Effects of quinacrine on vasopressin-induced changes in glycogen phosphorylase activity, Ca2+ transport and phosphoinositide metabolism in isolated hepatocytes.
In isolated hepatocytes, quinacrine (150-250 microM) inhibited vasopressin-induced increases in glucose release, glycogen phosphorylase a activity and 45Ca2+ efflux; and glucagon-induced increases in glucose release and cyclic AMP formation. These results indicate that a phospholipase A2 enzyme sensitive to quinacrine is unlikely to be involved in the process by which vasopressin stimulates glycogen phosphorylase activity in the liver cell. In cells labelled with [3H]inositol, much lower concentrations of quinacrine (20-50 microM) inhibited the stimulation by vasopressin of the accumulation of [3H]inositol. The drug had little effect on vasopressin-induced accumulation of [3H]inositol mono-, bis- and tris-phosphates. In the absence of vasopressin, higher concentrations of quinacrine caused a small stimulation of glycogen phosphorylase activity, 45Ca2+ release and the formation of [3H]inositol polyphosphates. Quinacrine did not inhibit the degradation by liver homogenates of inositol 1-phosphate, inositol 4,5-bisphosphate or inositol 1,4,5-trisphosphate. It is concluded that concentrations of quinacrine comparable with those which inhibit phospholipase A2 [G.J. Blackwell, W.G. Duncombe, R.J. Flower, M.F. Parsons and J.R. Vane, Br. J. Pharmac. 59, 353-366 (1977)] inhibit the stimulation by vasopressin of inositol utilization without significantly affecting coupling between hormone receptors and adenyl cyclase or phosphoinositide-specific phosphodiesterase, the action of the phosphodiesterase, and the degradation of inositol triphosphate.
Barritt
G J
GJ
Department of Medical Biochemistry, Flinders University School of Medicine, Bedford Park, South Australia.
Milton
S E
SE
Hughes
B P
BP
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D004837:Epinephrine / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism*; D010762:Phosphorylase a / Q000378:metabolism*; D006005:Phosphorylases / Q000378:metabolism*; D011796:Quinacrine / Q000494:pharmacology*; D051381:Rats; D014667:Vasopressins / Q000494:pharmacology*
D010716:Phosphatidylinositols; D014667:Vasopressins; D005934:Glucagon; D010762:Phosphorylase a; D006005:Phosphorylases; D011796:Quinacrine; D002118:Calcium; D004837:Epinephrine