Electrophysiological effects of fluoxetine in mammalian cardiac tissues

Fluoxetine is a widely used antidepressant compound having selective seroto nin reuptake inhibitor properties. In this study, the actions of fluoxetine were analyzed in guinea pig, rat, rabbit and canine ventricular myocardiac preparations using conventional microelectrode and whole cell voltage clam p techniques. Low concentrations of fluoxetine (1-10 mu mol/l) caused signi ficant shortening of action potential duration (APD) and depression of the plateau potential in guinea pig and rabbit papillary muscles and single can ine ventricular myocytes. In rat papillary muscle, APD was not affected by fluoxetine (up to 100 mu mol/l), however, the drug decreased the force of c ontraction with EC50 of 10 mu mol/l. Fluoxetine (10 mu mol/l) also decrease d the maximum velocity of depolarization and action potential overshoot in each species studied. At this concentration no effect was observed on the r esting membrane potential; high concentration (100 mu mol/l), however, caus ed depolarization. In voltage clamped canine ventricular myocytes, fluoxetine caused concentra tion-dependent block of the peak Ca2+ current at 0 mV with EC50 Of 5.4+/-0. 94 mu mol/l and Hill coefficient of 1.1+/-0.14 (n=6). In addition, 10 mu mo l/l fluoxetine shifted the midpoint of the steady-state inactivation curve of the Ca2+ current from -20.7+/-0.65 to -26.7+/-1 mV (P<0.001, n=8) withou t changing its slope factor. These effects of fluoxetine developed rapidly and were fully reversible. Fluoxetine did not alter voltage-dependence of a ctivation or time constant for inactivation of I-Ca. Fluoxetine had no effe ct on the amplitude of K+ currents (I-K1 and I-to). The inhibition of cardi ac Ca2+ and Na+ channels by fluoxetine may explain most cardiac side effect s observed occasionally with the drug. Our results suggest that fluoxetine may have antiarrhythmic (class I + IV type), as well as proarrhythmic prope rties (due to impairment of atrioventricular or intraventricular conduction and shortening of repolarization). Therefore, in depressed patients with c ardiac disorders, ECG control may be suggested during fluoxetine therapy.