The induction of glycogenolysis in the perfused liver by platelet activating factor is mediated by prostaglandin D2 from Kupffer cells

Induction of glycogenolysis in the perfused liver by platelet activating factor (PAF) was blocked by the cyclooxygenase inhibitor indomethacin. 3H-labeled PAF was shown to interact in the perfused liver primarily with Kupffer cells. The addition of PAF to Kupffer cells resulted in a dose-dependent stimulation of prostaglandin D2 (PGD2) production, which was identified as the main eicosanoid formed after PAF stimulation of the Kupffer cells. PGD2 was able to induce a dose-dependent stimulation of glycogenolysis both in the perfused liver and in isolated parenchymal cells. The time-dependency of the PGD2 production and the glucose output by the perfused liver is consistent with a primary interaction of PAF with the Kupffer cells, followed by PGD2 formation, which subsequently stimulates glucose production in parenchymal cells.     

Possible involvement of cyclooxygenase products in the actions of platelet-activating factor and of lipoxygenase products in the vascular effects of epinephrine in perfused rat liver

Platelet-activating factor (PAF) stimulates glycogenolysis and induces vasoconstriction in perfused rat liver. The effect of PAF was rapid but transient and it was blocked by indomethacin and bromophenacyl bromide which suggests a role of cyclooxygenase metabolites in its action. The homologous desensitization of glycogenolysis produced by PAF and the sensitivity of its actions to inhibitors of cyclooxygenase and phospholipase A2 markedly differentiate the mechanism of action of this agent with that of alpha 1-adrenergic agents, vasopressin or angiotensin II. No effect of PAF in isolated hepatocytes was observed which suggest that cells other than hepatocytes could be involved in its action in perfused liver. In addition nordihydroguaiaretic acid and bromophenacyl bromide abolished the vascular effect (but not the glycogenolysis) produced by epinephrine which suggest a role for lipoxygenase products in this effect.     

Stimulation of glycogenolysis and vasoconstriction in the perfused rat liver by the thromboxane A2 analogue U-46619

Infusion of the thromboxane A2 analogue U-46619 into isolated perfused rat livers resulted in dose-dependent increases in glucose output and portal vein pressure, indicative of constriction of the hepatic vasculature. At low concentrations, e.g. less than or equal to 42 ng/ml, glucose output occurred only during agonist infusion; whereas at concentrations greater than or equal to 63 ng/ml, a peak of glucose output also was observed upon termination of agonist infusion coincident with relief of hepatic vasoconstriction. Effluent perfusate lactate/pyruvate and beta-hydroxybutyrate/acetoacetate ratios increased significantly in response to U-46619 infusion. Hepatic oxygen consumption increased at low U-46619 concentrations (less than or equal to 20 ng/ml) and became biphasic with a transient spike of increased consumption followed by a prolonged decrease in consumption at higher concentrations. Increased glucose output in response to 42 ng/ml U-46619 was associated with a rapid activation of glycogen phosphorylase, slight increases in tissue ADP levels, and no increase in cAMP. At 1000 ng/ml, U-46619 activation of glycogen phosphorylase was accompanied by significant increases in tissue levels of AMP and ADP, decreases in ATP, and slight increases in cAMP. In isolated hepatocytes, U-46619 did not stimulate glucose output or activate glycogen phosphorylase. Reducing the perfusate calcium concentration from 1.25 to 0.05 mM resulted in a marked reduction of the glycogenolytic response to U-46619 (42 ng/ml) with no efflux of calcium from the liver. U-46619-induced glucose output and vasoconstriction displayed a similar dose dependence upon the perfusate calcium concentration. Thus, U-46619 exerts a potent agonist effect on glycogenolysis and vasoconstriction in the perfused rat liver. The present findings support the concept that U-46619 stimulates hepatic glycogenolysis indirectly via vasoconstriction-induced hypoxia within the liver.     

