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It has been reported that selective serotonin reuptake inhibitors (SSRIs) possess some cardiac effects. In the present study we have investigated the effect of paroxetine (PX), a potent SSRI agent, on spontaneously as well as ouabain-induced arrhythmia beating isolated guinea–pig atria. The Guinea-pig heart was rapidly removed; the auricles were dissected out in oxygenated modified Krebs solution. The rate and force of spontaneous contractions were recorded isometrically with a photosensitive transducer. PX (1-16 μg/ml) caused a dose-dependent decrease in the rate of contractions (14-70%) and contractile force (8-16%). Ouabain alone (1.2 μg/ml) produced arrhythmia at 7.2 ± 1.5 min and asystole at 20.1 ± 3.1 min. Pretreatment with PX (4 μg/ml) significantly increased the time of arrhythmia onset to 19.8 min. In addition, PX prolonged the duration of action beating from 20.1 ± 3.1 min to 43.1± 2.6 and delayed the occurrence of asystole. The pattern of contractile force by PX + ouabain treatment was more regular than that observed after administration of ouabain alone. The above findings may the probably be due to the inhibition of cardiac Na and Ca channels or autonomic nervous system. Results also suggest that PX may reduce the membrane conductance through inhibition of ionic channels to prevent ouabain-induced arrhythmia. © 2011 Tehran University of Medical Sciences. All rights reserved. Acta Medica Iranica 2011; 49(4): 258-261.