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Dapagliflozin reduces the amplitude of shortening and Ca2+ transient in ventricular myocytes from streptozotocin-induced diabetic rats

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Abstract

In the management of type 2 diabetes mellitus, Dapagliflozin (DAPA) is a newly introduced selective sodium-glucose co-transporter 2 inhibitor which promotes renal glucose excretion. Little is known about the effects of DAPA on the electromechanical function of the heart. This study investigated the effects of DAPA on ventricular myocyte shortening and intracellular Ca2+ transport in streptozotocin (STZ)-induced diabetic rats. Shortening, Ca2+ transients, myofilament sensitivity to Ca2+ and sarcoplasmic reticulum Ca2+, and intracellular Ca2+ current were measured in isolated rats ventricular myocytes by video edge detection, fluorescence photometry, and whole-cell patch-clamp techniques. Diabetes was characterized in STZ-treated rats by a fourfold increase in blood glucose (440 ± 25 mg/dl, n = 21) compared to Controls (98 ± 2 mg/dl, n = 19). DAPA reduced the amplitude of shortening in Control (76.68 ± 2.28 %, n = 37) and STZ (76.58 ± 1.89 %, n = 42) ventricular myocytes, and reduced the amplitude of the Ca2+ transients in Control and STZ ventricular myocytes with greater effects in STZ (71.45 ± 5.35 %, n = 16) myocytes compared to Controls (92.01 ± 2.72 %, n = 17). Myofilament sensitivity to Ca2+ and sarcoplasmic reticulum Ca2+ were not significantly altered by DAPA in either STZ or Control myocytes. L-type Ca2+ current was reduced in STZ myocytes compared to Controls and was further reduced by DAPA. In conclusion, alterations in the mechanism(s) of Ca2+ transport may partly underlie the negative inotropic effects of DAPA in ventricular myocytes from STZ-treated and Control rats.

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References

  1. International Diabetes Federation (2013) ATLAS. 6th ed. Brussels, Belgium

  2. Malik M, Bakir A, Saab BA, King H (2005) Glucose intolerance and associated factors in the multi-ethnic population of the United Arab Emirates: results of a national survey. Diabetes Res Clin Pract 69(2):188–195

    Article  CAS  PubMed  Google Scholar 

  3. Brownie S, Hunter L, Rossiter R, Hills AP, Robb W, Hag-Ali M (2014) Diabetes in the United Arab Emirates: the need for valid datasets for health service planning. Lancet Diabetes Endocrinol 14:70025–70027

    Google Scholar 

  4. Vaccaro O, Eberly LE, Neaton JD, Yang L, Riccardi G, Stamler J (2004) Impact of diabetes and previous myocardial infarction on long-term survival: 25-year mortality follow-up of primary screenees of the multiple risk factor intervention trial. Arch Intern Med 164(13):1438–1443

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Bakth S, Arena J, Lee W, Torres R, Haider B, Patel BC, Lyons MM, Regan TJ (1986) Arrhythmia susceptibility and myocardial composition in diabetes. Influence of physical conditioning. J Clin Investig 77(2):382–395

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Ewing DJ, Boland O, Neilson JM, Cho CG, Clarke BF (1991) Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients. Diabetologia 34(3):182–185

    Article  CAS  PubMed  Google Scholar 

  8. Grimm W, Langenfeld H, Maisch B, Kochsiek K (1990) Symptoms, cardiovascular risk profile and spontaneous ECG in paced patients: a five-year follow-up study. Pacing Clin Electrophysiol 13(12 Pt 2):2086–2090

    Article  CAS  PubMed  Google Scholar 

  9. Movahed MR, Hashemzadeh M, Jamal MM (2005) Increased prevalence of third-degree atrioventricular block in patients with type II diabetes mellitus. Chest 128(4):2611–2614

    Article  PubMed  Google Scholar 

  10. Fallow GD, Singh J (2004) The prevalence, type and severity of cardiovascular disease in diabetic and non-diabetic patients: a matched-paired retrospective analysis using coronary angiography as the diagnostic tool. Mol Cell Biochem 261(1–2):263–269

    Article  CAS  PubMed  Google Scholar 

  11. Chen J, Williams S, Ho S, Loraine H, Hagan D, Whaley JM, Feder JN (2010) Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diabetes Ther 1(2):57–92

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Banerjee SK, McGaffin KR, Pastor-Soler NM, Ahmad F (2009) SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovasc Res 84(1):111–118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Abdul-Ghani MA, Norton L, Defronzo RA (2011) Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev 32(4):515–531

    Article  CAS  PubMed  Google Scholar 

  14. Clar C, Gill JA, Court R, Waugh N (2012) Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2(5):e001007

    Article  PubMed Central  PubMed  Google Scholar 

  15. Musso G, Gambino R, Cassader M, Pagano G (2012) A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med 44(4):375–393

    Article  CAS  PubMed  Google Scholar 

  16. Stenlof K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, Canovatchel W, Meininger G (2013) Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 15(4):372–382

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. FDA Approves Invokana to treat type 2 diabetes. (2013) Food and Drug Administration

  18. Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JG, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN (2008) Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 51(5):1145–1149

    Article  CAS  PubMed  Google Scholar 

  19. Foote C, Perkovic V, Neal B (2012) Effects of SGLT2 inhibitors on cardiovascular outcomes. Diabetes Vasc Dis Res 9(2):117–123

    Article  Google Scholar 

  20. Carlson GF, Tou CK, Parikh S, Birmingham BK, Butler K (2011) Evaluation of the effect of dapagliflozin on cardiac repolarization: a thorough QT/QTc study. Diabetes Ther 2(3):123–132

