High extracellular Mg(2+) concentrations ([Mg(2+)](o)) caused a remarkable concentration-dependent and reversible increase in intracellular Mg(2+) concentrations ([Mg(2+)](i)) in beating and quiescent guinea-pig papillary muscles, accompanied by a definite decrease in intracellular Na(+) concentrations ([Na(+)](i)). A change in 1 mm [Mg(2+)](o) evoked a direct change in 0.0161 mm [Mg(2+)](i) and an inverse change in 0.0263 mm [Na(+)](i). Imipramine completely abolished the high [Mg(2+)](o)-induced decrease in [Na(+)](i) and remarkably diminished the high [Mg(2+)](o)-induced increase in [Mg(2+)](i) in papillary muscles. High [Mg(2+)](o) also produced a significant activation of p38 mitogen-activated protein (MAP) kinase and extracellular signal-related kinase 2 (ERK2) that was inhibited by pretreatment with imipramine. These results suggest that the high [Mg(2+)](o)-induced increase in [Mg(2+)](i) could be coupled with the decrease in [Na(+)](i), which might involve activation of the reverse mode of Na(+)-Mg(2+) exchange, accompanied by activation of p38 MAP kinase and ERK2 in the guinea-pig heart.