ABSTRACT
We documented chronic ventricular arrhythmias in a first group of 58 rats after myocardial infarction (MI), then assessed the effects of spironolactone and fosinopril on morphological indexes and arrhythmias in a second group (n = 33). Rats underwent Holter monitoring at 2 months after MI. Treatment was randomly given from 1 until 4 months after MI: placebo in 12 rats (P), fosinopril in 9 (F) and spironolactone + fosinopril in 12 (SF). The score of ventricular premature beats (VPBs) was related to the MI size and the delay from MI (p < 0.01). VPB's reduction/increase required to demonstrate anti/pro-arrhythmic effects were 55 and 59%. Mass indexes were lower in F and SF (p = 0.01). VPB's difference (4 months vs. 1) was positive in P, significantly lower in F and negative in SF (p = 0.04). In this relevant model of spontaneous and chronic ventricular arrhythmias, SF association did not increase mortality but lowered the arrhythmic score.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/etiology , Fosinopril/therapeutic use , Mineralocorticoid Receptor Antagonists/therapeutic use , Myocardial Infarction/complications , Spironolactone/therapeutic use , Ventricular Dysfunction/drug therapy , Ventricular Dysfunction/etiology , Ventricular Premature Complexes/drug therapy , Ventricular Premature Complexes/etiology , Animals , Arrhythmias, Cardiac/physiopathology , Chronic Disease , Disease Models, Animal , Electrocardiography, Ambulatory/drug effects , Heart Rate/drug effects , Heart Rate/physiology , Heart Ventricles/drug effects , Heart Ventricles/physiopathology , Male , Myocardial Infarction/physiopathology , Random Allocation , Rats , Rats, Wistar , Time Factors , Ventricular Dysfunction/physiopathology , Ventricular Premature Complexes/physiopathologyABSTRACT
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(+) 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 microM 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(+) currents and the increase in effective refractory period.