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-induce d mitochondrial swelling. In the present study we show that CsA's effe ct is only transient when the liver mitochondrial swelling is induced by Ca2+ plus tert-butylhydroperoxide (t-BH). After an initial inhibiti on, swelling is worsened by CsA as evidenced by an extent of mitochond rial swelling that exceeds that of the control. Unlike CsA, trimetazid ine (TMZ), an anti-ischemic drug decreases both the extent and the rat e of the swelling with an IC50 value of 214 +/- 24 mu M. Its inhibitio n effect on the initial swelling rate mimicks that of CsA but the mech anism may be independent. During long-term swelling, TMZ counteracts t he worsening effect of CsA. The inhibition of swelling induced by TMZ is assessed by the fact that TMZ significantly increases the EC50 of C a2+-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 tha t, under our experimental conditions, inhibits the mitochondrial swell ing induced by Ca2+ and t-BH with an IC50 value of 25 +/- 10 mu M. Bot h drugs are able to protect mitochondria from both phases (early and l ate) of the swelling, especially the late, which is enhanced in the pr esence of CsA. TFP and other phospholipase A(2) inhibitors were able t o displace [H-3]TMZ from its mitochondrial binding sites whereas CsA w as ineffective. We suggest that TMZ, like TFP, inhibits the CsA insens itive mechanism involved in the swelling process which is responsible for the worsening effect observed in the presence of CsA when the swel ling is generated by Ca2+ and t-BH.