Imipramine-Induced Cardiac Depression Is Responsible for the Increase in Intracellular Magnesium and the Activation of ERK 1/2 in Rats

Imipramine, an antidepressant drug, can cause potentially lethal cardiotoxic side effects including hypotension, ventricular tachycardia, and decreased cardiac output. This study investigated the mechanism responsible for imipramine-induced cardiac depression in rats. The left ventricular developed pressure (LVDP), velocity of the change in pressure (dP/dt), and heart rate (HR) accompanied with the total magnesium efflux ([Mg]_e) were measured in Langendorff-perfused intact rats hearts. Intracellular ionized magnesium concentrations ([Mg²⁺] _i) were measured using Mag-fura 2 AM in a single H9c2 cell. The activation of the extracellular signal-regulated kinases 1/2 (ERK 1/2) was analyzed by Western blot. Imipramine induced reversible decreases in LVDP, dP/dt, and HR, which were accompanied by increases in [Mg]_e. Imipramine also induced activation of ERK 1/2 and increase in the [Mg²⁺] _i, which was inhibited PD98059, ERK 1/2 inhibitor. These results suggest that imipramine-induced cardiac depression may be partly due to increases of [Mg²⁺]_i that are accompanied by the activation of ERK 1/2 in rats.