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 the mechanisms by which these adverse reactions may occur, especially with regard to newer drugs such as fluoxetine. We hypothesized that these side effects may have an electrophysiological basis at the level of the cardiac myocyte. Thus, we investigated the effects of fluoxetine and other antidepressants on action potentials and ionic currents of rat ventricular myocytes using the amphotericin B perforated patch clamp technique. Fluoxetine (10 microM) prolonged the action potential duration (APD50) to 146.7 +/- 12.9% of control value without altering resting membrane potential. Fluoxetine and sertraline potently inhibited the L-type Ca2+ current (IC50 = 2.82 and 2.31 microM, respectively), but did not significantly modify the steady-state inactivation. Amitriptyline and imipramine had similar, but slightly weaker, effects (IC50 = 3.75 and 4.05 microM, respectively). Fluoxetine attenuated the peak transient outward K+ current and also altered current kinetics, as shown 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 fluoxetine. In contrast to the other antidepressants tested, trazodone weakly inhibited the Ca2+ and K+ currents and moclobemide had no detectable effect. Our comparative pharmacology data suggest that selective serotonin reuptake inhibitors, such as fluoxetine, are as potent as tricyclic antidepressants in inhibiting L-type Ca2+ and transient outward K+ currents. These inhibitory effects may contribute to cardiovascular complications such as arrhythmias and orthostatic hypotension.
Park
K S
KS
Department of Physiology, Yonsei University Wonju College of Medicine, Korea.
Kong
I D
ID
Park
K C
KC
Lee
J W
JW
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D020746:Calcium Channels, L-Type; D004553:Electric Conductivity; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011188:Potassium / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function / Q000502:physiology*
D018687:Antidepressive Agents, Second-Generation; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D005473:Fluoxetine; D011188:Potassium