Impact of glucose concentration on cardiac ventricular repolarization under I Kr/I Ks 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 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.
Hreiche
Raymond
R
Faculté de Pharmacie, Université de Montréal, Montréal QC, Canada.
Plante
Isabelle
I
David
Louis-Philippe
LP
Simard
Chantale
C
Turgeon
Jacques
J
Drolet
Benoit
B
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002021:Buffers; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010477:Perfusion; D010627:Phenethylamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D002021:Buffers; D002839:Chromans; D051638:Ether-A-Go-Go Potassium Channels; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D005947:Glucose; C063533:dofetilide