Summary
Iminodibenzyl-, iminostilbene-, dibenzocycloheptadiene-, dibenzooxepine- and dibenzothiepine-derivatives of tricyclic antidepressant drugs were able to inhibit Na+-stimulated Mg2+ efflux in human erythrocytes at concentrations of 10−5−10−3 mol/l. Tricyclic antidepressant drugs belonging to other chemical groups, non-tricyclic antidepressant drugs and phenothiazines were less potent inhibitors (IC50 of 10−4 mol/l or higher).
Imipramine and dothiepine, the most potent compounds, inhibited the Mg" carrier with IC50 of 2.5 and 4 × 10−5 mol/1 respectively. These IC50 are of similar order of magnitude to those of some classical transport inhibitors (such as furosemide for the [Na+K+,Cl−]-cotransport system). In addition, these concentrations of imipramine and dothiepine were free of: i) side effects on other erythrocyte Na′ and K+ transport pathways (with the exception of a slight inhibition of Ca2+-sensitive K+-channels and [Na+,K+,Cl−]- and [K+,Cl−]-cotransport systems) and ii) toxic effects on the membrane leak for divalent or monovalent cations. Therefore, we selected imipramine as an useful tool for investigating fluxes catalyzed by the Na+-stimulated Mg2+ carrier.
Imipramine was tested on the initial rate of ouabain and bumetanide-resistant net Na+ influx in Na+-depleted, Mg2+-loaded erythrocytes. The compound was able to inhibit a Na+ influx of about 300–500 μmol (l · cells × h)−1 with an IC50 of about 3 x 10−5 mol/1. This imipramine-sensitive Na+ influx was coupled with an imipramine-sensitive Mg2+ efflux in a stoichiometry of 3.03±0.34 (mean±SEM of 7 experiments).
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Abbreviations
- MOPS:
-
4-morpholinopropanesulfonic acid
- PCMBS:
-
p-chloromercuribenzenesulfonate
- EGTA:
-
ethylene glycol bis-(beta-aminoethyl ether)N,N′N′N′-tetraacetic acid
- Tris:
-
tris(hydroxymethyl)aminomethane
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Féray, JC., Garay, R. Demonstration of a Na+: Mg2+ exchange in human red cells by its sensitivity to tricyclic antidepressant drugs. Naunyn-Schmiedeberg's Arch Pharmacol 338, 332–337 (1988). https://doi.org/10.1007/BF00173409
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DOI: https://doi.org/10.1007/BF00173409