Dofetilide is a new class III antiarrhythmic agent with demonstrated efficacy in ventricular and atrial tachyarrhythmias. We investigated its class HI actions and their modulation by stimulation rate in rabbit atrial myocardium.
Methods and Results
Standard microelectrode techniques were used to record action potentials from rabbit atrial tissue at varying stimulation rates. Dofetilide produced a dose-dependent prolongation of action potential duration at concentrations from 1 nM to 1 μM at an interstimulus interval of 1000 ms. Action potential duration at 90% repolarization (action potential duration) was prolonged from 116 ± 11.7 ms in control solutions to 148 ± 13.9 ms at 1nM dofetilide and 186 ± 49.3 ms at 1 μM dofetilide (P < .05 for 1 nM vs control; P < .01 for 1 μM vs control). Reduction of interstimulus interval to 500 ms had no significant effect on action potential duration prolongation by dofetilide. At faster rates than this, and particularly at an interstimulus interval less than 330 ms, a marked “reverse rate dependence” of the class III effect was observed. Specifically, the high therapeutic concentration of 10 nM showed no effect on action potential duration at interstimulus interval of 250 ms or 200 ms, and even at a concentration of 30 nM, the small class III effect was no longer statistically significant at these rates.
Conclusion
Dofetilide prolongs action potential duration in rabbit atrial myocardium, but this effect is significantly attenuated at stimulation rates above 2 Hz.
GwiltM., ArrowsmithJ., BlackburnK., BurgesRUK-68,798: A novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells.J Pharmacol Exp Ther256: 318, 1991
2.
CarmelietE.Effect of UK 68,798 on delayed K+ currents in cardiac myocytes.Circulation (Suppl 2) 84: II-176, 1991
3.
RasmussenH., AllenM., BlackburnK., ButrousG., DalrympleH.Dofetilide, a novel class III antiarrhythmic agent.J Cardiovasc Pharmacol20(suppl 2): S96, 1992
4.
GwiltM., BlackburnK., BurgesR., HigginsA., MilneA., SolcaA.Electropharmacology of UK-68,798, a new class III agent, in anesthetised dogs.Eur J Pharmacol215: 137, 1992
5.
JurkiewiczN., SanguinettiM.Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent.Circ Res72: 75, 1993
6.
KrafteD., VolbergW.Voltage dependence of cardiac delayed rectifier block by methanesulfonamide class III antiarrhythmic agents.J Cardiovasc Pharmacol23: 37, 1993
7.
ZuanettiG., CorrP.Antiarrhythmic efficacy of a new class III agent, UK-68,798, during chronic myocardial infarction: evaluation using three-dimensional mapping.J Pharmacol Exp Ther256: 325, 1991
8.
EchtD., LeeJ., MurrayK., VorperianVA randomised, double-blind, placebo-controlled dose-ranging study of intravenous UK 68,798 (Dofetilide) in patients with inducible sustained ventricular tachyarrhythmias.Circulation (suppl 2) 84: II-714, 1991
9.
ThomsenP., BashirY., KingmaJDofetilide in the treatment of sustained monomorphic ventricular tachycardia.Eur Heart J13: 304, 1992
10.
ConnellyD., ThomsenP., CammAEfficacy and safety of dofetilide, a novel class III antiarrhythmic agent, in atrioventricular nodal reentrant tachycardia.Eur Heart J13: 304, 1992
11.
BrachmannJ., HaverkampW., JohnsJ., ZehenderM., KingmaH., WiechaJ.The efficacy and safety of oral dofetilide in patients with sustained ventricular tachycardia.Circulation86: I-265, 1992
12.
SuttorpM., PolakP., Van't-HofA., RasmussenH., DunselmanP., KingmaJ.Efficacy and safety of a new selective class III antiarrhythmic agent dofetilide in paroxysmal atrial fibrillation or atrial flutter.Am J Cardiol69: 417, 1992
13.
MonteroM., BeyerT., BrachmannJ., KublerW.Electrophysiological effects of the new class III substance UK-68,798 on rabbit isolated sinus node and atrium (Ger Abstract)Z Kardiol80(suppl 3): 55, 1991
14.
TandeP., BjörnstadH., YangT., RefsumH.Rate-dependent class HI antiarrhythmic action, negative chronotropy, and positive inotropy of a novel IK blocking drug, UK-68,798: potent in guinea pig but no effect in rat myocardium.J Cardiovasc Pharmacol16: 401, 1990
15.
JosephsonI., Sanchez-ChapulaJ., BrownA.Early outward current in rat single ventricular cells.Circ Res54: 157, 1984
16.
