Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation. Importance of use-dependent effects on refractoriness.

Abstract

We conclude that antiarrhythmic drugs terminate experimental atrial fibrillation by increasing the wavelength for reentry at rapid rates, leading to a reduction in the number of functional reentry circuits and, eventually, failure of reentrant excitation. Use-dependent effects on refractoriness can limit (in the case of the reverse use dependence of sotalol) or contribute (in the case of propafenone) to antiarrhythmic drug efficacy against atrial fibrillation by determining drug-induced changes in wavelength at rapid atrial rates.

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.

“…30,31 In the present study, we found that the actions of d-sotalol on AERP show reverse use dependence, similar to our previous observations regarding d,lsotalol. 16,26 Ambasilide is a new class III drug, which has not previously been evaluated for efficacy against AF. Although at long cycle lengths, the effects of ambasilide on AERP were less than or equal to those of high-dose d-sotalol (Figs 3, 4, and 12), the drug showed less reverse use dependence of action and produced larger relative increases than d-sotalol at short cycle lengths.…”

“…This finding may explain the larger increases in AF cycle length produced by ambasilide (Fig 11), since the AF cycle length is determined by the AERP at the rapid rates of AF. 16,32 Larger increases in AERP during AF by ambasilide probably contributed to the greater effectiveness of ambasilide than equal doses of d-sotalol in terminating AF.…”

“…We have found that d,l-sotalol is capable of terminating AF and preventing its reinduction in an experimental dog model of AF but that reverse usedependent actions on atrial refractoriness appear to limit efficacy of the drug. 16 Since the latter experiments were conducted in dogs whose 3-adrenergic receptors were blocked with nadolol, presumably only the class III effects of sotalol were manifest. Rensma et al17 showed that similar doses of d-sotalol prevent the induction of nonsustained AF in conscious dogs.…”

Role of Fibrillation Cycle Length in Spontaneous and Drug-Induced Termination of Human Atrial Fibrillation-Spectral Analysis of Fibrillation Waves From Surface Electrocardiogram-

“…3 In canine models of AF, the mapping data suggest that the increase in FCL induced by antiarrhythmic drugs may relate to fusion of wavelets, an increase in the size of reentry circuits, a decrease in circuit number and finally, termination of AF. 4 Compared with drug-induced termination, the mechanism of spontaneous termination of human AF is still unclear. It is difficult to obtain intracardiac recordings just prior to spontaneous termination of paroxysmal AF for analysis of the fibrillation waves because spontaneous…”

Rate-Dependent Electrophysiologic Effects of the Class III Antiarrhythmic Drugs Nifekalant, Amiodarone, and Ibutilide on the Atrium in Patients With Persistent Atrial Fibrillation

“…5) Experimental studies in vagotonic and atrial tachycardia-related models of sustained AF have shown limited capacity of clinically-relevant doses of class III rapid delayed rectifier (I Kr )-selective blocking agents to terminate AF. [6][7][8] Wang, et al 6) showed that reverse use-dependent actions may limit class III drug efficacy at the rapid rates characteristic of AF but permit these drugs to prevent AF induction by premature complexes at slower resting sinus rates. Furthermore, recent experimental studies have shown that persistent AF causes progressive electrophysiologic changes in the atrial myocardium that make the atria more vulnerable to fibrillation.…”