SODIUM-DEPENDENT AND CALCIUM-DEPENDENT STEPS IN THE MECHANISM OF NEONATAL RAT CARDIAC MYOCYTE KILLING BY IONOPHORES .2. THE CALCIUM-CARRYING IONOPHORE, A23187

Several lines of evidence indicate a role for elevated intracellular Ca2+ in mechanisms of cell killing induced by a wide variety of agents. Cardiac myocytes are susceptible to killing under various conditions, including ischemia and exposure to monensin. In order to delineate the Ca2+-dependent cell killing mechanism(s) to which cardiac myocytes are susceptible, we have investigated the mechanism by which they are killed by Ca2+ plus the divalent cation ionophore A23187. Evidence has been obtained for two Ca2+-mediated injury steps followed by a Na+-mediated step leading to cell death detected as membrane permeabilization to trypan blue dye. The first Ca2+-mediated step requires the presence of A23187 and low extracellular Ca2+ concentrations (1-100 μm) and is inhibited by Mn2+ and Ni2+ ions. The second Ca2+-dependent step requires extracellular Ca2+ concentrations in approximately the physiological range (>1 mm), is not dependent on ionophore, and is not inhibited by Mn2+. Arachidonic acid release occurs during both Ca2+-mediated steps, but mostly during the second step. The second injury step is characterized by visible cell swelling and release of lactate dehydrogenase enzyme activity. The Na+-dependent step requires extracellular Na+ equal to or greater than half the physiological concentration (i.e., ≥75 mm). Li+, which has a smaller ionic radius than Na+, can partially substitute for it in the Na+-dependent step, whereas K+, Cs+, Rb+, and NH4+ (which have larger ionic radii) cannot. © 1992.