Impact of glucose concentration on cardiac ventricular repolarization under IKr/IKs blocking agents

Drug-induced QT interval prolongation is a condition likely to be aggravated by diabetes. The objective of this study was to evaluate how glucose concentration may modulate drug effects on ventricular repolarization and on cardiac repolarizing potassium currents. Guinea pig hearts were Langendorff-retroperfused and monophasic action potential duration (MAPD) was measured. Glucose (1, 5 or 20 mmol/L) was tested with either dofetilide (a specific IKr blocker), chromanol 293B (a specific IKs blocker) or both. Effects of glucose (1, 5 or 20 mmol/L) on IKr blockade mediated by dofetilide were also measured in HERG-transfected HEK293 cells in the absence vs presence of the P-glycoprotein drug transporter, using the whole cell patch-clamp technique. Our results suggest that both hypo- and hyperglycemia potentiate the MAPD-prolonging and IKr-blocking properties of dofetilide. P-glycoprotein drug extrusion efficacy appears as a key determinant of dofetilide's IKr-blocking effect. This efficacy appears to be affected by glucose concentration, particularly hyperglycemia.