Antidiabetic sulphonylureas activate mitochondrial permeability transition in rat skeletal muscle.
Antidiabetic sulphonylureas can bind to various intracellular organelles including mitochondria. The aim of this study was to monitor the influence of antidiabetic sulphonylureas on membrane permeability in mitochondria isolated from rat skeletal muscle. The effects of glibenclamide (and other sulphonylurea derivatives) on mitochondrial function were studied by measuring mitochondrial swelling, mitochondrial membrane potential, respiration rate and Ca2+ transport into mitochondria. We observed that glibenclamide induced mitochondrial swelling (EC50 = 8.2 +/- 2.5 microM), decreased the mitochondrial membrane potential and evoked Ca2+ efflux from the mitochondrial matrix. These effects were blocked by 2 microM cyclosporin A, an inhibitor of the mitochondrial permeability transition. Moreover, 30 microM glibenclamide accelerated the respiratory rate in the presence of glutamate/malate, substrates of complex I of the mitochondrial respiratory chain. In conclusion, we postulate that the antidiabetic sulphonylureas activate the mitochondrial permeability transition in skeletal muscle by increasing its sensitivity to Ca2+.
Skalska
Jolanta
J
Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., Warsaw 02-093, Poland.
Debska
Grazyna
G
Kunz
Wolfram S
WS
Szewczyk
Adam
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D005913:Glipizide / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D010539:Permeability / Q000187:drug effects*; D051381:Rats; D013453:Sulfonylurea Compounds / Q000494:pharmacology
D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D016572:Cyclosporine; C100171:glisoxepide; D010100:Oxygen; D005905:Glyburide; D002118:Calcium; D005913:Glipizide