Mechanism of flecainide's rate-dependent actions on action potential duration in canine atrial tissue.
Increases in action potential duration (APD) caused by most antiarrhythmic drugs are maximal at slow rates and are attenuated during tachycardia, causing decreased action during arrhythmias and maximum effects during sinus rhythm. This property, "reverse use-dependence," limits efficacy and contributes to proarrhythmic potential. We have shown that the class 1c antiarrhythmic drug flecainide increases atrial APD to a greater extent at faster rates and that this property may underlie some of the drug's antiarrhythmic actions. The present studies were designed to evaluate possible underlying ionic mechanisms. Standard whole-cell voltage clamp and microelectrode techniques were used to study ionic currents and action potentials of canine atrial tissue. Flecainide (4.5 microM) increased APD at cycle lengths ranging from 150 to 1000 msec and attenuated the APD shortening that resulted from increased activation rate, resulting in greater APD prolongation at faster rates. The major time-dependent outward current (Ito), was reduced by flecainide in a rate-independent fashion. Flecainide's effect on Ito was due to inhibition of the 4-aminopyridine-sensitive component (Ito1); flecainide did not alter inward calcium current or the calcium-sensitive component of Ito (Ito2). The specific sodium channel blocker tetrodotoxin (1 microM) and the Na+, K(+)-ATP'ase inhibitor ouabain (1 microM) suppressed rate-dependent APD shortening in a fashion similar to flecainide, and both flecainide and ouabain attenuated postoverdrive membrane hyperpolarization. We conclude that the rate-dependence of flecainide's action on APD is not explained by use-dependent changes in outward currents but may be due to sodium channel blockade resulting in decreased sodium loading and reduced Na+, K(+)-ATP'ase stimulation during tachycardia.
Wang
Z
Z
Department of Medicine, Montreal Heart Institute, Canada.
Fermini
B
B
Nattel
S
S
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016275:Atrial Function; D004285:Dogs; D004594:Electrophysiology; D005424:Flecainide / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013610:Tachycardia / Q000503:physiopathology; D013997:Time Factors
D015222:Sodium Channels; D005424:Flecainide