Effects of flecainide on the rate dependence of atrial refractoriness, atrial repolarization and atrioventricular node conduction in anesthetized dogs.
Flecainide is effective against certain supraventricular arrhythmias (atrial fibrillation and atrioventricular [AV] node reentrant tachycardia), but its mechanisms of action are unknown. Previous in vitro work suggests that flecainide attenuates rate-dependent action potential duration shortening, producing tachycardia-dependent prolongation of the refractory period. This study was designed to assess whether similar changes occur in vivo and whether the effects of flecainide on AV node conduction depend on heart rate and on direction of propagation (anterograde vs. retrograde). The effects of flecainide at three clinically relevant concentrations were assessed in open chest, morphine-chloralose-anesthetized dogs. Flecainide increased atrial refractory period in a concentration- and rate-related fashion (e.g., dose 3 increased the atrial effective refractory period by 9 +/- 4% at a cycle length of 1,000 ms but by 36 +/- 5% and 55 +/- 10% at a basic cycle length of 400 and 300 ms, respectively; p less than 0.001 for each). Flecainide attenuated the action potential duration accommodation (measured by monophasic action potentials) to heart rate, causing tachycardia-dependent action potential duration prolongation and accounting for most of the rate-dependent atrial effective refractory period changes. Flecainide increased Wenckebach cycle length, but the concentration-response curve was much steeper in the retrograde (slope 41 +/- 7 ms/mumol.liter-1) than in the anterograde direction (17 +/- 4 ms/mumol.liter-1; p less than 0.01), indicating more potent effects on retrograde conduction. The depressant action of the drug on the AV node was also rate dependent, with an effect on the AH interval at a basic cycle length of 400 ms that averaged 1.8, 1.5 and 2 times that at a basic cycle length of 1,000 ms for doses 1 (p less than 0.05), 2 (p less than 0.01) and 3 (p less than 0.001), respectively.


CONCLUSIONS
1) Flecainide suppresses atrial action potential duration accommodation to heart rate changes in vivo, leading to rate-dependent atrial effective refractory period prolongation, which may be important in suppressing atrial fibrillation. 2) The drug has frequency- and direction-dependent effects on AV node conduction, which may lead to selective antiarrhythmic actions during AV node reentry.
O'Hara
G
G
Department of Medicine, Montreal Heart Institute, Quebec, Canada.
Villemaire
C
C
Talajic
M
M
Nattel
S
S
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D016275:Atrial Function; D001283:Atrioventricular Node / Q000187:drug effects* / Q000502:physiology; D006328:Cardiac Catheterization / Q000379:methods; D002698:Chloralose; D003864:Depression, Chemical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005424:Flecainide / Q000097:blood / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D016018:Least-Squares Analysis; D008297:Male; D009020:Morphine; D013997:Time Factors
D002698:Chloralose; D009020:Morphine; D005424:Flecainide