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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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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.

Conflicts of interest

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

Author information

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) doi:10.1007/s11010-014-2262-5

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Keywords

  • Diabetes mellitus
  • SGLT2 inhibitors
  • Dapagliflozin
  • Ventricular myocytes
  • Streptozotocin-induced diabetic rats