Cyclosporine (Cys A) is a potent immunosuppressor used to reduce rejection in transplantation surgery. We studied its action upon mitochondrial functions: oxidative phosphorylation and Ca2+ movements through mitochondrial membrane. We show that Cys A exhibits an inhibitory effect upon mitochondrial respiration. This result is in good agreement with previous works and may be correlated with Cys A toxicity. The action of cyclosporine on calcium fluxes is more pronounced. Indeed it blocks mitochondrial calcium efflux and allows mitochondria to accumulate a large amount of calcium. If this effect occurs in the cell, it would induce a Ca2+ decrease in cytosol. This action might be correlated with the inhibitory effect of Cys A upon the mitogenic stimulation of T lymphocytes.

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Trimetazidine is an anti‐ischaemic drug effective in different experimental models but its mechanism of action is not fully understood. Data indicate that mitochondria could be the main target of this drug. The aim of this work was to investigate the binding of [3H]‐trimetazidine on a purified preparation of rat liver mitochondria. [3H]‐trimetazidine binds to two populations of mitochondrial binding sites with Kd values of 0.96 and 84 μm. The total concentration of binding sites is 113 pmol mg−1 protein. Trimetazidine binding sites are differently distributed. The high‐affinity ones are located on the outer membranes and represent only a small part (4%) of total binding sites, whereas the low‐affinity ones are located on the inner membranes and are more abundant (96%) with a Bmax=108 pmol mg−1 protein. Drug displacement studies with pharmacological markers for different mitochondrial targets showed that [3H]‐trimetazidine binding sites are different from previously described mitochondrial sites. The possible involvement of [3H]‐trimetazidine binding sites in the regulation of the mitochondrial permeability transition pore (MTP), a voltage‐dependent channel sensitive to cyclosporin A, was investigated with mitochondrial swelling experiments. Trimetazidine inhibited the mitochondrial swelling induced by Ca2+ plus tert‐butylhydroperoxide (t‐BH). This effect was concentration‐dependent with an IC50 value of 200 μm. Assuming that trimetazidine effectiveness may be related to its structure as an amphiphilic cation, we compared it with other compounds exhibiting the same chemical characteristic both for their ability to inhibit MTP opening and to displace [3H]‐trimetazidine bound to mitochondria. Selected compounds were drugs known to interact with various biological membranes. A strong correlation between swelling inhibition potency and low‐affinity [3H]‐trimetazidine binding sites was observed: r=0.907 (n=24; P<0.001). These data suggest that mitochondrial sites labelled with [3H]‐trimetazidine may be involved in the MTP inhibiton. British Journal of Pharmacology (1998) 123, 1385–1394; doi:

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Cyclosporine A (CsA) is a known potent inhibitor of pro-oxidant-induced mitochondrial swelling. In the present study we show that CsA's effect is only transient when the liver mitochondrial swelling in induced by Ca2+ plus tert-butylhydroperoxide (t-BH). After an initial inhibition, swelling is worsened by CsA as evidenced by an extent of mitochondrial swelling that exceeds that of the control. Unlike CsA, trimetazidine (TMZ), an anti-ischemic drug decreases both the extent and the rate of the swelling with an IC50 value of 214 +/- 24 microM. Its inhibition effect on the initial swelling rate mimicks that of CsA but the mechanism may be independent. During long-term swelling. TMZ counteracts the worsening effect of CsA. The inhibition of swelling induced by TMZ is assessed by the fact that TMZ significantly increases the EC50 of Ca(2+)-induced mitochondrial swelling (46.6 +/- 6.0 to 85 +/- 10 microM, P < 0.01), without affecting its cooperativity. Apparently, TMZ seems to behave like trifluoperazine (TFP), a phospholipase A2 inhibitor that, under our experimental conditions, inhibits the mitochondrial swelling induced by Ca2+ and t-BH with an IC50 value of 25 +/- 10 microM. Both drugs are able to protect mitochondria from both phases (early and late) of the swelling, especially the late, which is enhanced in the presence of CsA. TFP and other phospholipase A2 inhibitors were able to displace [3H]TMZ from its mitochondrial binding sites whereas CsA was ineffective. We suggest that TMZ, like TFP, inhibits the CsA insensitive mechanism involved in the swelling process which is responsible for the worsening effect observed in the presence of CsA when the swelling is generated by Ca2+ and t-BH.