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 Vm, more as activation rate increased, but flecainide was more potent than quinidine and had slower kinetics. The rate-dependence of Viax 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<O.OO1) 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<O.OOl) 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. (Circultion 1990;82:274-283) C lass IC drugs characteristically slow conduction without significantly altering refractory period.' Because slow conduction is an important predisposing factor to reentiy,2,3 these properties

Class III antiarrhythmic drug action in experimental atrial fibrillation. Differences in reverse use dependence and effectiveness between d-sotalol and the new antiarrhythmic drug ambasilide.

“…Positive use-dependent APD prolongation without sodium channel blockade would seem to be an ideal profile of antiarrhythmic drug action. 33,34 Ambasilide is considered a class III antiarrhythmic drug,19 a classification consistent with the significant increases in AERP and VERP and lack of change in atrial conduction velocity that we observed in the present experiments. Our results indicate that class III agents may exhibit different patterns of frequencydependent action on atrial refractoriness.…”

Time-dependent transients in an ionically based mathematical model of the canine atrial action potential

“…12C). Mean APD and maximum diastolic potentials were within the standard ranges for canine atrial APs established by Wang et al (33). Over the 35-min pacing interval, mean reductions of 10.3 and 12.8 ms were observed for APD 90 and APD 50 , respectively, with 79% and 75% of the change occurred dur- ing the initial 15 min.…”

Pharmacological Activation of Rapid Delayed Rectifier Potassium Current Suppresses Bradycardia-Induced Triggered Activity in the Isolated Guinea Pig Heart

“…This can lead to arrhythmia with no class III activity when needed the most. Likewise, the class IC compound flecainide has been shown to lose its beneficial effect at low heart rates (Wang et al, 1990). In contrast, we observed that NS3623-induced shortening of the QT interval is rate-independent meaning that it does not display reverse-use dependence.…”