EFFECTS OF ADRENERGIC AGENTS ON CARBOHYDRATE METABOLISM OF RAT LIVER: ACTIVITIES OF ADENYL CYCLASE AND GLYCOGEN OHOSPHORYLASE

¹ Department of Pharmacology, Division of Basic Health Sciences, Emory University, Atlanta, Georgia

The metabolic response of rat liver to adrenergic agonists and antagonists was reinvestigated using both in vitro and in vivo preparations. Isoproterenol (I) was found to be as effective as epinephrine (E) in increasing the activity of rat liver adenyl cyclase in vitro when the agents were added to concentrated homogenates and in increasing the activity of glycogen phosphorylase in vivo when the agents were given in small doses by i.v. infusions. These findings contrast with previous reports of the ineffectiveness of I on hepatic glycogen metabolism in the rat. The order of potency of four sympathomimetic amines that stimulated adenyl cyclase was: I > E > norepinephrine > salbutamol (-[-butylamino) methyl]-4- hydroxy-m-xylene- , 3-diol). A similar order of potency was found for increased rat liver phosphorylase activity in vivo; however , E produced a greater maximal response than I. These latter responses were compared with those for increased phosphorylase activity in dog liver for which the order of potency was : E = salbutamol norepinephrine. In the rat, large s.c. doses of I or salbutamol did not increase the activity of liver phosphorylase and inhibited the effect of i.v. infusions of I or E. On the other hand, s.c. I markedly increased phosphorylase activity in the dog liven. Propranolol (10⁶ M) blocked completely the effects of I or E on adenvl cvclase from rat liver whereas 100-fold higher concentrations of ergotamine or phenoxy benzamine produced only partial inhibition. In the intact rat, propranolol (0.5 mg/kg) blocked the phosphorylase activation produced by I but not that produced by E. A 10-fold larger dose of propranolol substantially increased the hepatic phosphorylase activity which prevented further assessment of its ability to inhibit E. In contrast , low doses of propranolol (0.2 mg/kg) blocked the effects of both E and I on phosphorylase activity in dog liver. These findings suggest that the adnenergic metabolic receptor in rat liver is similar in its response to agonists and antagonists to those receptors in other tissues which have been classified as beta receptors and that previous reports of the ineffectiveness of I in the rat resulted from its apparent autoinhibitory effect on the hepatic receptor of this species.