Class III Antiarrhythmic Effects of Dofetilide in Rabbit Atrial Myocardium

BACKGROUND: Dofetilide is a new class III antiarrhythmic agent with demonstrated efficacy in ventricular and atrial tachyarrhythmias. We investigated its class III 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 13.9 ms at 1 nM 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 has no significant effect on action potential duration prolongation by 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. CONCLUSIONS: Dofetilide prolongs action potential duration in rabbit atrial myocardium, but this effect is significantly attenuated at stimulation rates above 2 Hz.