This study investigated the signaling pathways responsible for ketamine-induced cardiac depression in guinea pigs. The left ventricular development pressure (LVDP), velocity of the change in pressure (dP/dt), and heart rate (HR) accompanied with the total magnesium efflux ([Mg](e)) were measured simultaneously in perfused hearts. The level of activation of the extracellular signal-regulated kinases 1/2 (ERK 1/2) and p38 mitogen-activated protein (MAP) kinase. The intracellular ionized magnesium concentration ([Mg2+](i)) was measured using Mag-fura 2 AM in a single cardiomyocyte. Ketamine produced reversible decreases in the LVDP, dP/dt, and HR accompanied by increases in the [Mg](e). Ketamine also produced significant activation of p38 MAP kinase and ERK 1/2, and produced a dose-dependent increase in the [Mg2+](i), which was inhibited SB203580 and PD98059. These results suggest that ketamine-induced cardiac depression can be partly responsible for the increase in [Mg2+](i) and [Mg](e), accompanied by the activation of p38 MAP kinase and ERK 1/2 in guinea pigs. (c) 2006 Elsevier Inc. All rights reserved.