Direct cardiac and endothelial effects of sodium/glucose cotransporter 2 inhibitors and the role of the sodium/hydrogen exchanger 1

Patients suffering from type 2 diabetes mellitus have at least twice as much chance to develop heart failure. A new class of anti-diabetic drug, named sodium/glucose cotransporter 2 inhibitors (SGLT2i’s), can reduce the risk of hospitalization for heart failure, an outcome that could not be attained by general cardiovascular risk factors reduction. This thesis provides insight that off-target and direct cardiac and endothelial actions of SGLT2i's may, at least partly, elicit the beneficial drug effects that could ultimately reduce the risk of heart failure. These mechanisms include changes in the cellular ion homeostasis, metabolism and inflammation and are to some extent modulated by the inhibition of the Na⁺/H⁺-exchanger. Our data show that SGLT2i's lower Na⁺/H⁺-exchanger activity and cytoplasmatic sodium levels in isolated cardiomyocytes and endothelial cells. In isolated hearts, SGLT2i empagliflozin caused 1) acute vasodilation in the healthy condition, 2) delayed the contracture onset during ischemia and 3) lowered lactate and increased α-ketoglutarate levels in the type 2 diabetic condition. Improved endothelial function, i.e. lower oxidative stress formation and increased nitric oxide bioavailability, during inflammation was observed with empagliflozin and dapagliflozin administration. Finally, this thesis shows that cytokine release during inflammation is dampened by canagliflozin through the reduction of hexokinase 2. In conclusion, SGLT2i’s provoke direct cardiac and endothelial effects that are to some extent modulated by inhibition of the Na⁺/H⁺-exchanger.