Inhibition of hormonal activation of hepatic phosphorylase by chlorpropamide: evidence for an intracellular site of drug action.

Phosphorylase a activity was measured in hepatocytes from fed rats, some of which received ip chlorpropamide injections for 5 days preceding death (20 mg/100 g BW X day for 5 days). Chlorpropamide treatment significantly depressed basal phosphorylase a activity and lessened the increments in the activity of this enzyme induced by 10(-10) -10(-8) M glucagon and arginine vasopressin. The reductions in phosphorylase a activity after treatment with chlorpropamide were more than sufficient to explain the accompanying decreases in hepatic glucose production. Since glucagon and arginine vasopressin stimulate alternate pathways of phosphorylase activation and since chlorpropamide antagonizes both hormones, it is likely that the drug acts at or distal to the intracellular site (phosphorylase kinase) at which the two activation pathways converge.