DICLOFENAC SODIUM AND MEFENAMIC-ACID - POTENT INDUCERS OF THE MEMBRANE-PERMEABILITY TRANSITION IN RENAL-CORTEX MITOCHONDRIA

The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to induce Ca2+-mediated/cyclosporin A-sensitive mitochondrial membrane permeabi lity transition (MMPT) was evaluated by monitoring swelling of isolate d rat renal cortex mitochondria in the presence of 20 mu M CaCl2. Dipy rone and paracetamol did not induce MMPT, while piroxicam and acetylsa licylic acid (and its metabolite salicylate) were poor inducers, In co ntrast, diclofenac sodium and mefenamic acid were potent triggering ag ents, inducing MMPT at 2 mu M, a concentration below those previously shown to uncouple and/or inhibit oxidative phosphorylation. When compa red to salicylate, a classical uncoupler and inducer of MMPT, the pote ncy of diclofenac sodium and mefenamic acid was about 50-fold greater. Swelling was completely prevented by EGTA, cyclosporin A, or MgCl2, a nd only partially by ADP or dithiothreitol, Under the same experimenta l conditions as for the swelling assays, the drugs depressed the membr ane potential of mitochondria, an effect prevented by cyclosporin A an d restored by EGTA. Also, the drugs did not induce membrane lipid pero xidation or changes in GSSG levels, but led to a small decrease in pro tein thiol content, as well as to a substantial decrease in the NADPH levels of mitochondria. Hence, membrane depolarization and pyridine nu cleotide oxidation seem to be involved in MMPT induction by these NSAI Ds. The potency in eliciting the process, like the uncoupling activity , seems to be influenced by the lipophilic character of the molecules. (C) 1997 Academic Press.