The stimulation of the alpha(1)-adrenergic receptor with phenylephrine results in the significant extrusion of Mg2+ from the rat heart and cardiomyocytes. Phenylephrine-induced Mg2+ extrusion is prevented by the removal of extracellular Ca2+ or by the presence of Ca2+-channel blockers such as verapamil, nifedipine, or (+)BAY-K8644. Mg2+ extrusion is almost completely inhibited by PD98059 (a MAP kinase inhibitor). The simultaneous addition of 5 mM Ca2+ and phenylephrine increases the extrusion of Mg2+ from perfused hearts and cardiomyocytes. This Mg2+ extrusion is inhibited by more than 90% when the hearts are preincubated with PD98059. ERKs are activated by perfusion with either phenylephrine or 5 mM Ca2+. This ERK activation is inhibited by PD98059. Overall, these results suggest that stimulating the cardiac alpha(1)-adrenergic receptor by phenylephrine causes the extrusion of Mg2+ via the Ca2+-activated, Na+-dependent transport pathway, and the ERKs assists in Mg2+ transport in the heart. (c) 2005 Elsevier Inc. All rights reserved.