Demonstration of a Na+: Mg2+ exchange in human red cells by its sensitivity to tricyclic antidepressant drugs

Abstract

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 Mg2+ carrier with IC50 of 2.5 and 4 x 10(-5) mol/l 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 mumol (1.cells x h)-1 with an IC50 of about 3 x 10(-5) mol/l. 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).

Sodium-dependent recovery of ionised magnesium concentration following magnesium load in rat heart myocytes

“…These drugs were used at 10-20 times the doses that cause 50% inhibition of Na + /Ca 2+ antiport [18][19][20] and as both drugs were ineffectual, it is unlikely that NCX1, NCX2 or NCX3 isoforms of the Na + /Ca 2+ antiport were involved [19]. In addition, Na + -dependent [fMg 2+ ] i recovery was completely abolished by imipramine, an inhibitor of Na + /Mg 2+ antiport in other tissues [8,11]. Although none of these drugs is particularly specific, the overall pharmacological profile supports the existence of a separate Mg 2+ transport system.…”

“…3 helping us characterise the transporter. It is thought to be 1Na + :1Mg 2+ in ferret red blood cells [11] and leech neurones [14], 2Na + :1Mg 2+ in rat red blood cells [13] and 3Na + :1Mg 2+ in guinea-pig Tenia cecum [38] and human red blood cells [8]. Unfortunately, a direct measurement of the stoichiometry in cardiac cells is not yet possible, as a highly selective inhibitor of the transporter is not available to dissect out the component of total Na + influx that can be attributed to the transporter.…”

Streptozotocin-induced diabetes impairs Mg2+homeostasis and uptake in rat liver cells

“…13). Although the transporter has not been cloned to date, the Na ϩ dependence of Mg 2ϩ extrusion is supported by results in various experimental models, which indicate that Mg 2ϩ extrusion is largely inhibited in the absence of extracellular Na ϩ (29,30) or in the presence of the Na ϩ transport inhibitors amiloride (15) and imipramine (12).…”

Sodium-Magnesium Exchange in Erythrocyte Membranes from Patients with Affective Disorders

“…We previously reported that tricyclic antidepressants inhibit the erythrocyte Na/Mg exchanger in vitro at con centrations of 50-100 pmol/1 [14], Blood concentrations of antidepressants in treated patients (*T0-6 mol/1) seem not sufficiently high to inhibit cell membrane Na/Mg exchange in vivo. However, the involvement of this phe nomenon requires further investigation.…”

“…an Na/Mg exchanger [13]. This new transport system was found to be sensitive to tricyclic antidepres sant drugs [14]. The maximal rate (Vmax) of the Na/Mg exchanger showed high interindividual variations on the one hand and, on the other hand, it was a more stable parameter in individuals than plasma or cell magnesium contents [15], The abnormal erythrocyte magnesium con tent in depression suggested to us a possible alteration in the Na/Mg exchanger.…”