Combined inhibition of key potassium currents has different effects on cardiac repolarization reserve and arrhythmia susceptibility in dogs and rabbits.
A reliable assessment of the pro-arrhythmic potential for drugs in the development phase remains elusive. Rabbits and dogs are commonly used to create models of pro-arrhythmia, but the differences between them with respect to repolarizing potassium currents are poorly understood. We investigated the incidence of drug-induced torsades de pointes (TdP) and measured conventional ECG parameters and the short-term variability of the QT interval (STVQT) following combined pharmacological inhibition of IK1+IKs and IK1+IKr in conscious dogs and anesthetized rabbits. A high incidence of TdP was observed following the combined inhibition of IK1+IKs in dogs (67% vs. 14% in rabbits). Rabbits exhibited higher TdP incidence after inhibition of IK1+IKr (72% vs. 14% in dogs). Increased TdP incidence was associated with significantly larger STVQT in both models. The relatively different roles of IK1 and IKs in dog and rabbit repolarization reserve should be taken into account when extrapolating the results from animal models of pro-arrhythmia to humans. A stronger repolarization reserve in dogs (likely due to stronger IK1 and IKs), and the more human-like susceptibility to arrhythmia of rabbits argues for the preferred use of rabbits in the evaluation of adverse pro-arrhythmic effects.
a Department of Pharmacology and Pharmacotherapy, University of Szeged; H-6720, Dóm tér 12, P.O. Box 427, Szeged, Hungary.
Zoltán
Z
Husti
a Department of Pharmacology and Pharmacotherapy, University of Szeged; H-6720, Dóm tér 12, P.O. Box 427, Szeged, Hungary.
Katalin
K
Tábori
a Department of Pharmacology and Pharmacotherapy, University of Szeged; H-6720, Dóm tér 12, P.O. Box 427, Szeged, Hungary.
Viktor
V
Juhász
a Department of Pharmacology and Pharmacotherapy, University of Szeged; H-6720, Dóm tér 12, P.O. Box 427, Szeged, Hungary.
Tibor
T
Hornyik
a Department of Pharmacology and Pharmacotherapy, University of Szeged; H-6720, Dóm tér 12, P.O. Box 427, Szeged, Hungary.|b MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, H-6720, Dóm tér 12, P.O. Box 427, Szeged, Hungary.
András
A
Varró
a Department of Pharmacology and Pharmacotherapy, University of Szeged; H-6720, Dóm tér 12, P.O. Box 427, Szeged, Hungary.
István
I
Baczkó
D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004357:Drug Synergism; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors; D011817:Rabbits; D013045:Species Specificity; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D011188:Potassium
IK1; IKs; canaux potassiques; cardiac electrophysiology; potassium channels; torsades de pointes; électrophysiologie cardiaque