Potentiation of E-4031-induced torsade de pointes by HMR1556 or ATX-II is not predicted by action potential short-term variability or triangulation.
OBJECTIVE
Torsade de pointes (TdP) can be induced by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether IKs blockade or enhancement of INa could potentiate TdP induced by IKr blockade and to investigate whether short-term variability (STV) or triangulation of action potentials preceded TdP.


METHODS
Experiments were performed in open-chest, pentobarbital-anaesthetized, alpha 1-adrenoceptor-stimulated, male New Zealand White rabbits, which received three consecutive i.v. infusions of either the IKr blocker E-4031 (1, 3 and 10 nmol kg(-1) min(-1)), the IKs blocker HMR1556 (25, 75 and 250 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. In a second study rabbits received either the same doses of E-4031, the INa enhancer, ATX-II (0.4, 1.2 and 4.0 nmol kg(-1)) or both of these drugs. ECGs and epicardial monophasic action potentials were recorded.


RESULTS
HMR1556 alone did not cause TdP but increased E-4031-induced TdP from 25 to 80%. ATX-II alone caused TdP in 38% of rabbits, as did E-4031; 75% of rabbits receiving both drugs had TdP. QT intervals were prolonged by all drugs but the extent of QT prolongation was not related to the occurrence of TdP. No changes in STV were detected and triangulation was only increased after TdP occurred.


CONCLUSIONS
Giving modulators of ion channels in combination substantially increased TdP but, in this model, neither STV nor triangulation of action potentials could predict TdP.
Michael
G
G
Strathclyde Institute of Pharmacy and Biomedical Sciences, Division of Physiology and Pharmacology, University of Strathclyde, Glasgow, UK.
Dempster
J
J
Kane
K A
KA
Coker
S J
SJ
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002839:Chromans / Q000008:administration & dosage / Q000633:toxicity*; D003064:Cnidarian Venoms / Q000008:administration & dosage / Q000633:toxicity*; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004562:Electrocardiography; D004594:Electrophysiology; D005544:Forecasting; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000633:toxicity*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000633:toxicity*; D011817:Rabbits; D015222:Sodium Channels / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000633:toxicity*; D016171:Torsades de Pointes / Q000139:chemically induced*
D002839:Chromans; D003064:Cnidarian Venoms; D051668:Delayed Rectifier Potassium Channels; C420023:HMR 1556; D010880:Piperidines; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D015222:Sodium Channels; D013449:Sulfonamides; C059983:potassium channel protein I(sk); C063968:E 4031; C028800:toxin II (Anemonia sulcata)