Stimulation of glycogenolysis by adenine nucleotides in the perfused rat liver

Abstract

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 rat liver glycogen synthesis by the adenosine kinase inhibitor 5-iodotubercidin

“…ATP and adenosine are known to affect the activity state of synthase and phosphorylase [4][5][6]11,15,32,[38][39][40]. Adenosine has been reported to activate adenylate cyclase in the livers from fed rats [4][5][6]32,33] whereas other groups failed to observe an increase in cyclic AMP in the presence of adenosine in livers of fasted rats [11,15].…”

“…Itu has been used to distinguish between the effects of adenosine and its phosphorylated products [4]. Adenosine interacts with P1-receptors that activate adenylate cyclase, whereas ATP interacts with P2 -receptors and evokes a transient Ca2+-response [4][5][6]. Itu alone has no effects on P1-or P2-receptors [3,4].…”

Exogenous Mg-ATP Induces a Large Inhibition of Pyruvate Kinase in Intact Rat Hepatocytes

“…It is well known that purinergic receptor activation is responsible for a large variety of metabolic effects (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). ATP or adenosine or several analogues of purinergic receptors have been noted to affect liver glucose metabolism: i.e.…”

“…ATP or adenosine or several analogues of purinergic receptors have been noted to affect liver glucose metabolism: i.e. stimulation of glycogenolysis (12,13), increase (19,25,26) or decrease (11) of gluconeogenesis, and decrease of glycolysis (25). These effects have been related to a cAMP-dependent mechanism (12), a cAMP-independent inositol 3-phosphate/calcium-mediated signaling (13,14,16,18,21,23), a phospholipase C activation (18), or a transcriptional effect (25).…”

Possible involvement of eicosanoids in the actions of sympathetic hepatic nerves on carbohydrate metabolism and hemodynamics in perfused rat liver

“…Therefore, the nerve effects were compared to the actions of noradrenaline, the accepted sympathetic neurotransmitter, and of ATP, a possible sympathetic 'cotransmitter' [23]. In perfused liver noradrenaline has been shown previously to increase glucose and lactate output and to decrease perfusion flow under an enforced constant pressure [5-71 or to increase portal pressure at constant flow [lo]; similarly, ATP has been reported to increase glucose output and portal pressure [24,25].…”