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.
Department of Cell Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yukihisa
Y
Hamaguchi
Yasushi
Y
Tatematsu
Koichi
K
Furukawa
Tatsuaki
T
Matsubara
Shinsuke
S
Nakayama
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