Combined pharmacological block of I(Kr) and I(Ks) increases short-term QT interval variability and provokes torsades de pointes.
OBJECTIVE
Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug-induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short-term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of I(Ks) and I(Kr) block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP.


METHODS
ECGs were recorded from conscious dogs and from anaesthetized rabbits given the I(Kr) blocker dofetilide (DOF), the I(Ks) blocker HMR-1556 (HMR) and their combination, intravenously. PQ, RR and QT intervals were measured and QTc and short-term variability of RR and QT intervals calculated.


RESULTS
DOF increased QTc interval by 20% in dogs and 8% in rabbits. HMR increased QTc in dogs by 12 and 1.9% in rabbits. Combination of DOF+HMR prolonged QTc by 33% in dogs, by 16% in rabbits. DOF or HMR given alone in dogs or HMR given alone in rabbits induced no TdP. Incidence of TdP increased after DOF+HMR combinations in dogs (63%) and following HMR+DOF (82%) and DOF+HMR combinations (71%) in rabbits. STV(QT) markedly increased only after administration of DOF+HMR combinations in both dogs and rabbits.


CONCLUSIONS
STV(QT) was markedly increased by combined pharmacological block of I(Kr) and I(Ks) and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation.
Lengyel
C
C
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged, Hungary.
Varró
A
A
Tábori
K
K
Papp
J G
JG
Baczkó
I
I
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002839:Chromans / Q000008:administration & dosage / Q000633:toxicity; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D010627:Phenethylamines / Q000008:administration & dosage / Q000633:toxicity; D011188:Potassium / Q000097:blood; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000502:physiology*; D011817:Rabbits; D012964:Sodium / Q000097:blood; D013045:Species Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000633:toxicity; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology*
D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; C420023:HMR 1556; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C059983:potassium channel protein I(sk); D012964:Sodium; C063533:dofetilide; D011188:Potassium