Glibenclamide interferes with mitochondrial bioenergetics by inducing changes on membrane ion permeability.
The interference of glibenclamide, an antidiabetic sulfonylurea, with mitochondrial bioenergetics was assessed on mitochondrial ion fluxes (H+, K+, and Cl-) by passive osmotic swelling of rat liver mitochondria in K-acetate, KNO3, and KCl media, by O2 consumption, and by mitochondrial transmembrane potential (Deltapsi). Glibenclamide did not permeabilize the inner mitochondrial membrane to H+, but induced permeabilization to Cl- by opening the inner mitochondrial anion channel (IMAC). Cl- influx induced by glibenclamide facilitates K+ entry into mitochondria, thus promoting a net Cl-/K+ cotransport, Deltapsi dissipation, and stimulation of state 4 respiration rate. It was concluded that glibenclamide interferes with mitochondrial bioenergetics of rat liver by permeabilizing the inner mitochondrial membrane to Cl- and promoting a net Cl-/K+ cotransport inside mitochondria, without significant changes on membrane permeabilization to H+.
Fernandes
Maria A S
MA
Departamento de Zoologia, Universidade de Coimbra, 3004-517 Coimbra, Portugal. mfer@ci.uc.pt
Santos
Maria S
MS
Moreno
António J M
AJ
Duburs
Gunars
G
Oliveira
Catarina R
CR
Vicente
Joaquim A F
JA
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects*; D019069:Cell Respiration / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D005905:Glyburide / Q000633:toxicity*; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D011522:Protons; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000378:metabolism
D002712:Chlorides; D007004:Hypoglycemic Agents; D011522:Protons; D013385:Succinate Dehydrogenase; D011188:Potassium; D005905:Glyburide