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++, cyclospor ine A (CsA) induced both an accumulation of this ion and a decrease in oxidative phosphorylation. Trimetazidine (TMZ) reversed both phenomen a in a dose-dependent manner. These two effects were demonstrated in s eparate experiments. A decrease in oxidative phosphorylation was obser ved with succinate as substrate. V-3 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 mu M) and restored by TMZ. Ca++ ac cumulation in mitochondria was observed when it was added to the mitoc hondrial suspension.; its uptake was followed by a new equilibrium. Cs A prolonged Its duration, whereas TMZ reduced it in a dose-dependent m anner. The same phenomenon was observed when ADP was used instead of C sA. 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 mu M. C ompared 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 e xplain the Correction of deleterious effect of CsA on V-3 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++ i ntracellular homeostasis, TMZ seems to be a candidate for alleviation of CsA nephrotoxic effects in humans.