Effect of nonsteroidal anti-inflammatory drugs on glycogenolysis in isolated hepatocytes.
E-series prostaglandins have previously been demonstrated to inhibit hormone-stimulated glycogenolysis when added to isolated hepatocytes of the rat. In the present study, the effect of nonsteroidal anti-inflammatory drugs, which inhibit cyclo-oxygenase activity, on glycogenolysis was examined in the hepatocyte model. Ibuprofen (80 microM), indomethacin (50 microM) and meclofenamate (60 microM) all increased rates of glycogenolysis when added under basal conditions. In contrast, piroxicam (50 microM) had no effect on glycogenolysis in the hepatocyte system. Concentrations of ibuprofen below 80 microM did not significantly increase rates of glycogenolysis. Ibuprofen (80 microM) had no effect on glycogenolysis in the presence of 10(-5)M adrenaline or 5 X 10(-7)M glucagon, but did increase glycogenolytic rates in the presence of 5 X 10(-8)M glucagon. Ibuprofen-stimulated glycogenolysis was inhibited by addition of prostaglandin E2 (PGE2). Under conditions where glucagon-stimulated glycogenolysis was inhibited by exogenous PGE2, addition of ibuprofen (80 microM) increased the rate of glycogenolysis. Ibuprofen had no effect on basal or glucagon-stimulated hepatocyte adenylate cyclase activity. In conclusion, these results demonstrate that nonsteroidal anti-inflammatory drugs which are carboxylic acids can increase the rate of glycogenolysis in isolated hepatocytes. The high concentrations of drug required to stimulate glycogenolysis, the lack of effect of piroxicam, and the demonstration of stimulation by ibuprofen in the presence of exogenous PGE2 all suggest that the stimulation of glycogenolysis by ibuprofen, indomethacin and meclofenamate is independent of cyclooxygenase inhibition. These observations are consistent with reports that carboxylic acid nonsteroidal anti-inflammatory drugs can interfere with hepatic intracellular calcium handling.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000201:enzymology; D015232:Dinoprostone; D005934:Glucagon / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D011458:Prostaglandins E / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000893:Anti-Inflammatory Agents; D008112:Liver Glycogen; D011458:Prostaglandins E; D005934:Glucagon; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D007052:Ibuprofen