Potential mechanisms responsible for cardioprotective effects of sodium–glucose co-transporter 2 inhibitors

Table 7 Summary of the effects of SGLT-2 inhibitors on cardiac ionic homeostasis in animal models

Animal species	Model	Drug/dose/route	Major findings	Interpretation	References
Rabbits and rats	In vitro isolated ventricular myocytes	Empagliflozin (1 μmol/l)/media/3 h	↓ Myocardial [Na⁺]_c and [Ca²⁺]_c ↑ Myocardial [Ca²⁺]_m These effects were strongly reduced after pre-treated with NHE inhibitor	Empagliflozin has cardiac effects by decreasing myocardial cytoplasmic [Na⁺]_c and [Ca²⁺]_c and increasing [Ca²⁺]_m through inhibition of NHE directly	[116]
ob/ob mice	T2DM/obesity (LV diastolic dysfunctions)	Empagliflozin (10 mg/kg/days)/PO/6 weeks	↑ SERCA2a/PLN ratio, PLN phosphorylation	Empagliflozin enhances SERCA2a activity leading to improve cardiac contractile dysfunction in ob/ob mice	[60]
Seipin knockout (SKO) mice	Diabetic lipodystrophic cardiomyopathy	Dapagliflozin (1 mg/kg/days)/PO/8 weeks	↑ SERCA2a/PLN ratio	Dapagliflozin enhances SERCA2a activity leading to improve cardiac contractile dysfunction in SKO mice	[69]

[Na⁺]_c cytoplasmic Na⁺ concentration, [Ca²⁺]_c cytoplasmic Ca²⁺ concentration, [Ca²⁺]_m mitochondrial Ca²⁺ concentration, NHE Na⁺/H⁺ exchange, T2DM type 2 diabetic mellitus, LV left ventricular, PO per oral, SERCA2a sarcoplasmic endoplasmic reticulum calcium (Ca²⁺) ATPase, PLN phospholamban

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