Adrenaline reveals the torsadogenic effect of combined blockade of potassium channels in anaesthetized guinea pigs.
OBJECTIVE
Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I(Kr) and I(Ks) blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP.


METHODS
Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I(Kr) blocker E-4031 (3, 10 and 30 nmol kg(-1) min(-1)), the I(Ks) blocker HMR1556 (75, 250, 750 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K(+) channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded.


RESULTS
TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K(+) channel blockers in combination, but was not observed in guinea pigs treated with either I(K) blocker alone, or in phenylephrine-stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP.


CONCLUSIONS
Combined blockade of both I(Kr) and I(Ks) plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur.
Michael
G
G
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Kane
K A
KA
Coker
S J
SJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002839:Chromans / Q000008:administration & dosage / Q000633:toxicity; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004837:Epinephrine / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D008954:Models, Biological; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage / Q000633:toxicity; D013449:Sulfonamides / Q000008:administration & dosage / Q000633:toxicity; D016171:Torsades de Pointes / Q000139:chemically induced*
D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; C420023:HMR 1556; D010880:Piperidines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D013449:Sulfonamides; C059983:potassium channel protein I(sk); C063968:E 4031; D010656:Phenylephrine; D004837:Epinephrine