Comparison of the effects of cyclosporine A and trimetazidine on Ca2+-dependent mitochondrial swelling

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 is 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 mu M. 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 Ca2+-induced mitochondrial swelling (46.6 +/- 6.0 to 85 +/- 10 mu M, P < 0.01), without affecting its cooperativity. Apparently, TMZ seems to behave like trifluoperazine (TFP), a phospholipase A(2) inhibitor that, under our experimental conditions, inhibits the mitochondrial swelling induced by Ca2+ and t-BH with an IC50 value of 25 +/- 10 mu M. 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 A(2) inhibitors were able to displace [H-3]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.