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Antidiabetic sulphonylureas activate mitochondrial permeability transition in rat skeletal muscle
Author(s) -
Skalska Jolanta,
Debska Grazyna,
Kunz Wolfram S,
Szewczyk Adam
Publication year - 2005
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706214
Subject(s) - glibenclamide , mitochondrion , mitochondrial permeability transition pore , skeletal muscle , inner mitochondrial membrane , membrane potential , medicine , intracellular , chemistry , mitochondrial matrix , endocrinology , biology , biochemistry , pharmacology , enzyme , cytosol , programmed cell death , apoptosis , diabetes mellitus
1 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. 2 The effects of glibenclamide (and other sulphonylurea derivatives) on mitochondrial function were studied by measuring mitochondrial swelling, mitochondrial membrane potential, respiration rate and Ca 2+ transport into mitochondria. 3 We observed that glibenclamide induced mitochondrial swelling (EC 50 =8.2±2.5 μ M ), decreased the mitochondrial membrane potential and evoked Ca 2+ efflux from the mitochondrial matrix. These effects were blocked by 2 μ M cyclosporin A, an inhibitor of the mitochondrial permeability transition. 4 Moreover, 30 μ M glibenclamide accelerated the respiratory rate in the presence of glutamate/malate, substrates of complex I of the mitochondrial respiratory chain. 5 In conclusion, we postulate that the antidiabetic sulphonylureas activate the mitochondrial permeability transition in skeletal muscle by increasing its sensitivity to Ca 2+ .British Journal of Pharmacology (2005) 145 , 785–791. doi: 10.1038/sj.bjp.0706214