Effects of nitric oxide on platelet-activating factor- and alpha-adrenergic-stimulated vasoconstriction and glycogenolysis in the perfused rat liver.

Effects of nitric oxide (NO) on hemodynamic and glycogenolytic responses to platelet-activating factor (PAF) and phenylephrine were investigated in perfused livers derived from fed rats. Infusion of NO (34 microM) into perfused livers inhibited PAF (0.22 nM)-induced increases in hepatic glucose output and portal pressure approximately 90 and 85%, respectively, and abolished effects of PAF on hepatic oxygen consumption. NO attenuated PAF-stimulated increases in glucose output and portal pressure, the latter indicative of hepatic vasoconstriction, with a similar dose dependence with an IC50 of approximately 8 microM. In contrast to its effects on PAF-induced responses in the perfused liver, NO inhibited increases in hepatic portal pressure in response to phenylephrine (10 microM) approximately 75% without altering phenylephrine-stimulated glucose output and oxygen consumption. Similarly, infusion of NO into perfused livers significantly inhibited increases in hepatic portal pressure but not in glucose output in response to a submaximal concentration of phenylephrine (0.4 microM). Like NO, sodium nitroprusside (83 microM) significantly inhibited hemodynamic but not glycogenolytic responses to phenylephrine in perfused livers. However, PAF (0.22 nM)-stimulated alterations in hepatic portal pressure, glucose output, and oxygen consumption were unaffected by infusion of sodium nitroprusside (83 microM) into perfused livers. These results provide the first evidence for regulatory effects of NO in the perfused liver and support the contention that PAF, unlike phenylephrine, stimulates glycogenolysis by mechanisms secondary to hepatic vasoconstriction. These observations raise the intriguing possibility that NO may act in liver to regulate hemodynamic responses to vasoactive mediators.     

Relative contribution of glycogenolysis and gluconeogenesis to basal, glucagon- and nerve stimulation-dependent glucose output in the perfused liver from fed and fasted rats

The relative contribution to basal, glucagon- and nerve stimulation-enhanced glucose output of glycogenolysis (glucose output in the presence of the gluconeogenic inhibitor mercaptopicolinate) and gluconeogenesis (difference in glucose output in the absence and presence of the inhibitor) was investigated in perfused livers from fed rats with high and from fasted animals with low levels of glycogen. 1) Basal glucose output in both states was due only to gluconeogenesis. 2) Glucagon-enhanced glucose output was due about equally to glycogenolysis and gluconeogenesis in the fed state, but predominantly to gluconeogenesis (80%) in the fasted state. 3) Nerve stimulation-increased glucose output was due mainly to glycogenolysis (65%) in the fed state and about equally to both processes in the fasted state. The results suggest that under basal conditions of normal demands the liver supplies glucose only via gluconeogenesis and thus spares its glycogen stores, and that in situations of enhanced demands signalled by an increase in glucagon or sympathetic tone the liver liberates glucose mainly via glycogenolysis.     

Stimulation of glycogenolysis by adenine nucleotides in the perfused rat liver.

