CHLORPROMAZINE PROTECTION AGAINST CA2-DEPENDENT AND OXIDATIVE CELL INJURY - LIMITATIONS DUE TO DEPRESSED MITOCHONDRIAL-FUNCTION()

Chlorpromazine (CPZ), a phenothiazine, demonstrated both cytoprotectiv e and toxic effects on cardiomyocytes. CPZ markedly reduced cytotoxici ty caused by two toxic challenges, each with a distinct cytotoxic mech anism. Lethal cell injury was induced in cultured neonatal cardiomyocy tes by either: (1) ionomycin, a Ca2+ inophore that caused Ca2+-depende nt cell injury; or (2) ethacrynic acid (EA), a glutathione (GSH) deple tor that killed cells primarily via peroxidative damage. Pretreatment with 50 mu M CPZ reduced the extent of ionomycin-induced cell death, a s measured by lactate dehydrogenase (LDH) leakage, but enhanced the lo ss of intracellular ATP and collapsed the mitochondrial transmembrane potential (Delta Psi). In EA-treated cultures, 50 mu M CPZ also lowere d LDH leakage and diminished the peroxidative damage responsible for t he cytotoxicity, but again enhanced the loss of intracellular ATP and collapsed the Delta Psi. CPZ protection was incomplete and limited to a narrow concentration range that was essentially identical for both t oxic challenges. Maximum protection was observed with 50 mu M CPZ, yet the amount of residual damage was similar to the degree of injury cau sed by a mitochondrial uncoupler, carbonylcyanide-m-chlorophenylhydraz one alone. In the absence of either challenge, 50 mu M CPZ did not aff ect cellular energy status or kill the cells, but a higher concentrati on of CPZ (150 mu M) did deenergize unchallenged cardiomyocytes. These data demonstrate that CPZ can reduce cytotoxicity caused by either Ca 2+-dependent events or oxidative stress. However, even at an optimally protective level, CPZ in combination with either ionomycin or EA deen ergized the cells, although neither toxic challenge nor 50 mu M CPZ al one seriously affected Delta Psi. It would appear that intracellular p erturbations induced by either challenge promote a depression of mitoc hondrial function by CPZ, which limits the protective action of the dr ug. Since both of the challenges used contain toxicologic features exh ibited by a wide variety of toxic insults, results of this study have both mechanistic and clinical implications.