Inhibition of hepatic gluconeogenesis by the Rp-diastereomer of adenosine cyclic 3',5'-phosphorothioate

• Published in: Biochemical journal Vol. 237; no. 2; pp. 463 - 468
• Main Authors: Dragland-Meserve, C J, Olivieri, M C, Botelho, L H
• Format: Journal Article
• Language: English
• Published: England 15.07.1986
• Subjects: Animals; Cyclic AMP - analogs & derivatives; Cyclic AMP - pharmacology; Glucagon - pharmacology; Gluconeogenesis - drug effects; Glycogen Synthase - metabolism; In Vitro Techniques; Liver - drug effects; Liver - metabolism; Male; Protein Kinases - metabolism; Rats; Rats, Inbred Strains; Stereoisomerism; Thionucleotides - pharmacology
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/bj2370463

The specific intracellular cyclic AMP-dependent protein kinase antagonist, the Rp-diastereomer of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS), inhibited both basal and cyclic AMP-agonist-induced rates of gluconeogenesis in hepatocytes isolated from fasted rats. Incubation of the cells in the presence of pyruvate and lactate and either the Sp-diastereomer of adenosine cyclic 3',5'-phosphorothioate (Sp-cAMPS) or glucagon produced a concentration-dependent increase in the rate of gluconeogenic glucose production which was shifted to higher concentrations of Sp-cAMPS or glucagon in the presence of Rp-cAMPS. Incubation of the cells with Rp-cAMPS in the absence of agonist produced no increase in the rate of glucose production and, in most cases, 100 microM-Rp-cAMPS resulted in 14-20% decrease in the substrate-stimulated rate of glucose production. Sp-cAMPS-induced gluconeogenesis was inhibited half-maximally at 1 microM-Rp-cAMPS and glucagon-induced gluconeogenesis was inhibited half-maximally at 12 microM-Rp-cAMPS. Approx. 10-15% of the inhibition of gluconeogenesis observed in the presence of Rp-cAMPS was due to conversion of glucose 6-phosphate to liver glycogen, consistent with Rp-cAMPS-induced reactivation of glycogen synthase. The remaining 85-90% inhibition of gluconeogenic glucose production resulted from the action of Rp-cAMPS on the cyclic AMP-sensitive enzymes controlling the rate of gluconeogenesis.