Infusion of adenine nucleotides and adenosine into perfused rat livers resulted in stimulation of hepatic glycogenolysis, transient increases in the effluent perfusate [3-hydroxybutyrate]/[acetoacetate] ratio, and increased portal vein pressure. In livers perfused with buffer containing 50 microM-Ca2+, transient efflux of Ca2+ was seen on stimulation of the liver with adenine nucleotides or adenosine. ADP was the most potent of the nucleotides, stimulating glucose output at concentrations as low as 0.15 microM, with half-maximal stimulation at approx. 1 microM, and ATP was slightly less potent, half-maximal stimulation requiring 4 microM-ATP. AMP and adenosine were much less effective, doses giving half-maximal stimulation being 40 and 20 microM respectively. Non-hydrolysed ATP analogues were much less effective than ATP in promoting changes in hepatic metabolism. ITP, GTP and GDP caused similar changes in hepatic metabolism to ATP, but were 10-20 times less potent than ATP. In livers perfused at low (7 microM) Ca2+, infusion of phenylephrine before ATP desensitized hepatic responses to ATP. Repeated infusions of ATP in such low-Ca2+-perfused livers caused homologous desensitization of ATP responses, and also desensitized subsequent Ca2+-dependent responses to phenylephrine. A short infusion of Ca2+ (1.25 mM) after phenylephrine infusion restored subsequent responses to ATP, indicating that, during perfusion with buffer containing 7 microM-Ca2+, ATP and phenylephrine deplete the same pool of intracellular Ca2+, which can be rapidly replenished in the presence of extracellular Ca2+. Measurement of cyclic AMP in freeze-clamped liver tissue demonstrated that adenosine (150 microM) significantly increased hepatic cyclic AMP, whereas ATP (15 microM) was without effect. It is concluded that ATP and ADP stimulate hepatic glycogenolysis via P2-purinergic receptors, through a Ca2+-dependent mechanism similar to that in alpha-adrenergic stimulation of hepatic tissue. However, adenosine stimulates glycogenolysis via P1-purinoreceptors and/or uptake into the cell, at least partially through a mechanism involving increase in cyclic AMP. Further, the hepatic response to adenine nucleotides may be significant in regulating hepatic glucose output in physiological and pathophysiological states.     

Stimulation of hepatic glycogenolysis by 12-O-tetradecanoylphorbol-13-acetate (TPA) via a calcium requiring process

12-O-Tetradecanoylphorbol-13-acetate (TPA) stimulated glycogenolysis in perfused rat liver which was perfused with Krebs-Ringer-bicarbonate buffer containing 1 mM CaCl2 but no substrate. Verapamil (100 microM), diltiazem (100 microM) and trifluoperazin (100 microM), all inhibited the effect of TPA in the presence of CaCl2. Omission of CaCl2 from the perfusate or the addition of EGTA markedly attenuated the effect of TPA. TPA decreased net release of 45Ca from 45Ca-preloaded liver. The effect of maximal concentration of TPA (20 ng/ml) was not additive to that of 0.6 microM A23187. These data suggest that TPA increases calcium influx into hepatocytes and stimulates glycogenolysis through a calcium-calmodulin dependent mechanism.     

Endotoxin stimulates glycogenolysis in the liver by means of intercellular communication

Escherichia coli endotoxin (lipopolysaccharide) was shown to increase glycogenolysis in the perfused liver 2-3-fold. In isolated parenchymal liver cells, however, endotoxin did not influence glycogenolysis, whereas stimulation by endotoxin of glycogenolysis in the perfused liver could be blocked by aspirin. This suggests that the effect of endotoxin on liver glycogenolysis is mediated by eicosanoids. The amount of prostaglandin D2 (which is the major prostanoid formed by Kupffer cells) in the liver perfusates was increased 5-fold upon endotoxin addition, with a time course which preceded the increase in glucose output. It is concluded that endotoxin stimulates glycogenolysis in the liver by stimulating prostaglandin D2 release from Kupffer cells, with a subsequent activation of glycogenolysis in parenchymal liver cells. This mechanism of intercellular communication may be designed to provide the carbohydrate source of energy necessary for the effective destruction of invaded microorganisms, by phagocytic cells, including the Kupffer cells.     

