Cellular and in vivo electrophysiological effects of dronedarone in normal and post myocardial infracted rats. J Pharmacol Exp Ther

Abstract

ABSTRACT We studied the effects of dronedarone (SR 33589) on the action potentials, membrane ionic currents, and arrhythmic activity in control rats and in rats after myocardial infarction, a model known to develop anomalous electrical activity. Dronedarone increased action potential duration in normal hearts. It had little effect on the action potentials that were already prolonged in the postmyocardial infarcted (PMI) rats. Particularly, dronedarone reduced the late sustained K ϩ current, I K (or Isus) by 69%. Dronedarone induced only a tonic block of I K . Similar relative inhibitions of I K by dronedarone were obtained in young, sham, and PMI rats, even if I K was less in sham than in young and further reduced in PMI rats. The EC 50 values were 0.78 and 0.85 M in sham and PMI rats. Dronedarone induced a weak increase in the fast transient outward current, I to . Time-to-peak and inactivation time constant of I to were decreased by dronedarone that also induced a marked slowing of I to recovery from inactivation. Similar effects were observed on the reduced I to recorded in PMI rats. Holter monitoring study in control, unthetered animals showed that dronedarone had no proarrhythmic effect. On rats, which after myocardial infarction exhibited ventricular premature beats, dronedarone significantly decreased beat occurrence during the 7-day treatment; this effect was sustained for two more weeks. Thus, dronedarone exerts antiarrhythmic effects on PMI rat heart. Its effects are attributable for the most part to the inhibition of outward K ϩ currents and the increase in effective refractory period. Arrhythmias are one of the most important causes of mortality in patients with heart failure (HF), although the mechanisms of ventricular arrhythmias (VA) during the development of the disease remain unclear Dronedarone, previously labeled SR 33589, is a noniodinated benzofurane derivative structurally related to amiodarone with proven effectiveness on ischemia and reperfusion-induced arrhythmias in animal models, but presumably without its deleterious effects The present study combines in vitro and in vivo models. Our purpose was to investigate the cellular electrophysiological effects of dronedarone on both ionic currents and action potential characteristics, as well as its effects on arrhythmias, in control rats and in postmyocardial infarcted (PMI) rats, a well documented model of ventricular remodeling with significant electrophysiological alteration