Differential effect of beta-adrenergic stimulation on the frequency-dependent electrophysiologic actions of the new class III antiarrhythmics dofetilide, ambasilide, and chromanol 293B.
BACKGROUND
Blockade of the rapid delayed rectifier potassium current (IKr) as an important mechanism for current Class III antiarrhythmics is less effective in action potential prolongation during beta-adrenergic activation. We hypothesized that blockade of the increased slow IK (IKs) current during beta-adrenergic stimulation could improve action potential prolongation and tested this hypothesis by comparison of three different IK blockers: dofetilide, a selective blocker of IKr; ambasilide, a nonselective blocker of IK; and chromanol 293B, a selective blocker of IKs.


RESULTS
Transmembrane action potential duration was determined in guinea pig papillary muscles. After equilibration with the potassium channel blockers (dofetilide 10 nM, ambasilide 10 microM, chromanol 293B 10 microM), isoproterenol (10 and 100 nM) was added. The action potential prolonging effect of dofetilide was reduced in the presence of increasing concentrations of isoproterenol whereas the effect of ambasilide was much less reduced. In contrast, the effect of chromanol 293B clearly was increased in the presence of both concentrations of isoproterenol. No afterdepolarizations were observed after application of isoproterenol in control. Following isoproterenol, but not before, dofetilide and chromanol 293B induced early afterdepolarizations in 20% and 17% of the papillary muscles, whereas ambasilide and chromanol 293B induced delayed afterdepolarizations in 27% and 33%, respectively.


CONCLUSIONS
In contrast to dofetilide, the Class III effect of ambasilide is less reduced and the effect of chromanol 293B is enhanced during beta-adrenergic stimulation. Our data support the hypothesis that IKs blockade improves the efficacy of antiarrhythmics in action potential prolongation during beta-adrenergic activation; however, this effect may increase the risk of afterdepolarizations.
Schreieck
J
J
I. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Wang
Y
Y
Gjini
V
V
Korth
M
M
Zrenner
B
B
Schömig
A
A
Schmitt
C
C
D000200:Action Potentials / Q000187:drug effects; D062365:Aminobenzoates / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
D062365:Aminobenzoates; D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002839:Chromans; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D011943:Receptors, Adrenergic, beta; D013449:Sulfonamides; C075113:ambasilide; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; C063533:dofetilide