We, here for the first time, reported that DAPA-treatment provided marked cardioprotection by improving prolonged QT-interval in ECG and depressed LVDP in MetS rats through, at least, augmentation in ionic-mechanisms at the cellular level. DAPA-treatment-associated improvements in prolonged ventricular repolarization seemed to be through the augmentation in depressed voltage-gated K
+-channel currents (I
K). We also observed significantly increased Na
+-influx via not only voltage-gated Na
+-channels but also increased the expression level of SGLT2 in cardiomyocytes from MetS rats. Interestingly, although the amplitude of action potentials was significantly high in MetS cardiomyocytes being parallel to increased Na
+-influx, the basal level of intracellular free Na
+ ([Na
+]
i) was not significantly different in these cardiomyocytes. However, Lambert et al. [
33] demonstrated elevated [Na
+]
i in both diabetic humans and rat model, providing a hypothesis via an enhanced SGLT in these samples. Our observation of similar [Na
+]
i in both MetS and control rats may arise due to several different but crossing mechanisms. First, we have observed a significant decrease in the level of intracellular free H
+ ([H
+]
i or pH
i) with a significant increase in intracellular free Ca
2+ ([Ca
2+]
i) in MetS cardiomyocytes. These observations are supported by previously published ones. It seems that the increased [Ca
2+]
i which occurs due to not Ca
2+-influx into cell by voltage-dependent Ca
2+-channels, but most probably via the reverse-mode action of the Na
+/Ca
2+ exchanger (NCX) may balance the level of [Na
+]
i in MetS cardiomyocytes. Another explanation can be due to the increased activity of Na
+/H
+ exchanger (NHE) in MetS rat heart [
37]. Indeed, in support of these two possible hypotheses, we detected both an increase in basal [Ca
2+]
i and decrease in basal [H
+]
i in MetS rat cardiomyocytes. SGLT2 inhibition markedly normalized and/or protected these changes in MetS rat heart. Of note, although we did not determine the other parameters, contributing to the intracellular ionic homeostasis, others have already documented an important role of SGLT2 inhibitors on Ca
2+-handling proteins. SGLT2 inhibitors could provide positive effects on depressed LV in hyperglycemic samples via affecting activities of several proteins responsible from Ca
2+-homeostasis, such as SERCA2a, CaMKII, phosphorylation level of RyR2. Therefore, it significantly could reduce SR Ca
2+-leak and improve the depressed contractility [
31,
38]. In these regards, our present data are nicely associated with previously published ones, because we have reported here that any reduction of myocardial [Na
+]
i by inhibition of NCX or NHE improves the heart dysfunction [
39]. More importantly, a recent study identified an important role of SGLT2 inhibitor through its direct cardiac effects by lowering myocardial [Na
+]
i and [Ca
2+]
i and enhancing mitochondrial [Ca
2+], which occurs in an impairment of myocardial NHE flux, independent of SGLT2 activity [
39]. Although we did not check these last parameters, we observed a significant recovery in a mitochondrial function in DAPA-treated MetS rat cardiomyocytes. Therefore, all together, SGLT2 inhibitor DAPA may inhibit a myocardial NHE leading to increased mitochondrial [Ca
2+] and decreased cytoplasmic [Ca
2+]
i and [H
+]
i through mitochondrial NCX activity in MetS rat heart. In line with these findings above, Uthman and co-workers recently demonstrated a direct effect of DAPA on the heart via inhibition of NHE flux and followed by reducing [Na
+]
i, which came up a conclusion on its potential side to combat heart failure and diabetic cardiac dysfunction [
40].