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Howarth FC, Qureshi MA, White E (2002) Effects of hyperosmotic shrinking on ventricular myocyte shortening and intracellular Ca(2+) in streptozotocin-induced diabetic rats. Pflügers Arch 444(3):446–451

    Article  CAS  PubMed  Google Scholar 

  22. Isenberg G, Klockner U (1982) Calcium tolerant ventricular myocytes prepared by preincubation in a “KB medium”. Pflügers Arch 395(1):6–18

    Article  CAS  PubMed  Google Scholar 

  23. Zhao Y, Xu J, Gong J, Qian L (2009) L-type calcium channel current up-regulation by chronic stress is associated with increased alpha(1c) subunit expression in rat ventricular myocytes. Cell Stress Chaperones 14(1):33–41

    Article  PubMed Central  PubMed  Google Scholar 

  24. Kerfant BG, Vassort G, Gomez AM (2001) Microtubule disruption by colchicine reversibly enhances calcium signaling in intact rat cardiac myocytes. Circ Res 88(7):E59–E65

    Article  CAS  PubMed  Google Scholar 

  25. Sun Q, Ma Y, Zhang L, Zhao YF, Zang WJ, Chen C (2010) Effects of GH secretagogues on contractility and Ca2+ homeostasis of isolated adult rat ventricular myocytes. Endocrinology 151(9):4446–4454

    Article  CAS  PubMed  Google Scholar 

  26. Howarth FC, Qureshi MA, Sobhy ZH, Parekh K, Yammahi SR, Adrian TE, Adeghate E (2011) Structural lesions and changing pattern of expression of genes encoding cardiac muscle proteins are associated with ventricular myocyte dysfunction in type 2 diabetic Goto-Kakizaki rats fed a high-fat diet. Exp Physiol 96(8):765–777

    Article  CAS  PubMed  Google Scholar 

  27. 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  CAS  PubMed  Google Scholar 

  28. Spurgeon HA, DuBell WH, Stern MD, Sollott SJ, Ziman BD, Silverman HS, Capogrossi MC, Talo A, Lakatta EG (1992) Cytosolic calcium and myofilaments in single rat cardiac myocytes achieve a dynamic equilibrium during twitch relaxation. J Physiol 447:83–102:83–102

  29. Bassani JW, Yuan WL, Bers DM (1995) Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. Am J Physiol 37:C1313–C1319

    Google Scholar 

  30. Howarth FC, Calaghan SC, Boyett MR, White E (1999) Effect of the microtubule polymerizing agent taxol on contraction, Ca2+ transient and L-type Ca2+ current in rat ventricular myocytes. J Physiol 516(Pt 2):409–419

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Levi AJ, Hancox JC, Howarth FC, Croker J, Vinnicombe J (1996) A method for making rapid changes of superfusate whilst maintaining temperature at 37 degrees C. Pflügers Arch 432(5):930–937

    Article  CAS  PubMed  Google Scholar 

  32. 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  CAS  PubMed  Google Scholar 

  33. von Lewinski D, Rainer PP, Gasser R, Huber MS, Khafaga M, Wilhelm B, Haas T, Machler H, Rossl U, Pieske B (2010) Glucose-transporter-mediated positive inotropic effects in human myocardium of diabetic and nondiabetic patients. Metabolism 59(7):1020–1028

    Article  Google Scholar 

  34. Zhou L, Cryan EV, D’Andrea MR, Belkowski S, Conway BR, Demarest KT (2003) Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J Cell Biochem 90(2):339–346

    Article  CAS  PubMed  Google Scholar 

  35. von Lewinski D, Gasser R, Rainer PP, Huber MS, Wilhelm B, Roessl U, Haas T, Wasler A, Grimm M, Bisping E, Pieske B (2010) Functional effects of glucose transporters in human ventricular myocardium. Eur J Heart Fail 12(2):106–113

    Article  Google Scholar 

  36. Bracken N, Howarth FC, Singh J (2006) Effects of streptozotocin-induced diabetes on contraction and calcium transport in rat ventricular cardiomyocytes. Ann NY Acad Sci 1084:208–222

    Article  CAS  PubMed  Google Scholar 

  37. Bracken NK, Woodall AJ, Howarth FC, Singh J (2004) Voltage-dependence of contraction in streptozotocin-induced diabetic myocytes. Mol Cell Biochem 261(1–2):235–243

    Article  CAS  PubMed  Google Scholar 

  38. Bean BP (1984) Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state. Proc Natl Acad Sci USA 81:6388–6392

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Hering S, Aczel S, Kraus RL, Berjukow S, Striessnig J, Timin EN (1997) Molecular mechanism of use-dependent calcium channel block by phenylalkylamines: role of inactivation. Proc Natl Acad Sci USA 94(24):13323–13328

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Hess P, Lansman JB, Tsien RW (1983) Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists. Nature 311:538–544

    Article  Google Scholar 

Download references

Acknowledgments

The work has been supported by a grant from the College of Medicine & Health Sciences, United Arab Emirates University. Research in our laboratory is also supported by LABCO, a partner of Sigma-Aldrich.

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The authors declare no conflicts of interest. The pharmaceutical industry has no influence or input in this scientific work.

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Correspondence to F. C. Howarth.

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Hamouda, N.N., Sydorenko, V., Qureshi, M.A. et al. Dapagliflozin reduces the amplitude of shortening and Ca2+ transient in ventricular myocytes from streptozotocin-induced diabetic rats. Mol Cell Biochem 400, 57–68 (2015). https://doi.org/10.1007/s11010-014-2262-5

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