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I Kr vs. I Ks blockade and arrhythmogenicity in normoxic rabbit Purkinje fibers: does it really make a difference?
Author(s) -
Puddu Paolo Emilio,
Legrand JeanChristophe,
Sallé Laurent,
Rouet René,
Ducroq Joffrey
Publication year - 2011
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2010.00920.x
Subject(s) - dofetilide , sotalol , purkinje fibers , blockade , medicine , stimulation , bradycardia , chemistry , cardiology , anesthesia , afterdepolarization , electrophysiology , repolarization , heart rate , qt interval , atrial fibrillation , receptor , blood pressure
The electrophysiological (standard intracellular microelectrode technique) and pro‐arrhythmic (occurrence of early after‐depolarization) effects of five class III agents acting on delayed rectifier current ( I K ), rapid ( I Kr ), and/or slow ( I Ks ) components have been studied in rabbit Purkinje fibers taken near the septum and submitted in vitro to reduced stimulation rate (from 1 to 0.5 Hz) in the absence or presence of epinephrine (10 n m ) during normoxic conditions. There were two I Kr blockers (d‐sotalol and dofetilide), two I Ks blockers (chromanol 293B and HMR 1556), and a non‐selective I K blocker (azimilide). d‐sotalol, dofetilide, and azimilide lengthened APD 60 and APD 90 in a concentration‐dependent manner. Both d‐sotalol and dofetilide showed pro‐arrhythmia at highest concentrations and in the presence of epinephrine and lower stimulation rate. Despite azimilide markedly lengthened APD 90 , it was globally less pro‐arrhythmic than dofetilide. Thus, in normoxic rabbit Purkinje fibers, I Kr blockade prolonged action potential duration (APD) and increased the incidence of early after‐depolarizations, particularly so in the presence of adrenergic stimulation and bradycardia, I Ks blockade did neither, and non‐selective I K blockade (by azimilide) behaved principally as I Kr blockade. It is concluded that in normoxic rabbit Purkinje fibers, I Ks blockade was neutral, whereas I Kr blockade was pro‐arrhythmic, which may make a difference worth exploration in more complex models.