Trimetazidine reverses calcium accumulation and impairment of phosphorylation induced by cyclosporine A in isolated rat liver mitochondria.
When applied to rat liver mitochondria in contact with Ca++, cyclosporine A (CsA) induced both an accumulation of this ion and a decrease in oxidative phosphorylation. Trimetazidine (TMZ) reversed both phenomena in a dose-dependent manner. These two effects were demonstrated in separate experiments. A decrease in oxidative phosphorylation was observed with succinate as substrate. V3 and P/O (ratio corresponds to the number of ADP molecules added in the medium per oxygen atom consumed during phosphorylation and represents the yield of ATP synthesis) were simultaneously decreased by CsA (1 microM) and restored by TMZ. Ca++ accumulation in mitochondria was observed when it was added to the mitochondrial suspension; its uptake was followed by a new equilibrium. CsA prolonged its duration, whereas TMZ reduced it in a dose-dependent manner. The same phenomenon was observed when ADP was used instead of CsA. Ca++ efflux from mitochondria could be induced by TMZ without the addition of CsA. It was immediate and always partial and followed by a reuptake process only observed at concentrations of TMZ of >1 microM. Compared with ruthenium red, which blocks Ca++ uniporter, TMZ seemed to act on Ca++ efflux mechanisms. Interestingly, low TMZ doses promote a Ca++ efflux process without activating reentry mechanism, which may explain the correction of deleterious effect of CsA on V3 and P/O. As nephrotoxicity observed in humans after CsA chronic administration is considered to be related, at least in part, to an alteration of Ca++ intracellular homeostasis, TMZ seems to be a candidate for alleviation of CsA nephrotoxic effects in humans.
Salducci
M D
MD
Laboratoire de Biophysique, Faculté de Pharmacie, Marseille, France.
Chauvet-Monges
A M
AM
Tillement
J P
JP
Albengres
E
E
Testa
B
B
Carrupt
P
P
Crevat
A
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D014665:Vasodilator Agents; D016572:Cyclosporine; D014292:Trimetazidine; D002118:Calcium