The influence of hypothyroidism on the adrenergic stimulation of glycogenolysis in perfused rat liver

The ability of noradrenaline (1 microM), phenylephrine (10 microM), and isoproterenol (1 microM) to stimulate glycogenolysis in euthyroid and hypothyroid perfused rat livers was investigated. It was found that hypothyroidism severely impaired alpha-receptor-mediated (noradrenaline, phenylephrine) glucose release. The initial Ca2+ efflux and K+ influx induced by these agonists in the euthyroid control group were almost totally absent in the hypothyroid group, while glycogen phosphorylase a activity in the hypothyroid rat livers was markedly lower than in the controls after infusing noradrenaline for 1 min. Diminished CA2+ efflux (and possibly diminished K+ influx) is likely to play a role in the large impairment in the action of noradrenaline or phenylephrine on glycogenolysis in the perfused hypothyroid rat liver. After prolonged stimulation (15 min) with noradrenaline, however, the phosphorylase a activity in the hypothyroid and euthyroid groups did not differ significantly. This was accompanied by Ca2+ influx in the hypothyroid livers, probably facilitated by a beta-adrenergic effect of noradrenaline in this group. Hypothyroidism potentiated the effect of isoproterenol on glycogenolysis. The glucose 6-phosphate content in the hypothyroid rat livers was markedly higher than in the euthyroid group after stimulation by noradrenaline or isoproterenol.     

Regulation of glycogenolysis in the liver of the newborn rat in vivo inhibitory effect of glucose

Newborn rats were injected immediately after delivery with glucose or glucose plus mannoheptulose, and the time-courses of liver glycogen, plasma glucose, insulin and glucagon concentration were studied. The administration of glucose prevented both liver glycogenolysis and the increase in plasma glucagon concentration which normally occurs immediately after delivery. In addition, the administration of glucose prevented the decrease of plasma glucose and insulin concentration which normally occurs during the first hour of extrauterine life. Supplementation of glucose with mannoheptulose prevented the increase of plasma insulin concentrations caused by the administration of glucose; liver glycogenolysis, however, was not stimulated in these circumstances. The increase in the rate of glycogenolysis caused by the administration of glucagon was prevented in newborn rats previously treated with glucose. These results suggest that glucose exerts an inhibitory effect on the stimulation of neonatal liver glycogenolysis by glucagon.     

Prostaglandin D2 mediates the stimulation of glycogenolysis in the liver by phorbol ester.

The tumour-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), when added to the perfused liver, stimulates glycogenolysis 2-fold. This stimulation is not seen when aspirin is present in the perfusion medium. In isolated parenchymal liver cells. PMA is not able to stimulate glycogenolysis, suggesting that its effect on glycogenolysis might be indirect and depends on the presence of the non-parenchymal liver cell types. To test the possible operation of an indirect mechanism, we measured the amount of prostaglandin (PG) D2 in liver perfusates. After addition of PMA, the amount of PGD2 is doubled, in parallel with the increase in glycogenolysis. Glycogenolysis in both isolated parenchymal liver cells and perfused liver could be stimulated by the addition of PGD2. Our data indicate that stimulation of glycogenolysis in the liver by PMA may be mediated by non-parenchymal liver cells, which produce PGD2 in response to PMA. Subsequently PGD2 activates glycogenolysis in the parenchymal liver cells. The intercellular communication inside the liver in response to PMA adds a new mechanism to the complex regulation of glucose homoeostasis by the liver.     

Attenuation of platelet activating factor (PAF)-induced stimulation of rabbit platelet GTPase by phorbol ester, dibutyryl cAMP, and desensitization: concomitant effects on PAF receptor binding characteristics

The GTPase activities of rabbit platelet membrane were stimulated by platelet activating factor (PAF) in a receptor-mediated manner. The activities of the GTPase were investigated in the platelets which had been pretreated with tetradecanoyl phorbol acetate (TPA), dibutyryl cAMP, and PAF. The specific binding of PAF to intact platelet cells was also determined in these treated cells. In platelets which had been pretreated with PAF and then specifically desensitized to PAF, higher concentrations were required for stimulation of the receptor-coupled GTPase. In addition the extent of stimulation of the GTPase by PAF was also decreased. By contrast thrombin stimulation of GTPase activity was unaffected by this process. In platelets pretreated with high levels of dibutyryl cAMP (greater than 4 mM), the specific binding of PAF was reduced to nearly 50% of the control. Although this specific binding apparently was not inhibited by lower concentrations of dibutyryl cAMP (less than 2 mM), PAF could stimulate the receptor-coupled GTPase only to a much lower extent in these treated cells. TPA had virtually no effect on PAF specific binding. However, higher concentrations were needed for stimulation of the GTPase. On the other hand, the extent of PAF stimulation of the GTPase was not altered. Interestingly in the TPA-treated platelet membrane, thrombin stimulated GTPase activity to a higher level than that in untreated platelet membrane. Thus, TPA, dibutyryl cAMP, and desensitization affected the PAF receptor binding and the receptor-coupled GTPase activities in a characteristic fashion. The molecular mechanisms of these effects are discussed.     

