I(Kr) vs. I(Ks) blockade and arrhythmogenicity in normoxic rabbit Purkinje fibers: does it really make a difference?
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 nm) 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.
Dipartimento di Fisiopatologia Cardiocircolatoria, Anestesiologia e Chirurgia, Istituto del Cuore "Attilio Reale", Laboratory of Biotechnologies Applied to Cardiovascular Medicine, Sapienza Università di Roma, Viale del Policlinico, 155, Rome 00161, Italy. paoloemilio.puddu@uniroma1.it
Paolo Emilio
PE
Puddu
Jean-Christophe
JC
Legrand
Laurent
L
Sallé
René
R
Rouet
Joffrey
J
Ducroq
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D006827:Hydantoins; D048289:Imidazolidines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011690:Purkinje Fibers / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011817:Rabbits; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; C420023:HMR 1556; D006827:Hydantoins; D048289:Imidazolidines; D010627:Phenethylamines; D010879:Piperazines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C059983:potassium channel protein I(sk); C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; C086123:azimilide; D013015:Sotalol; C063533:dofetilide; D004837:Epinephrine