title: Effects of flecainide and quinidine on human atrial action potentials. Role of rate-dependence and comparison with guinea pig, rabbit, and dog tissues.
abstract: Flecainide and other class IC antiarrhythmic drugs are effective in the prevention and termination of atrial fibrillation, but the mechanism of this action is unknown. To gain insights into potential cellular mechanisms, we evaluated the response of human atrial action potentials to equimolar therapeutic concentrations of flecainide and quinidine and compared this response to that of guinea pig, rabbit, and dog atria. Both compounds reduced Vmax more as activation rate increased, but flecainide was more potent than quinidine and had slower kinetics. The rate-dependence of Vmax reduction was similar for all species, but human tissue was more sensitive to the drugs tested. In contrast to changes in Vmax, drug-induced alterations in action potential duration showed opposite rate-dependence for the two drugs. Quinidine increased action potential duration to 95% repolarization (APD95) in human atria by 33 +/- 7% (mean +/- SD) at a cycle length of 1,000 msec, but this effect was reduced as cycle length decreased, to 12 +/- 4% (p less than 0.001) at a cycle length of 300 msec. Flecainide increased APD95 (by 6 +/- 3%) much less than quinidine at a cycle length of 1,000 msec, but its effect was increased by faster pacing, to 27 +/- 12% at a cycle length of 300 msec and 35 +/- 8% (p less than 0.001) at the shortest 1:1 cycle length. The rate-dependent response of APD to drugs was qualitatively similar but quantitatively different among species. Human tissue showed the greatest frequency-dependent drug effects on repolarization, followed by tissue from dogs and rabbits. Guinea pig atria showed the least (and statistically nonsignificant) rate-dependence of drug effect on APD. Drug-induced changes in refractoriness paralleled those in APD. We conclude that: 1) flecainide and quinidine both increase APD in human atrial tissue but with opposite rate-dependence, 2) the effects of flecainide to increase atrial APD and refractoriness are enhanced by the rapid rates typical of atrial fibrillation, and 3) animal tissues may differ importantly from human in both their sensitivity and rate-dependent response to antiarrhythmic drugs. The salutary response of atrial fibrillation to flecainide may be due to enhancement of drug action by the rapid atrial activation rates characteristic of this arrhythmia.
authors.affiliation: Department of Medicine, Montreal Heart Institute, Quebec, Canada.
authors.forename: Z G
authors.initials: ZG
authors.lastname: Wang
authors.forename: L C
authors.initials: LC
authors.lastname: Pelletier
authors.forename: M
authors.initials: M
authors.lastname: Talajic
authors.forename: S
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000368:Aged; D000818:Animals; D004285:Dogs; D005260:Female; D005424:Flecainide / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006325:Heart Atria; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D011802:Quinidine / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D011802:Quinidine; D005424:Flecainide