Phorbol esters inhibit alpha1 adrenergic stimulation of glycogenolysis in isolated rat hepatocytes

Tumor promoting phorbol esters can stimulate Ca⁺⁺-phospholipid-dependent protein kinase. It has been suggested that this enzyme may mediate the effects of calcium-dependent hormones. In this paper the effects of phorbol 12-myristate 13-acetate (TPA) on isolated rat hepatocyte metabolism were studied. Phorbol esters completely blocked alpha₁-adrenergic stimulation of glycogenolysis. This effect is quite specific for alpha₁-adrenergic actions, as the stimulations of glycogenolysis by vasopressin, angiotensin II, ionophore A-23187 and glucagon were unaffected by TPA. The potencies of the different phorbol esters used in this study suggests that the inhibitory effects of these agents may be due to activation of protein kinase C. The effect of phorbol esters on alpha₁-adrenergic actions seems to occur at an early step of the alpha₁-adrenergic action. TPA (10^?11–10^?6M) was unable to stimulate glycogenolysis. Urea synthesis, which is stimulated by vasopressin and alpha₁-adrenergic agents, was not stimulated by phorbol ester, neither alone nor in combination with the Ca⁺⁺ ionophore A-23187.     

Lack of effect of somatostatin on the stimulation of hepatic glycogenolysis by epinephrine in isolated canine hepatocytes

The effects of somatostatin on epinephrine's ability to stimulate glucose output have been examined in hepatocytes isolated from dogs fasted overnight. Half-maximal stimulation of phosphorylase a activity and glucose output occurred at an epinephrine concentration of approx. 5 X 10(-9) M. Somatostatin at 10, 100 or 1000 ng/ml had no effect on the ability of a maximal (1 X 10(-7) M) and a submaximal (1 X 10(-8) M) dose of epinephrine to activate phosphorylase at 2 min, or to stimulate glucose output over 20 min. Since the doses of somatostatin used in the present study are up to 50-fold higher than the blood concentrations commonly found when somatostatin is used in vivo to inhibit pancreatic hormone secretion, it seems unlikely that use of somatostatin in this way would affect stimulation of hepatic glycogenolysis by epinephrine in vivo.     

Hormonal control of glycogenolysis in parenchymal liver cells by Kupffer and endothelial liver cells

Conditioned media of isolated Kupffer and endothelial liver cells were added to incubations of parenchymal liver cells, in order to test whether secretory products of Kupffer and endothelial liver cells could influence parenchymal liver cell metabolism. With Kupffer cell medium an average stimulation of glucose production by parenchymal liver cells of 140% was obtained, while endothelial liver cell medium stimulated with an average of 127%. The separation of the secretory products of Kupffer and endothelial liver cells in a low and a high molecular weight fraction indicated that the active factor(s) had a low molecular weight. Media, obtained from aspirin-pretreated Kupffer and endothelial liver cells, had no effect on the glucose production by parenchymal liver cells. Because aspirin blocks prostaglandin synthesis, it was tested if prostaglandins could be responsible for the effect of media on parenchymal liver cells. It was found that prostaglandin (PG) E1, E2, and D2 all stimulated the glucose production by parenchymal liver cells, PGD2 being the most potent. Kupffer and endothelial liver cell media as well as prostaglandins E1, E2, and D2 stimulated the activity of phosphorylase, the regulatory enzyme in glycogenolysis. The data indicate that prostaglandins, present in media from Kupffer and endothelial liver cells, may stimulate glycogenolysis in parenchymal liver cells. This implies that products of Kupffer and endothelial liver cells may play a role in the regulation of glucose homeostasis by the liver.     

