Swelling of mitochondria by the platelet antiaggregating agent ticlopidine.

Our studies on the effects of ticlopidine on mitochondrial functions led us to an intriguing observation related to its interaction with mitochondrial membranes. Liver mitochondria were isolated from Sprague-Dawley rats and assayed for swelling by spectrophotometry. When ticlopidine was added to mitochondria preincubated in an isotonic test medium, an induced-swelling activity was observed. This activity was time and concentration dependent and occurred in different isosmotic solutions. Several analogues of ticlopidine, assayed under identical conditions, produced only a minor effect. Respiratory chain inhibitors, uncouplers, ATP, and phosphate protected the mitochondria against the ticlopidine-induced swelling, whereas oligomycin did not. Comparative studies with the drugs chloramphenicol, nitroso-chloramphenicol, and salicylate (known for their association with mitochondrial injury) showed the first two to have little effect while the third one caused swelling as expected. On the other hand, oxypolarographic tests of respiring mitochondria in the presence of ticlopidine showed that the drug is not an uncoupling agent. These results indicate that the antiaggregating agent ticlopidine interacts with mitochondrial membranes causing swelling which, in turn, may alter mitochondrial permeability; however, unlike some other swelling agents, it does not act as a classical uncoupler.