Impact of glucose concentration on cardiac ventricular repolarization under I_Kr/I_Ks blocking agents

Abstract 

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 I_Kr blocker), chromanol 293B (a specific I_Ks blocker) or both. Effects of glucose (1, 5 or 20 mmol/L) on I_Kr 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 I_Kr-blocking properties of dofetilide. P-glycoprotein drug extrusion efficacy appears as a key determinant of dofetilide's I_Kr-blocking effect. This efficacy appears to be affected by glucose concentration, particularly hyperglycemia.

Keywords: Diabetes, Cardiac repolarization, QT prolongation, Drugs, P-glycoprotein