Evidence for two calcium-dependent steps and a sodium-dependent step in the mechanism of cell killing by calcium ions in the presence of ionophore A23187

Elevated intracellular Ca²⁺ appears to play an important role in the mechanism of cell killing in certain pathologic states such as ischemia. The authors have examined aspects of the biochemical mechanism of cell killing by elevated intracellular Ca²⁺ using a model system cultured fibroblasts treated with ionophore A23187 in Ca²⁺-containing medium. Evidence has been obtained for two Ca²⁺-mediated steps and a Na⁺-mediated step in the cell killing process. The first Ca²⁺-mediated step occurs in low extracellular Ca²⁺ concentrations (1-100 μM) and exhibits a variety of characteristics in common with the arachidonic acid release response stimulated under the same conditions. These results are consistent with the arachidonic acid release response constituting or closely monitoring the initial injury process. The second Ca²⁺-mediated process is achieved at near physiologic extracellular Ca²⁺ concentrations in the abscence of A23187. Killing of cells injured by the two Ca²⁺-dependent steps requires extracellular Na⁺ ions at half or more the physiologic concentration.