CA2-STIMULATED MITOCHONDRIAL REACTIVE OXYGEN SPECIES GENERATION AND PERMEABILITY TRANSITION ARE INHIBITED BY DIBUCAINE OR MG2+()

Mitochondrial swelling and membrane protein thiol oxidation associated with mitochondrial permeability transition induced by Ca2+ and t-buty l hydroperoxide or inorganic phosphate, but not 4,4'-diisothiocyanatos tilbene-2,2'-disulfonic acid or phenylarsine oxide, are inhibited by t he local anesthetic dibucaine, Dibucaine promotes an inhibition of the Ca2+-induced increase in mitochondrial H2O2 generation measured by th e oxidation of scopoletin in the presence of horseradish peroxidase, T his decrease in mitochondrial H2O2 generation may be attributed to the reduction of Ca2+ binding to the membrane induced by dibucaine, as as sessed by measuring Ca-45(2+) binding to the mitochondrial membrane. M g2+ also inhibited Ca2+ binding to the mitochondrial membrane, mitocho ndrial swelling, membrane protein thiol oxidation, and H2O2 generation induced by Ca2+. Together, these results demonstrate that the mechani sm by which dibucaine and Mg2+ inhibit mitochondrial permeability tran sition is related to the decrease in reactive oxygen species generatio n induced by Ca2+-promoted alterations of inner mitochondrial membrane properties. (C) 1998 Academic Press.