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.
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