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

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 Ca(2+) transport in streptozotocin (STZ)-induced diabetic rats. Shortening, Ca(2+) transients, myofilament sensitivity to Ca(2+) and sarcoplasmic reticulum Ca(2+), and intracellular Ca(2+) 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 Ca(2+) 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 Ca(2+) and sarcoplasmic reticulum Ca(2+) were not significantly altered by DAPA in either STZ or Control myocytes. L-type Ca(2+) current was reduced in STZ myocytes compared to Controls and was further reduced by DAPA. In conclusion, alterations in the mechanism(s) of Ca(2+) transport may partly underlie the negative inotropic effects of DAPA in ventricular myocytes from STZ-treated and Control rats.

Effect of sodium‐glucose co‐transporter‐2 inhibitors on impaired ventricular repolarization in people with Type 2 diabetes

“…Previous studies showed that blood pressure control and weight loss were effective for improving ventricular repolarization abnormality [10,11]. The possibility of a direct effect of SGLT2 inhibitors on electrophysiology of the heart cannot be excluded, however, because SGLT2 inhibitors affect intracellular Ca 2+ handling and activity of the Na + /H + exchanger in cardiomyocytes [15,16]. In addition, change in QTc dispersion was positively correlated with change in systolic blood pressure, although the correlation was not very close.…”

Regional effects of streptozotocin-induced diabetes on shortening and calcium transport in epicardial and endocardial myocytes from rat left ventricle

“…; Hamouda et al. ). Diabetes was induced in male (250 g) Wistar rats by a single intraperitoneal injection of STZ (60 mg/kg bodyweight) as previously described (Howarth et al.…”

“…; Hamouda et al. ). Bodyweight, nonfasting blood glucose, and heart weight were measured prior to the experiments.…”

“…; Hamouda et al. ). In brief, animals were killed using a guillotine and hearts were removed rapidly and mounted for retrograde perfusion on a Langendorff system.…”

Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: A comprehensive review of clinical and preclinical studies

“…In a study published in February 2015 showed that dapagliflozin alters the mechanism of calcium transport (L Ca + 2 current) which may partly exert the negative inotropic effects in ventricular myocytes from streptozotocin-treated and control rats [29].…”