title: Differential effect of imipramine and related compounds on Mg2+ efflux from rat erythrocytes.
abstract: The effect of imipramine on Mg2+ efflux in NaCl medium (Na+/Mg2+ antiport), on Mg2+ efflux in choline.Cl medium (choline/Mg2+ antiport) and on Mg2+ efflux in sucrose medium (Cl- -coupled Mg2+ efflux) was investigated in rat erythrocytes. In non-Mg2+-loaded rat erythrocytes, imipramine stimulated Na+/Mg2+ antiport but inhibited choline/Mg2+ antiport and Cl- -coupled Mg2+ efflux. The same effect could be obtained by several other compounds structurally related to imipramine. These drugs contain a cyclic hydrophobic ring structure to which a four-membered secondary or tertiary amine side chain is attached. At a physiological pH, the amine side chain expresses a cationic choline-like structure. The inhibitory effect on choline/Mg2+ antiport is lost when the amine side chain is modified or abandoned, pointing to competition of the choline-like side chain with choline or another cation at the unspecific choline antiporter or at the Cl- -coupled Mg2+ efflux. Other related drugs either stimulated Na+/Mg2+ antiport and choline/Mg2+ antiport, or they were ineffective. For stimulation of Na+/Mg2+ antiport and choline/Mg2+ antiport, there is no specific common structural motif of the drugs tested. The effects of imipramine on Na+/Mg2+ antiport and choline/Mg2+ antiport are not mediated by PKCalpha but are caused by a direct reaction of imipramine with these transporters. By increasing the intracellular Mg2+ concentration, the stimulation of Na+/Mg2+ antiport at a physiological intracellular Mg2+ concentration changed to an inhibition of Na+/Mg2+ antiport. This effect can be explained by the hypothesis that Mg2+ loading induced an allosteric transition of the Mg2+/Mg2+ exchanger with low Na+/Mg2+ antiport capacity to the Na+/Mg2+ antiporter with high Na+/Mg2+ antiport capacity. Both forms of the Mg2+ exchanger may be differently affected by imipramine.
authors.affiliation: Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Institut für Klinische Physiologie, Hindenburgdamm 30, 12200 Berlin, Germany. hans.ebel@charite.de
authors.forename: H
authors.initials: H
authors.lastname: Ebel
authors.forename: M
authors.initials: M
authors.lastname: Hollstein
authors.forename: T
authors.initials: T
authors.lastname: Günther
mesh_terms: D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D001692:Biological Transport; D002712:Chlorides / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism*; D007099:Imipramine / Q000737:chemistry / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects*; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism*; D008297:Male; D011189:Potassium Chloride / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D013395:Sucrose / Q000378:metabolism
chemical_list: D017920:Antiporters; D002712:Chlorides; D013395:Sucrose; D011189:Potassium Chloride; D012964:Sodium; D008274:Magnesium; D002794:Choline; D007099:Imipramine