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Fluoxetine inhibits L-type Ca2+ and transient outward K+ currents in rat ventricular myocytes
1Department of Physiology, Yonsei University Wonju College of Medicine, Korea.
Abstract:
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.
Insights
New research reveals antidepressants like fluoxetine can prolong cardiac action potential duration and inhibit key ionic currents in heart cells. These electrophysiological effects may explain common cardiovascular side effects such as arrhythmias and orthostatic hypotension.
Area of Science:
- Cardiovascular Pharmacology
- Cardiac Electrophysiology
- Neuroscience
Background:
- Antidepressants, particularly newer selective serotonin reuptake inhibitors (SSRIs) like fluoxetine, are associated with cardiovascular side effects including cardiac arrhythmias and orthostatic hypotension.
- The precise electrophysiological mechanisms underlying these adverse cardiovascular events remain largely unknown.
- Understanding these mechanisms is crucial for improving the cardiovascular safety profile of antidepressant medications.
Purpose of the Study:
- To investigate the electrophysiological effects of fluoxetine and other antidepressants on cardiac myocytes.
- To elucidate the potential mechanisms by which these drugs may cause cardiovascular side effects.
- To compare the effects of SSRIs with tricyclic antidepressants (TCAs) on cardiac ionic currents.
Main Methods:
- Utilized the amphotericin B perforated patch clamp technique on rat ventricular myocytes.
- Measured the effects of various antidepressants (fluoxetine, sertraline, amitriptyline, imipramine, trazodone, moclobemide) on action potentials and ionic currents (L-type Ca2+ current, transient outward K+ current).
- Determined drug potencies (IC50 values) and effects on current kinetics and voltage-dependence.
Main Results:
- Fluoxetine significantly prolonged action potential duration (APD50) without altering resting membrane potential.
- Fluoxetine, sertraline, amitriptyline, and imipramine potently inhibited the L-type Ca2+ current and the transient outward K+ current.
- SSRIs demonstrated comparable potency to TCAs in inhibiting these crucial cardiac ionic currents, suggesting a shared electrophysiological mechanism for cardiovascular effects.
Conclusions:
- The study provides evidence for an electrophysiological basis of cardiovascular side effects associated with antidepressants.
- Inhibition of L-type Ca2+ and transient outward K+ currents by SSRIs and TCAs may contribute to cardiac arrhythmias and orthostatic hypotension.
- Comparative pharmacology highlights that SSRIs possess significant electrophysiological effects on cardiac myocytes, similar to TCAs.