title: Effects of caffeine on gluconeogenesis and urea synthesis induced by alpha-adrenergic stimulation in suspensions of rat hepatocytes.
abstract: Effects of caffeine on gluconeogenesis and urea synthesis of rat isolated hepatocytes were investigated in the presence of hormonal agonists. Phenylephrine at 10 microM stimulated 1.7-fold gluconeogenesis and 1.9-fold (compared to control) urea synthesis from 4 mM glutamine. Stimulative effects of caffeine in the range from 0.1 to 10 mM were biphasic depending on its concentration, and it showed maxima at about 1 mM. Caffeine at 1 mM stimulated 2.1-fold gluconeogenesis and 2.4-fold urea synthesis. Caffeine without phenylephrine did not stimulate both syntheses. These effects of caffeine and phenylephrine diminished in the absence of extracellular Ca2+. Results on uptake of 45Ca2+ into hepatocytes and change in quin-2 fluorescence indicated that phenylephrine induced Ca2+ influx into the cell and consequently increased the intracellular Ca2+ concentration, [Ca2+], and that the addition of caffeine did not further stimulate the effect of phenylephrine on [Ca2+]. Therefore, we suggest that stimulation of gluconeogenesis and urea synthesis by phenylephrine is due to increase in [Ca2+]. Since caffeine is known to inhibit phosphodiesterase, the additional stimulation of both syntheses by caffeine plus phenylephrine may be due to the synergistic effect of increases in cAMP and [Ca2+]. The increase in the rates of gluconeogenesis and urea synthesis similarly depended on the caffeine concentration. Furthermore, the ratio of [acetoacetate]/[3-OH-butyrate] which shows intramitochondrial redox state, also depended on the caffeine concentration, indicating a possible coupling of the redox function of mitochondria with [Ca2+].
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003584:Cytological Techniques; D005110:Extracellular Space / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains; D012119:Respiration / Q000187:drug effects; D014508:Urea / Q000096:biosynthesis*
chemical_list: D000316:Adrenergic alpha-Agonists; D010656:Phenylephrine; D002110:Caffeine; D014508:Urea; D002118:Calcium