Does empagliflozin bind to cardiac late sodium channels and improve functional recovery after ischemia in preclinical models?
Empagliflozin may exert cardioprotective effects by binding to the cardiac late sodium channel (Nav1.5), similar to ranolazine and local anesthetics.
BACKGROUND: . METHODS: Electrophysiological, in silico molecular docking, molecular, calcium imaging, and whole heart perfusion techniques were used to address this question. RESULTS: activator veratridine in a similar manner to tetrodotoxin, ranolazine, and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a three-dimensional homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 (nuclear-binding domain-like receptor 3) inflammasome and improved functional recovery after ischemia. CONCLUSIONS: may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.
Philippaert et al. (2021) studied this question.