Proarrhythmic actions of flecainide in an isolated tissue model of ischemia and reperfusion.
Flecainide may increase the incidence of cardiac arrhythmias in acute ischemia. The objective of this study was to determine the cellular actions underlying this effect in an isolated tissue model of acute ischemia and reperfusion. Transmembrane electrical activity was recorded with conventional microelectrode techniques from epi- and endocardial surfaces of right ventricular free walls from guinea pig hearts. Endocardium was stimulated. Tissues were equilibrated in Tyrode's solution for 60 min, then exposed to simulated ischemia (hypoxia, acidosis, lactate, hyperkalemia, no glucose) for 15 min and reperfused with normal Tyrode's solution for 30 min. In the absence of flecainide, sustained and nonsustained ventricular tachycardia occurred in 78% of hearts during ischemic conditions and 78% in early reperfusion (n = 14). Premature beats occurred in 14% of hearts in early reperfusion. Ventricular tachycardia was associated with abbreviation of endocardial effective refractory period and action potential duration, plus prolongation of transmural conduction time. Flecainide abolished premature beats at a concentration of 1 mumol/l or higher. However, an increase in the incidence of ventricular tachycardia occurred in both ischemia and reperfusion at all concentrations of flecainide (0.03-10.0 mumol/l). Proarrhythmic effects of flecainide were associated with selective prolongation of transmural conduction time in ischemia and early reperfusion. In epicardial slices flecainide lengthened conduction time transverse, but not parallel to fiber orientation. Our results suggest that proarrhythmic effects of flecainide in acute ischemia and reperfusion are mediated by potentiation of the arrhythmogenic effects of ischemia on anisotropic properties of the myocardium.
Heisler
B E
BE
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Ferrier
G R
GR
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D005424:Flecainide / Q000633:toxicity*; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D005424:Flecainide