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+ current, IK (or Isus) by 69%. Dronedarone induced only a tonic block ofIK. Similar relative inhibitions ofIK by dronedarone were obtained in young, sham, and PMI rats, even if IK was less in sham than in young and further reduced in PMI rats. The EC50 values were 0.78 and 0.85 μM in sham and PMI rats. Dronedarone induced a weak increase in the fast transient outward current, Ito. Time-to-peak and inactivation time constant of Ito were decreased by dronedarone that also induced a marked slowing ofIto recovery from inactivation. Similar effects were observed on the reduced Itorecorded 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.
Footnotes
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Send reprint requests to: Dr. G. Vassort, INSERM U-390, CHU Arnaud de Villeneuve, F-34295 Montpellier Cédex 5, France. E-mail: vassort{at}montp.inserm.fr
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↵1 This work is part of the thesis of F.A. and L.B.
- Abbreviations:
- HF
- heart failure
- VA
- ventricular arrhythmia
- PMI
- postmyocardial infarction
- AP
- action potential
- VPB/h
- ventricular beats per hour
- Received May 24, 1999.
- Accepted September 29, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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