Stimulation of hepatic glycogenolysis by acetylglyceryl ether phosphorylcholine

1-O-Alkyl-2-acetyl-sn-glyceryl 3-phosphorylcholine or acetylglyceryl ether phosphorylcholine (AGEPC) stimulated glycogenolysis in perfused livers from fed rats at concentrations as low as 10(-11) M. At the lower AGEPC concentrations, e.g. 2 X 10(-10) M, a single transient phase of enhanced hepatic glucose output was elicited upon infusion of this agonist. At higher concentrations, e.g. 2 X 10(-8) M, a sharp transient spike of glucose output was observed, followed by a stable elevated steady state rate of glucose output until the AGEPC infusion was terminated. Increased rates of lactate and acetoacetate output and a diminished hepatic oxygen consumption were characteristic of the response of the livers to AGEPC at 2 X 10(-10) M. Neither alpha- nor beta-adrenergic antagonists blocked the glycogenolytic response of AGEPC. Repeated infusion of AGEPC led to homologous desensitization of the response, but the response of the liver to the alpha-adrenergic agonist, phenylephrine, or to glucagon, subsequent to AGEPC stimulation, was unaffected. Increasing the period of perfusion between successive additions of AGEPC, from 7 to 30 min, resulted in an increased glycogenolytic response to this agonist. When the perfusate calcium concentration was reduced from 1.25 to 0.05 mM, the glycogenolytic response to AGEPC was markedly diminished; calcium efflux from the liver following stimulation with AGEPC was not observed. The data presented in this study illustrate a potent agonist effect of AGEPC on the glycogenolytic system in the rat liver.     

Platelet-activating factor increases inositol phosphate production and cytosolic free Ca2+ concentrations in cultured rat Kupffer cells

Platelet-activating factor (PAF) stimulates glycogenolysis in perfused livers but not in isolated hepatocytes [(1984) J. Biol. Chem. 259, 8685-8688]. PAF-induced glycogenolysis in liver is associated closely with a pronounced constriction of the hepatic vasculature [(1986) J. Biol. Chem. 261, 644-649]. These and other observations suggest that PAF stimulates glycogenolysis in liver indirectly by interactions with cells other than hepatocytes. We have evaluated effects of PAF on hepatic Kupffer cells, which regulate flow through the hepatic sinusoids. Application of PAF to [3H]inositol-labeled Kupffer cells produced dose-dependent increases in [3H]inositol phosphates with an EC50 value of 4 x 10(-10) M. Increases in inositol phosphate production in response to PAF were inhibited by a specific PAF receptor antagonist, SRI 63-675 (2 x 10(-7) M), and stimulus of protein kinase C, phorbol 12-myristate 13-acetate (1 x 10(-7) M). Measurements of cytosolic free Ca2+ concentrations ([Ca2+]i) in single Kupffer cells loaded with Fura-2 demonstrated that application of PAF (2 x 10(-9) M) resulted in significant increases in [Ca2+]i. These observations lead us to propose that interactions of PAF with Kupffer cells may result in the hemodynamic and metabolic responses to PAF in liver.     

