Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation

Abstract

Aims/hypothesis Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) constitute a novel class of glucose-lowering (type 2) kidney-targeted agents. We recently reported that the SGLT2i empagliflozin (EMPA) reduced cardiac cytosolic Na þ ([Na þ ] c ) and cytosolic Ca 2þ ([Ca 2þ ] c ) concentrations through inhibition of Na þ /H þ exchanger (NHE). Here, we examine (1) whether the SGLT2i dapagliflozin (DAPA) and canagliflozin (CANA) also inhibit NHE and reduce [Na þ ] c ; (2) a structural model for the interaction of SGLT2i to NHE; (3) to what extent SGLT2i affect the haemodynamic and metabolic performance of isolated hearts of healthy mice. Methods Cardiac NHE activity and [Na þ ] c in mouse cardiomyocytes were measured in the presence of clinically relevant concentrations of EMPA (1 μmol/l), DAPA (1 μmol/l), CANA (3 μmol/l) or vehicle. NHE docking simulation studies were applied to explore potential binding sites for SGTL2i. Constant-flow Langendorff-perfused mouse hearts were subjected to SGLT2i for 30 min, and cardiovascular function, O 2 consumption and energetics (phosphocreatine (PCr)/ATP) were determined. Results EMPA, DAPA and CANA inhibited NHE activity (measured through low pH recovery after NH 4 þ pulse: EMPA 6.69 ± 0.09, DAPA 6.77 ± 0.12 and CANA 6.80 ± 0.18 vs vehicle 7.09 ± 0.09; p < 0.001 for all three comparisons) and reduced [Na þ ] c (in mmol/l: EMPA 10.0 ± 0.5, DAPA 10.7 ± 0.7 and CANA 11.0 ± 0.9 vs vehicle 12.7 ± 0.7; p < 0.001). Docking studies provided high binding affinity of all three SGLT2i with the extracellular Na þ -binding site of NHE. EMPA and CANA, but not DAPA, induced coronary vasodilation of the intact heart. PCr/ATP remained unaffected. Conclusions/interpretation EMPA, DAPA and CANA directly inhibit cardiac NHE flux and reduce [Na þ ] c , possibly by binding with the Na þ -binding site of NHE-1. Furthermore, EMPA and CANA affect the healthy heart by inducing vasodilation. The [Na þ ] c -lowering class effect of SGLT2i is a potential approach to combat elevated [Na þ ] c that is known to occur in heart failure and diabetes.

SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management

“…Other explanations include alterations of cardiac substrate metabolism and direct effects on the cardiomyocyte (26,27).…”

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

“…This elevation hampers mitochondrial antioxidative defense, promoting the production of reactive oxygen species and their disruptive effects on cardiomyocyte contractility and homeostasis . It is therefore noteworthy that SGLT2 inhibitors reduce intracellular sodium in cardiomyocytes, an action that is independent of glucose . This effect has been confirmed in the clinical setting and has been proposed to underlie the cardioprotective effect of these drugs seen in randomized controlled trials …”

Evaluation of the effect of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR‐Reduced trial

“…However, the findings of experimental studies have provided inconsistent support for this hypothesis . Instead, it has been proposed that SGLT2 inhibitors may slow the course of cardiomyocyte injury and loss by inhibiting the sodium–hydrogen exchanger‐1 (NHE‐1) in the myocardium, whose overactivity may lead to increases in intracellular sodium and calcium, which can impair cardiomyocyte function and viability . Interestingly, empagliflozin has also been shown to inhibit the activation of Ca++/calmodulin‐dependent kinase II, which contributes to the activation of NHE‐1 in the heart .…”

“…[23][24][25] Instead, it has been proposed that SGLT2 inhibitors may slow the course of cardiomyocyte injury and loss by inhibiting the sodium-hydrogen exchanger-1 (NHE-1) in the myocardium, whose overactivity may lead to increases in intracellular sodium and calcium, which can impair cardiomyocyte function and viability. [26][27][28][29][30][31] Interestingly, empagliflozin has also been shown to inhibit the activation of Ca++/calmodulin-dependent kinase II, which contributes to the activation of NHE-1 in the heart. [32][33][34] The actions of empagliflozin to prevent calcium overload may explain why the drug prevents the time-dependent decline in systolic cardiac function seen in experimental pressure overload-induced heart failure.…”