Effects of Caffeine on Gluconeogenesis and Urea Synthesis Induced by α-Adrenergic Stimulation in Suspensions of Rat Hepatocytes

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Effects of caffeine on gluconeogenesis and urea synthesis of rat isolated hepatocytes were investigated in the presence of hormonal agonists. Phenylephrine at 10μM stimulated 1.7-fold gluconeogenesis and 1.9-fold (compared to control) urea synthesis from 4mM glutamine. Stimulative effects of caffeine in the range from 0.1 to 10mM were biphasic depending on its concentration, and it showed maxima at about 1mM. Caffeine at 1mM 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⁺].