Glibenclamide depletes ATP in renal proximal tubular cells by interfering with mitochondrial metabolism.
until further notice
SourceBritish Journal of Pharmacology, 145, 8, (2005), pp. 1069-75
Article / Letter to editor
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British Journal of Pharmacology
SubjectIGMD 9: Renal disorder; NCEBP 14: Cardiovascular diseases; NCMLS 5: Membrane transport and intracellular motility; UMCN 2.2: Vascular medicine and diabetes; UMCN 5.4: Renal disorders
Sulfonylurea drugs, like glibenclamide, stimulate insulin secretion by blocking ATP-sensitive potassium channels on pancreatic beta cells. Renal tubular epithelial cells possess a different class of K(ATP) channels with much lower affinities for sulfonylurea drugs, necessitating the use of micromolar glibenclamide concentrations to study these channels. Here, we describe the toxic effects of these concentrations on mitochondrial energy metabolism in freshly isolated renal proximal tubular cells. Glibenclamide, at concentrations of 50 and 100 microM, reduced intracellular ATP levels by 28+/-4 and 53+/-5%, respectively (P<0.01). This decline in ATP could be attributed to a dose-dependent inhibition of mitochondrial respiration. Glibenclamide (10-500 microM) inhibited ADP-stimulated mitochondrial oxygen consumption. In addition to this toxic effect, specific association of radiolabeled and fluorescent glibenclamide to renal mitochondria was found. Association of [(3)H]glibenclamide with renal mitochondria revealed a low-affinity site with a K(D) of 16+/-6 microM and a B(max) of 167+/-29 pmol mg(-1). We conclude that micromolar concentrations of glibenclamide interfere with mitochondrial bioenergetics and, therefore, should be used with care for inhibition of epithelial K(ATP) channels.
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