of Medicine & Health Sciences, UAE University, P.O. Box 17666, Al Ain, UAE

    Manal M. A. Smail, Muhammad Anwar Qureshi, Anatoliy Shmygol & Frank Christopher Howarth

  4. Department of Basic Medical Sciences, College of Medicine, Qatar University, Doha, Qatar

    Murat Oz

  5. School of Forensic & Applied Sciences, University of Central Lancashire, Preston, UK

    Jaipaul Singh

Authors
  1. Lina Al Kury
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vadym Sydorenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manal M. A. Smail
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muhammad Anwar Qureshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anatoliy Shmygol
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Murat Oz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jaipaul Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Frank Christopher Howarth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank Christopher Howarth.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al Kury, L., Sydorenko, V., Smail, M.M.A. et al. Voltage dependence of the Ca2+ transient in endocardial and epicardial myocytes from the left ventricle of Goto–Kakizaki type 2 diabetic rats. Mol Cell Biochem 446, 25–33 (2018). https://doi.org/10.1007/s11010-018-3269-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-018-3269-0

Keywords

Search

Navigation