TY - JOUR
T1 - Differential effect of β-adrenergic stimulation on the frequency- dependent electrophysiologic actions of the new Class III antiarrhythmics dofetilide, ambasilide, and chromanol 293B
AU - Schreieck, Jürgen
AU - Wang, Yanggan
AU - Gjini, Viktor
AU - Korth, Michael
AU - Zrenner, Bernhard
AU - Schömig, Albert
AU - Schmitt, Claus
PY - 1997
Y1 - 1997
N2 - Class III Antiarrhythmics and β-Adrenergic Stimulation. Introduction: Blockade of the rapid delayed rectifier potassium current (I(Kr)) as an important mechanism for current Class III antiarrhythmics is less effective in action potential prolongation during β-adrenergic activation. We hypothesized that blockade of the increased slow I(K) (I(Ks)) current during β-adrenergic stimulation could improve action potential prolongation and tested this hypothesis by comparison of three different I(K) blockers: dofetilide, a selective blocker of I(Kr); ambasilide, a nonselective blocker of I(K); and chromanol 293B, a selective blocker of I(Ks). Methods and Results: Transmembrane action potential duration was determined in guinea pig papillary muscles. After equilibration with the potassium channel blockers (dofetilide 10 nM, ambasilide 10 μM, chromanol 293B 10 μM), 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. Conclusion: In contrast to dofetilide, the Class III effect of ambasilide is less reduced and the effect of chromanol 293B is enhanced during β-adrenergic stimulation. Our data support the hypothesis that I(Ks) blockade improves the efficacy of antiarrhythmics in action potential prolongation during β-adrenergic activation; however, this effect may increase the risk of afterdepolarizations.
AB - Class III Antiarrhythmics and β-Adrenergic Stimulation. Introduction: Blockade of the rapid delayed rectifier potassium current (I(Kr)) as an important mechanism for current Class III antiarrhythmics is less effective in action potential prolongation during β-adrenergic activation. We hypothesized that blockade of the increased slow I(K) (I(Ks)) current during β-adrenergic stimulation could improve action potential prolongation and tested this hypothesis by comparison of three different I(K) blockers: dofetilide, a selective blocker of I(Kr); ambasilide, a nonselective blocker of I(K); and chromanol 293B, a selective blocker of I(Ks). Methods and Results: Transmembrane action potential duration was determined in guinea pig papillary muscles. After equilibration with the potassium channel blockers (dofetilide 10 nM, ambasilide 10 μM, chromanol 293B 10 μM), 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. Conclusion: In contrast to dofetilide, the Class III effect of ambasilide is less reduced and the effect of chromanol 293B is enhanced during β-adrenergic stimulation. Our data support the hypothesis that I(Ks) blockade improves the efficacy of antiarrhythmics in action potential prolongation during β-adrenergic activation; however, this effect may increase the risk of afterdepolarizations.
KW - Action potentials
KW - Afterdepolarizations
KW - Ambasilide
KW - Beta-adrenergic activation
KW - Chromanol 293B
KW - Class III antiarrhythmic agents
KW - Dofetilide
KW - Isoproterenol
UR - http://www.scopus.com/inward/record.url?scp=0031468470&partnerID=8YFLogxK
U2 - 10.1111/j.1540-8167.1997.tb01039.x
DO - 10.1111/j.1540-8167.1997.tb01039.x
M3 - Article
C2 - 9436780
AN - SCOPUS:0031468470
SN - 1045-3873
VL - 8
SP - 1420
EP - 1430
JO - Journal of Cardiovascular Electrophysiology
JF - Journal of Cardiovascular Electrophysiology
IS - 12
ER -