Sodium- and calcium-dependent steps in the mechanism of neonatal rat cardiac myocyte killing by ionophores. II. 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 Ca(2+)-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 Ca(2+)-mediated injury steps followed by a Na(+)-mediated step leading to cell death detected as membrane permeabilization to trypan blue dye. The first Ca(2+)-mediated step requires the presence of A23187 and low extracellular Ca2+ concentrations (1-100 microM) and is inhibited by Mn2+ and Ni2+ ions. The second Ca(2+)-dependent step requires extracellular Ca2+ concentrations in approximately the physiological range (greater than 1 mM), is not dependent on ionophore, and is not inhibited by Mn2+. Arachidonic acid release occurs during both Ca(2+)-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., greater than or equal to 75 mM). Li+, which has a smaller ionic radius than Na+, can partially substitute for its in the Na(+)-dependent step, whereas K+, Cs+, Rb+, and NH4+ (which have larger ionic radii) cannot.
DuBourdieu
D J
DJ
Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55455.
Shier
W T
WT
D000465:Algorithms; D000818:Animals; D000831:Animals, Newborn; D016718:Arachidonic Acid / Q000378:metabolism; D000001:Calcimycin / Q000633:toxicity*; D002118:Calcium / Q000032:analysis / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008345:Manganese / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000473:pathology*; D051381:Rats; D012964:Sodium / Q000494:pharmacology*; D014316:Tritium
D002250:Carbon Radioisotopes; D014316:Tritium; D016718:Arachidonic Acid; D000001:Calcimycin; D008345:Manganese; D012964:Sodium; D007770:L-Lactate Dehydrogenase; D002118:Calcium