Actions of the novel antidiabetic agent englitazone in rat hepatocytes
| Autor: | R. Kirk McPherson, Peter F. Blackmore, R W Stevenson |
|---|---|
| Rok vydání: | 1993 |
| Předmět: |
Male
medicine.medical_specialty Glycogenolysis Vasopressins Endocrinology Diabetes and Metabolism Biology Glucagon Rats Sprague-Dawley chemistry.chemical_compound Glycogen phosphorylase Adenosine Triphosphate Endocrinology Internal medicine Cyclic AMP medicine Animals Hypoglycemic Agents Benzopyrans Phosphorylase a Cyclic adenosine monophosphate Cells Cultured Dose-Response Relationship Drug Gluconeogenesis Phosphodiesterase Englitazone Rats Kinetics Thiazoles Liver chemistry Mechanism of action Calcium Thiazolidinediones medicine.symptom |
| Zdroj: | Metabolism. 42:1583-1587 |
| ISSN: | 0026-0495 |
| Popis: | We examined effects of a novel antidiabetic agent, racemic englitazone (CP 68,722, Pfizer), on normal rat hepatocytes in vitro. For optimal effects, CP 68,722 must be preincubated for approximately 20 minutes. CP 68,722 inhibited the actions of glucagon on glycogenolysis (measured by monitoring cyclic adenosine monophosphate [cAMP] levels, phosphorylase activation, and glucose output) and gluconeogenesis (from 14 C-lactate). Since CP 68,722 was able to attenuate the ability of glucagon to increase cAMP levels, this may account for part of its inhibitory actions on glucogenolysis and gluconeogenesis. The observation that CP 68,722 also inhibits the ability of the cAMP analog, 8-(4-chlorophenylthio)-adenosine 3′:5′-cyclic monophosphate (8 CPT cAMP), to stimulate phosphorylase a is consistent with an effect of CP 68,722 to activate cAMP-dependent phosphodiesterase. The ability of vasopressin (an agonist known to stimulate glycogenolysis via a Ca 2+ -dependent mechanism) to stimulate phosphorylase a was slightly inhibited by CP 68,722. Another site of action of CP 68,722 was to inhibit hormonal-mediated Ca 2+ influx, an effect that would decrease intracellular free calcium ([Ca 2+ ] i ), thereby inhibiting the actions of the Ca 2+ -dependent hormones such as α 1 -adrenergic agonists and vasopressin, agents known to promote glucose output from the liver. In summary, CP 68,722 inhibits glucagon-stimulated glycogenolysis and gluconeogenesis in hepatocytes by a mechanism that may include activation of cAMP phosphodiesterase and inhibition of Ca 2+ influx. |
| Databáze: | OpenAIRE |
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