The action of glibenclamide on glycogen catabolism and related parameters in the isolated perfused rat liver.
Inhibitory effects on glycogenolysis have been reported for glibenclamide in the presence of insulin after stimulation of glycogenolysis by glucagon. Inhibition of oxidative phosphorylation, which has been equally reported for this drug, however, should stimulate glycogenolysis. The present work aimed to find an answer to the question of how glibenclamide affects glycogen catabolism in the liver of fed rats undergoing substrate- and hormone-free perfusion. The experimental system was the isolated perfused liver of ad libitum fed rats. Metabolites in the outflowing perfusate were assayed enzymatically. Oxygen uptake was measured polarographically. Glibenclamide (25-500 microM) stimulated glucose production and lactate release, with a clear correlation between concentrations and effects. Maximal stimulations were 132 and 127% for lactate production and glucose release, respectively. At low glibenclamide concentrations (up to 100 microM) both oxygen uptake and pyruvate production were stimulated, but at higher concentrations inhibition took place. Uric acid production was stimulated by glibenclamide. All effects of glibenclamide are probably due to decreases in oxidative phosphorylation. Stimulation of glucose release is the opposite of what should be expected for a hypoglycemic drug and it also contrasts with some reports of diminishing effects in the presence of glucagon plus insulin. This means that the stimulatory action on glycogenolysis that was seen as a net effect under the specific conditions of the present work could be counterbalancing inhibitory effects in vivo. This combination of events could eventually diminish the effectiveness of the drug as a hypoglycemic agent in the fed state.
Carvalho-Martini
Mirian
M
Laboratory of Liver Metabolism, Department of Biochemistry, University of Maringá, Maringá, Brazil 87020-900.
de Oliveira
Denise S
DS
Suzuki-Kemmelmeier
Fumie
F
Bracht
Adelar
A
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D010101:Oxygen Consumption; D010477:Perfusion; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014527:Uric Acid / Q000378:metabolism
D007004:Hypoglycemic Agents; D007773:Lactates; D008112:Liver Glycogen; D011773:Pyruvates; D014527:Uric Acid; D005947:Glucose; D005905:Glyburide