ChadwickC., EzrinA., O'ConnorBIdentification of a specific radioligand for the cardiac rapidly activating delayed rectifier K+ channel.Circ Res72: 707, 1993
17.
VarroA., LathropD., HesterS., NanasiP., PappJ.Ionic currents and action potentials in rabbit, rat and guinea pig ventricular myocytes.Basic Res Cardiol88/2: 93, 1993
18.
SedgwickM., RasmussenH., CobbeS.Effects of the class III antiarrhythmic drug dofetilide on ventricular monophasic action potential duration and QT interval dispersion in stable angina pectoris.Am J Cardiol70: 1432, 1992
19.
ThamT., MacLennanB., BurkeM., HarronD.Pharmacodynamics and pharmacokinetics of the class III antiarrhythmic agent dofetilide (UK-68,798) in humans.J Cardiovasc Pharmacol21: 507, 1993
20.
HondeghemL., SnydersD.Class III antiarrhythmic agents have a lot of potential but a long way to go: reduced effectiveness and dangers of reverse use dependence.Circulation81: 686, 1990
21.
ColatskyT., SinghB.Potassium channel blockers as antiarrhythmic agents. In SinghB., DzauV., VanhoutteP., WoosleyR. (eds). Cardiovascular Pharmacology and Therapeutics.Churchill LivingstoneNew York, pp. 675–688, 1994
22.
BaskinE., SerikC., WallaceAEffects of new and potent methanesulfonanilide class III antiarrhythmic agents on myocardial refractoriness and contractility in isolated cardiac muscle.J Cardiovasc Pharmacol18: 406, 1991
23.
BeyerT., MarschangH., KüblerW., BrachmannJ.Reverse “use-dependent” class III effects of UK-68,798 in relation to extracellular potassium concentration.Eur Heart J (suppl)13: 303, 1992
24.
BaskinE., LynchJ.Comparative effects of increased extracellular potassium and pacing frequency on the class III activities of methanesulfonanilide IKr blockers dofetilide, d-sotalol, E-4031, and MK-499.J Cardiovasc Pharmacol24: 199, 1994
25.
WangZ., PelletierC., TalajicM., NattelS.Effects of flecainide and quinidine on human atrial action potentials: role of rate-dependence and comparison with guinea pig, rabbit, and dog tissue.Circulation82: 274, 1990
26.
WangZ., PageP., NattelS.Mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation.Circ Res71: 271, 1992
27.
WangJ., BourneG., WangZ., VillemaireC., TalajicM., NattelS.Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation: importance of use-dependent effects on refractoriness.Circulation88: 1030, 1993
28.
WangZ., FerminiB., NattelS.Mechanism of flecainide's rate dependent actions on action potential duration in canine atrial tissue.J Pharmacol Exp Ther267: 575, 1993
29.
KnilansT., LathropD., NánásiP., SchwartzA., VarróA.Rate and concentration-dependent effects of UK-68,798, a potent new class III antiarrhythmic, on canine Purkinje fiber action potential duration and Vmax.Br J Pharmacol103: 1568, 1991
30.
WangZ., FerminiB., NattelS.Delayed rectifier outward current and repolarization in human atrial myocytes.Circ Res73: 276, 1993
31.
DuanD., FerminiB., NattelS.Potassium channel blocking properties of propafenone in rabbit atrial myocytes.J Pharmacol Exp Ther264: 1113, 1993
32.
YangT., TandeP., LathropD., RefsumH.Class III antiarrhythmic action by potassium channel blockade: dofetilide attenuates hypoxia induced electromechanical changes.Cardiovasc Res26: 1109, 1992
33.
WangJ., FengJ., NattelS.Class III antiarrhythmic drug action in experimental atrial fibrillation.Circulation90: 2032, 1994
34.
CarmelietE.Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide.J Pharmacol Exp Ther262: 809, 1992
35.
KrafteD., VolbergW.Voltage dependence of cardiac delayed rectifier block by methanesulfonamide class III antiarrhythmic agents.J Cardiovasc Pharmacol23: 37, 1994
36.
OhlerA., AmosG.J., WettwerE., RavensU.Frequency-dependent effects of E-4031, almokalant, dofetilide and tedisamil on action potential duration: no evidence for “reverse use dependent” block.Naunyn-Schmiedebergs Arch Pharmacol, 349: 602, 1994
37.
MeinertzT.Clinical implications of new insights into mechanism of antiarrhythmic drug action.J Cardiovasc Pharmacol20 (supp 2): S23, 1992
