ANTIFIBRILLATORY AND PROFIBRILLATORY ACTIONS OF SELECTED CLASS-I ANTIARRHYTHMIC AGENTS

We wished to examine selected class I antiarrhythmic agents for their potential to exhibit proarrhythmic or antifibrillatory actions. Quinid ine, lidocaine, aprindine, and flecainide were evaluated in an experim ental model that made use of rabbit isolated perfused heart. Hearts we re stabilized with oxygenated buffer (95% O2/5% CO2) with or without p inacidil (1.25 muM) and then were subjected to hypoxia (95% N2/5% CO2) for 12 min, followed by 40-min normoxic perfusion (95% O2/5% CO2). Te st drugs were added to the perfusion medium 5 min before hypoxia was i nduced. Prevention of spontaneous ventricular fibrillation (VF) was de termined. To characterize the electrophysiologic effects of the select ed antiarrhythmic agents, we determined the changes in threshold curre nt and effective refractory period (ERP) before and after drug treatme nt. Addition of the potassium channel agonist, pinacidil, to the perfu sion medium invariably resulted in VF during the hypoxic interval or s hortly after reoxygenation. Pretreatment of the heart with glibenclami de prevented pinacidil-induced VF. Quinidine, aprindine, lidocaine, an d flecainide each were studied at a single concentration. The respecti ve drug concentrations were selected to produce comparable changes in ventricular refractory period. Of the class I agents selected for stud y, only quinidine prolonged the ventricular ERP and provided significa nt protection against pinacidil-induced VF. In contrast, aprindine and lidocaine decreased ventricular ERP and did not prevent VF induced by the combination of pinacidil and hypoxia. Quinidine, aprindine, and l idocaine did not exhibit proarrhythmic effects in the presence of hypo xia when pinacidil was not added to the perfusion medium. Flecainide, when added to the perfusion medium without pinacidil elicited proarrhy thmic activity leading to VF when the hearts were made hypoxic. Flecai nide-induced VF was antagonized by glibenclamide. The data suggest tha t VF can be provoked by the potassium channel agonist pinacidil or by flecainide under conditions that reduce intracellular ATP concentratio n. Glibenclamide, a selective antagonist of the K(ATP) Channel prevent ed the profibrillatory actions of pinacidil and flecainide. Quinidine, but not lidocaine and aprindine, prevented VF induced by pinacidil an d hypoxia.