Mechanisms involved in alpha-adrenergic effects of catecholamines on liver metabolism.

Recent results have indicated that alpha-adrenergic receptors are the major mediators of catecholamine actions on liver metabolism in several species. It is well-established that cAMP and cAMP-dependent protein kinase are not involved in hepatic alpha-adrenergic effects. This review presents evidence that alpha-adrenergic stimulation of glycogenolysis in rat liver involves the mobilization of Ca2+ ions from mitochondria and stimulation of phosphorylase kinase by the resulting increase in cytosolic Ca2+ concentration.

Mechanisms of catecholamine actions on liver carbohydrate metabolism.

Epinephrine rapidly activates phosphorylase in hepatocytes, mainly by a mechanism(s) involving alpha-adrenergic and not beta-adrenergic receptors. The alpha-adrenergic mechanism does not involve accumulation of cAMP or activation of cAMP-dependent protein kinase. It is impaired when hepatocytes are depleted of calcium by EGTA treatment and is rapidly restored by readdition of calcium.

Gluconeogenesis in the suckling rat.

Gluconeogenesis from lactate was increased more than twofold in perfused livers and isolated hepatocytes from 10- and 15-day-old suckling rats compared with adult rats and was not increased by fasting. Glucagon (10(-19)-10(-7) M) induced minimal activation of gluconeogenesis in hepatocytes from such animals even though it promoted accumulation of cAMP. Suckling rats had low plasma insulin levels and high plasma glucagon levels.

Studies on alpha-adrenergic activation of hepatic glucose output. Studies on role of calcium in alpha-adrenergic activation of phosphorylase.

The role of Ca2+ ions in alpha-adrenergic activation of hepatic phosphorylase was studied using isolated rat liver parenchymal cells. The activation of glucose release and phosphorylase by the alpha-adrenergic agonist phenylephrine was impaired in cells in which calcium was depleted by ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid (EGTA) treatment and restored by calcium addition, whereas the effects of a glycogenolytically equivalent concentration of glucagon on these processes were unaffected. EGTA treatment also reduced basal glucose release and phosphorylase alpha activity, but did not alter the level of cAMP or the protein kinase activity ratio (-cAMP/+cAMP) or impair viability as determined by trypan blue exclusion, ATP levels, or gluconeogenic rates.

Studies on the role of cAMP-dependent protein kinase in the actions of glucagon and catecholamines on liver glycogen metabolism.

Glucagon causes a rapid activation of cAMP-dependent protein kinase in rat liver parenchymal cells which correlates well with the accumulation of cAMP. Full activation of phosphorylase or inactivation of glycogen synthase is achieved with half-maximal or less activation of protein kinase. Epinephrine stimulates glycogen breakdown in these cells mainly by mechanisms involving alpha-adrenergic receptors and not beta-receptors.

Studies on the alpha-andrenergic activation of hepatic glucose output. II. Investigation of the roles of adenosine 3':5'-monophosphate and adenosine 3':5'-monophosphate-dependent protein kinase in the actions of phenylephrine in isolated hepatocytes.

The effects of the alpha-adrenergic agonist phenylephrine on the levels of adenosine 3':5'-monophosphate (cAMP) and the activity of the cAMP-dependent protein kinase in isolated rat liver parenchymal cells were studied. Cyclic AMP was very slightly (5 to 13%) increased in cells incubated with phenylephrine at a concentration (10(-5) M) which was maximally effective on glycogenolysis and gluconeogenesis. However, the increase was significant only at 5 min.

Studies on the alpha-adrenergic activation of hepatic glucose output. I. Studies on the alpha-adrenergic activation of phosphorylase and gluconeogenesis and inactivation of glycogen synthase in isolated rat liver parenchymal cells.

Epinephrine and the alpha-adrenergic agonist phenylephrine activated phosphorylase, glycogenolysis, and gluconeogenesis from lactate in a dose-dependent manner in isolated rat liver parenchymal cells. The half-maximally active dose of epinephrine was 10-7 M and of phenylephrine was 10(-6) M. These effects were blocked by alpha-adrenergic antagonists including phenoxybenzamine, but were largely unaffected by beta-adrenergic antagonists including propranolol.

Carbohydrate metabolism in perfused livers of adrenalectomized and steroid-replaced rats.

In livers from fasted rats perfused with bicarbonate buffer containing bovine albumin and erythrocytes, adrenalectomy decreased glycogen levels and glucose production, impaired the incorporation of 14C from [14C]lactate into glucose or glycogen, and decreased the activity of the active (I) form of glycogen synthase. Cortisol treatment restored gluconeogenesis after 1 h and glycogen synthesis after 2 h. Adrenalectomy did not alter the production of glucose or lactate or the levels of gluconeogenic intermediates in livers from fasted rats perfused with fructose, but reduced the formation of glycogen from this substrate.

Hepatic metabolism of genetically diabetic (db/db) mice. I. Carbohydrate metabolism.

Hepatic carbohydrate metabolism in genetically diabetic mice (db/db) and their normal littermates has been studied. In db/db mice, body water was below normal and declined with age. The liver of db/db mice was abnormally large in relation to the metabolic mass of the body at all ages studied.

Role of cyclic AMP in the actions of catecholamines on hepatic carbohydrate metabolism.

Studies using perfused rat liver and isolated liver parenchymal cells show that low concentrations of epinephrine, norepinephrine, and phenylephrine can activate glycogenolysis and gluconeogenesis by a mechanism mediated by alpha-adrenergic receptors and not involving accumulation of cAMP. The glycogenolytic and gluconeogenic activites of epinephrine, norepinephrine, and phenylephrine are inhibited by the alpha-adrenergic receptor antagonists phentolamine and dihydroergotamine, but are negligibly affected by the beta-adrenergic receptor antagonist propranolol. Epinephrine, norephinephrine, and the beta-adrenergic receptor agonists isoproterenol, soterenol, and salbutamol increase cAMP accumulation; and this effect is antagonized by propranolol.