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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 29, 2007; DOI: 10.1124/jpet.107.132456

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Received for publication October 4, 2007.
Revised November 28, 2007.
Accepted for publication November 28, 2007.

Inhibition of the cardiac L-type calcium channel current by antidepressant drugs

Ivan Zahradnik 1, Igor Minarovic 1, Alexandra Zahradnikova 1*

1 Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences

* Address correspondence to: E-mail: alexandra.zahradnikova{at}savba.sk

Abstract

Antidepressants inhibit many membrane receptors and ionic channels, including the L-type calcium channel. Here we investigated the inhibition of calcium current (ICa) by antidepressants in enzymatically isolated rat ventricular myocytes using whole-cell patch-clamp. The molecular mechanism of inhibition was studied by comparing the voltage- and state-dependence of antidepressant inhibition of ICa to the respective properties of calcium antagonists, and by studying the effect of BayK 8644 or diltiazem on the inhibitory potency of the antidepressants. All selected antidepressants inhibited calcium currents reversibly and dose-dependently. At a stimulation frequency of 0.33 Hz, the antidepressants imipramine, clomipramine, desipramine, amitriptyline, maprotiline, citalopram, and dibenzepin blocked ICa with IC50 values of 8.3, 11.6, 11.7, 23.2, 31.0, 64.5 and 364 µmol/L. The antidepressant drugs shifted steady-state inactivation curves of ICa to negative voltages. The extent of the shift was similar to that induced by diltiazem or verapamil, but significantly smaller than that induced by felodipine. The use-dependent component of the antidepressant-induced block was similar to that of diltiazem, and significantly more and less, respectively, than those of felodipine and verapamil. In the presence of Bay K 8644, antidepressants were more effective in inhibiting ICa. However, the inhibitory effect of antidepressants was also augmented by diltiazem, suggesting that these drugs do not compete with diltiazem for a single binding site. These data suggest that antidepressants exert their inhibitory action on cardiac L-type calcium channels by a specific interaction at a receptor site similar to, but distinct from, the benzothiazepine site.


Key words: antidepressants, benzothiazepines, calcium current, cooperativity, dihydropyridines, phenylalkylamines




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