Tricyclic antidepressants inhibit voltage-dependent calcium channels and Na+–Ca2+ exchange in rat brain cortex synaptosomes

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Abstract
We have used a resting (5 mM K+) or depolarizing (60 mM K+) choline-based medium, and a nondepolarizing sodium-based or choline-based medium, to characterize the inhibitory potential of tricyclic antidepressants against the voltage-dependent calcium channels or the Na+-Ca2+ exchange process, respectively, in synaptosomes from rat brain cortex. Imipramine, desipramine, amitriptyline, and clomipramine inhibited net K+-induced 45CA uptake with similar IC50 values (26-31 .mu.M), and this uptake was also inhibited by diltiazem with an IC50 of 36 .mu.M; these results indicate an inhibition of voltage-dependent calcium channels by tricyclic antidepressants. The net uptake of 45Ca induced by Na+-Ca2+ exchange was also inhibited by the four tricyclic antidepressants tested, but not by diltiazem; imipramine (IC50 = 94 .mu.M) was a more potent inhibitor of this process than desipramine (IC50 = 151 .mu.M), and the IC50 values of amitriptyline (107 .mu.M) and clomipramine (97 .mu.M) were similar to that of imipramine. Some degree (.apprx. 25%) of brain calcium channel blockade could be present at the steady-state concentrations of tricyclic antidepressants expected to occur during therapeutic use of these compounds to treat depression or panic disorder.