Fluoxetine inhibits L-type Ca2+ and transient outward K+ currents in rat ventricular myocytes

The most common cardiovascular side effects of antidepressants are cardiac arrhythmias and orthostatic hypotension. Little is known, however, about th e mechanisms by which these adverse reactions may occur, especially with re gard to newer drugs such as fluoxetine. We hypothesized that these side eff ects may have an electrophysiological basis at the level of the cardiac myo cyte. Thus, we investigated the effects of fluoxetine and other antidepress ants on action potentials and ionic currents of rat ventricular myocytes us ing the amphotericin B perforated patch clamp technique. Fluoxetine (10 mu M) prolonged the action potential duration (APD(50)) to 146.7 +/- 12.9% of control value without altering resting membrane potential. Fluoxetine and s ettraline potently inhibited the L-type Ca2+ current (IC50, = 2.82 and 2.31 mu M, respectively), but did not significantly modify the steady-state ina ctivation. Amitriptyline and imipramine had similar, but slightly weaker, e ffects (IC50 = 3.75 and 4.05 mu M, respectively). Fluoxetine attenuated the peak transient outward K+ current and also altered current kinetics, as sh own by accelerated decay. Fluoxetine did not change the voltage-dependence of the steady-state inactivation. Sertraline, amitriptyline and imipramine inhibited the transient outward K+ current with potencies very similar to f luoxetine. In contrast to the other antidepressants tested, trazodone weakl y inhibited the Ca2+ and K+ currents and moclobemide had no detectable effe ct. Our comparative pharmacology data suggest that selective serotonin reup take inhibitors, such as fluoxetine, are as potent as tricyclic antidepress ants in inhibiting L-type Ca2+ and transient outward K+ currents. These inh ibitory effects may contribute to cardiovascular complications such as arrh ythmias and orthostatic hypotension.