Imipramine inhibition of TRPM-like plasmalemmal Mg2+ transport in vascular smooth muscle cells.
Depression is associated with vascular disease, such as myocardial infarction and stroke. Pharmacological treatments may contribute to this association. On the other hand, Mg(2+) deficiency is also known to be a risk factor for the same category of diseases. In the present study, we examined the effect of imipramine on Mg(2+) homeostasis in vascular smooth muscle, especially via melastatin-type transient receptor potential (TRPM)-like Mg(2+) -permeable channels. The intracellular free Mg(2+) concentration ([Mg(2+) ](i) ) was measured using (31) P-nuclear magnetic resonance (NMR) in porcine carotid arteries that express both TRPM6 and TRPM7, the latter being predominant. pH(i) and intracellular phosphorus compounds were simultaneously monitored. To rule out Na(+) -dependent Mg(2+) transport, and to facilitate the activity of Mg(2+) -permeable channels, experiments were carried out in the absence of Na(+) and Ca(2+) . Changing the extracellular Mg(2+) concentration to 0 and 6 mM significantly decreased and increased [Mg(2+) ](i) , respectively, in a time-dependent manner. Imipramine statistically significantly attenuated both of the bi-directional [Mg(2+) ](i) changes under the Na(+) - and Ca(2+) -free conditions. This inhibitory effect was comparable in influx, and much more potent in efflux to that of 2-aminoethoxydiphenyl borate, a well-known blocker of TRPM7, a channel that plays a major role in cellular Mg(2+) homeostasis. Neither [ATP](i) nor pH(i) correlated with changes in [Mg(2+) ](i) . The results indicate that imipramine suppresses Mg(2+) -permeable channels presumably through a direct effect on the channel domain. This inhibitory effect appears to contribute, at least partially, to the link between antidepressants and the risk of vascular diseases.
Hamaguchi
Yukihisa
Y
Department of Cell Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Tatematsu
Yasushi
Y
Furukawa
Koichi
K
Matsubara
Tatsuaki
T
Nakayama
Shinsuke
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology*; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects; D008274:Magnesium / Q000378:metabolism* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D013552:Swine; D050053:TRPM Cation Channels / Q000378:metabolism*
D000929:Antidepressive Agents, Tricyclic; D020033:Protein Isoforms; D050053:TRPM Cation Channels; D000255:Adenosine Triphosphate; D012964:Sodium; D008274:Magnesium; D007099:Imipramine; D002118:Calcium