title: Nicotine increases hepatic oxygen uptake in the isolated perfused rat liver by inhibiting glycolysis.
abstract: Nicotine influences energy metabolism, yet mechanisms remain unclear. Since the liver is one of the largest organs and performs many metabolic functions, the goal of this study was to determine whether nicotine would affect respiration and other metabolic functions in the isolated perfused liver. Infusion of 85 microM nicotine caused a rapid 10% increase in oxygen uptake over basal values of 105 +/- 5 micromol/g/h in perfused livers from fed rats, and an increase of 27% was observed with 850 microM nicotine. Concomitantly, rates of glycolysis of 105 +/- 8 micromol/g/h were decreased to 52 +/- 9 micromol/g/h with nicotine, whereas ketone body production was unaffected. Nicotine had no effect on oxygen uptake in glycogen-depleted livers from 24-h fasted rats. Furthermore, addition of glucose to perfused livers from fasted rats partially restored the stimulatory effect of nicotine. Infusion of atractyloside, potassium cyanide, or glucagon blocked the nicotine-induced increase in respiration. Intracellular calcium was increased in isolated hepatocytes by nicotine, a phenomenon prevented by incubation of cells with d-tubocurarine, a nicotinic acetylcholine receptor antagonist. Respiration was also increased approximately 30% in hepatocytes isolated from fed rats by nicotine, whereas hepatocytes isolated from fasted rats showed little response. In the presence of N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), an inhibitor of cyclic AMP-dependent protein kinase A, nicotine failed to stimulate respiration. These data support the hypothesis that inhibition of glycolysis by nicotine increases oxygen uptake due to an ADP-dependent increase in mitochondrial respiration.
authors.affiliation: Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, CB #7365, Mary Ellen Jones Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Brian_Dewar@med.unc.edu
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Dewar
authors.forename: Blair U
authors.initials: BU
authors.lastname: Bradford
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Thurman
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002469:Cell Separation; D003367:Cotinine / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007657:Ketone Bodies / Q000096:biosynthesis; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000378:metabolism / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology; D010477:Perfusion; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014403:Tubocurarine / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D007657:Ketone Bodies; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D019344:Lactic Acid; D009538:Nicotine; D019289:Pyruvic Acid; D005934:Glucagon; D000226:Mitochondrial ADP, ATP Translocases; D005947:Glucose; D003367:Cotinine; D002118:Calcium; D014403:Tubocurarine