Pharmacological Modulation of Long Cardiac QT Interval in Ex Vivo and in Vitro Experimental Models

Prolongation of cardiac QT interval is one of the most dangerous consequences of hyperglycemia, acting on accumulation of reactive oxygen species and impairment of ionic pumps. Previous studies showed that the selective inhibition of the endogenous aldose reductase 2 (ALR2) activities, responsible of the oxidative heart damage following diabetes, could be a therapeutic treatment for the high glucose-related cardiac alterations. Indeed, the newly synthetized ALR2 inhibitor, the benzofuroxane derivative 5(6)-(benzo[d]thiazol-2-ylmethoxy)benzofuroxane (BF-5m), dose-dependently reduced the long cardiac QT interval in isolated rat hearts perfused with high glucose, by increasing in parallel the expression and activity of endogenous antioxidant pathways and free radical scavengers such as SIRT1 and its targets MnSOD and FOXO-1. The reduction of the oxidative stress induced by BF-5m lead also modifications of the expression of KCNQ1/KCNE1 potassium channels subunits in H9c2 cardiomyocytes exposed to high glucose, modifying the expression levels of miR-1, involved in KCNQ1 and KCNE1 expression.