Imipramine inhibition of TRPM-like plasmalemmal Mg(2+) 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.