Endothelin, a potent peptide agonist in the liver

Endothelin, a peptide mediator produced by vascular endothelial cells, caused sustained vasoconstriction of the portal vasculature in the perfused rat liver. The vasoactive effect of endothelin was accompanied by increased glycogenolysis and alterations in hepatic oxygen consumption. The endothelin-induced increase in the portal pressure was concentration-dependent with an EC50 of 1 nM. Endothelin-induced hepatic glycogenolysis was dose-dependent but exhibited a different EC50 than for the vasoconstrictive effects of endothelin. Hepatic vasoconstriction and glycogenolysis following endothelin infusion were inhibited when Ca2+ was removed from the perfusion medium. The endothelin-induced responses in the liver were not altered by prior infusion of phenylephrine (alpha-adrenergic agonist), isoproterenol (beta-adrenergic agonist), angiotensin II, glucagon, platelet-activating factor, or the platelet-activating factor antagonist, BN52021. However, repeated infusion of endothelin resulted in desensitization of the glycogenolytic response but was without a significant effect on hepatic vasoconstriction. Endothelin also stimulated metabolism of inositol phospholipids in isolated hepatocytes and Kupffer cells in primary culture. The present experiments demonstrate, for the first time, that endothelin is a very potent agonist in the liver eliciting both a sustained vasoconstriction of the hepatic vasculature and a significant increase in hepatic glucose output.     

Non-hormonal and hormonal control of glycogen metabolism in isolated sheep liver cells

1. Control of glycogen metabolism by various substrates and hormones was studied in ruminant liver using isolated hepatocytes from fed sheep. 2. In these cells glucose appeared uneffective to stimulate glycogen synthesis whereas fructose and propionate activated glycogen synthase owing to (i) a decrease in phosphorylase a activity and (ii) changes in the intracellular concentrations of glucose 6-phosphate and adenine nucleotides. 3. The activation of hepatic glycogenolysis by glucagon and alpha 1-adrenergic agents was associated with increased phosphorylase a and decreased glycogen synthase activities. 4. The simultaneous changes in these two enzyme activities suggest that in sheep liver, activation of phosphorylase a is not a prerequisite step for synthase inactivation. 5. In sheep hepatocytes, in the presence of propionate and after a lag period, insulin activated glycogen synthase without affecting phosphorylase a. 6. This latter result suggests that the direct activation of glycogen synthase by insulin is mediated by a glycogen synthase-specific kinase or phosphatase. Insulin also antagonized glucagon effect on glycogen synthesis by counteracting the rise of cAMP.     

Effects of epinephrine and norepinephrine on glucose release from chinook salmon (Oncorhynchus tshawytscha) liver incubated in vitro

The effects of two catecholamines, epinephrine (EP) and norepinephrine (NE), on carbohydrate metabolism were studied by incubating chinook salmon liver in vitro. Basal release of glucose over the course of a 5-h incubation was 7.93 +/- 1.70 mumol/g dry weight. Both EP and NE (2 X 10(-7) M) stimulated glucose release rapidly during the first hour. After 5 h, EP and NE significantly increased glucose release over basal levels to 43.55 +/- 9.01 and 32.75 +/- 6.17 mumol/g dry weight, respectively. Epinephrine- and NE-stimulated glucose release was dose dependent, with a minimum effective dose of 10(-9) M. ED50 for both agents was approximately 2 X 10(-7) M; maximal stimulation occurred at 10(-5) M. No difference in potency between the two catecholamines was found. The effects of adrenergic agonists and antagonists were also studied. Alpha-agonists, methoxamine and phenylephrine, had no effect on glucose release. Isoproterenol, a beta-agonist, stimulated glucose release in a manner similar to EP. The beta-antagonist, propranolol, inhibited both catecholamine- and isoproterenol-stimulated glucose release. Alpha-antagonists (phentolamine, prazosin, and yohimbine) had no effect on either catecholamine- or isoproterenol-stimulated glucose release. Epinephrine and NE stimulate glycogen phosphorylase activity; propranolol inhibits catecholamine-stimulated phosphorylase activity. These results indicate that catecholamines stimulate glucose mobilization in salmon liver by promoting glycogenolysis mediated through beta-adrenergic receptors.