Dose-related inversion of cinnarizine and flunarizine effects on mitochondrial permeability transition

We investigated the effects of cinnarizine and flunarizine on mitochondrial permeability transition, ATP synthesis, membrane potential and NAD(P)H oxidation. Both drugs were effective in inhibiting the mitochondrial permeability transition induced either by Ca2+ alone or in the presence of tert-butylhydroperoxide. This protective effect occurred at low concentrations (< 50 microM) of these drugs and was accompanied by the inhibition of NAD(P)H oxidation and the restoration of the mitochondrial membrane potential decreased by a high concentration of Ca2+ (25 microM). However, at higher concentrations (> 50 microM) of cinnarizine and flunarizine and in the absence of both tert-butylhydroperoxide and Ca2+, their effects on the mitochondria were reversed as follows: mitochondrial permeability transition was generated, mitochondrial NAD(P)H was oxidized and membrane potential collapsed. These deleterious effects were not antagonized by cyclosporine A, the most potent inhibitor of the mitochondrial permeability transition, but by 2,6-di-tert-butyl-4-methylphenol, a known antioxidant agent. This mitochondrial effect was neither accompanied by an increase in malondialdehyde production nor by an increase in H2O2 generation, which attested that the effect of both drugs was not due to an increase in reactive oxygen species production. The dual effects of both cinnarizine and flunarizine on mitochondrial functions is discussed with regard to both the protective effect afforded by these drugs against ischemia-reperfusion injury and their side effect observed in some therapeutic situations where an overdosage seems likely.