Actions of extracellular UTP and ATP in perfused rat liver

Abstract

1. In perfused rat liver infusion of UTP and ATP in micromolar concentrations increased the portal pressure, with UTP being three times more effective than ATP at concentrations below 50 pM. Whereas ATP (up to 100 pM) increased oxygen consumption, there was a dose-dependent inhibition of oxygen uptake by UTP.2. Both nucleotides stimulated hepatic glucose output; however, the time-courses were different. Withdrawal of UTP, but not of ATP (up to 100 pM) caused a further transient, but substantial stimulation of glucose output.3. ATP led to a transient net K + uptake by the liver being followed by a K+-release phase. Similar changes were observed with UTP; however, the initial K + uptake was prolonged compared to ATP (1.9 min versus 3.5 min) and withdrawal of UTP, but not of ATP, stimulated hepatic K + release markedly.4. Metabolic and hemodynamic effects comparable to those induced by ATP were obtained with j-and y-thio substituted ATP, whereas p,y-methylene-substituted ATP was much less effective. The characteristic effects of UTP on glucose output, portal pressure and K + fluxes were preserved during constant infusion of ATP or its p,ymethylene derivative, pointing to additive effects.5. ATP (20 pM) led to a net Ca2' release (50-60 nmol/g liver) within 2-3 min. When the extracellular Ca2+ concentration was lowered from 1.25 mM to 0.3 mM, this Ca2+ release was increased to about 110 nmol/g liver whereby its time course remained largely unchanged. With 1.25 mM Ca2+, UTP induced Ca2+ movements only near the detection level (i.e. below 10-20 nmol/g liver); however, with 0.3 mM Ca2' in influent perfusate, there was a slow Ca2+ release (not completed within 5 -6 min). The maximal rates of Ca2+ efflux following ATP and UTP (20 pM each) were 70 nmol and 30 nmol g-' min-'. Withdrawal of UTP led to a short Ca2+ release superimposing a phase of net Ca2+ uptake.6 . The data show that extracellular UTP is a potential and effective regulator of hepatic metabolism, ion fluxes across the hepatocyte membrane and hemodynamics. Compared to ATP, UTP seems to be more effective and the responses to both nucleotides are different. The data suggest that the action of UTP could involve a receptor distinct from the purinergic Pz receptor, whereas the ATP action involves predominantly the Pzy purinoceptor sub type. [6]. However, these studies were carried out with unphysiologically low extracellular Ca2+ concentrations (50 pM) and it was shown in perfused rat liver that the pattern of net Ca2+ movements across the plasma membrane following the addition of Ca2+-mobilizing hormones such as phenylephrine or vasopressin, strongly depends on the extracellular Ca2 ' concentration [23].Only a few data are available on the effects of other extracellular nucleotides. In perfused rat liver ITP, GTP and GDP caused similar changes of hepatic metabolism compared to ATP, but were 10-20 times less potent than ATP [6]. In Ehrlich ascites tumor cells ITP, UTP or GTP induced Ca2' transients identical with those observed with ATP, whereas CTP and TTP were ...

The ecto-nucleoside triphosphate diphosphohydrolase NTPDase2/CD39L1 is expressed in a novel functional compartment within the liver

“…These include bile ductular secretion, 2,4,25,26 regulatory cell volume changes, [27][28][29] carbohydrate metabolism, 30 and hepatocyte canalicular contractility, 31 to name a few. Extracellular nucleotides induce downstream changes in liver cells through activation of P2Y (and perhaps P2X) nucleotide receptors.…”

Regulation of transepithelial ion transport and intracellular calcium by extracellular ATP in human normal and cystic fibrosis airway epithelium

“…Extracellular adenosine triphosphate (ATP) has been shown to regulate a variety of biological processes including nonvascular smooth muscle contraction (Maguire & Satchell, 1979;Brown & Burnstock, 1981) and vascular tone (Burnstock & Kennedy, 1986;Haeussinger et al, 1987), platelet aggregation (Born & Kratzer, 1984), neurotransmission (Burnstock, 1971;Burnstock & Sneddon, 1985), and cellular ion transport (Burgess et al, 1979;Gallacher, 1982) and secretory activities (Chapal & Loubatieres-Mariani, 1981;Pearson et al, 1983). These effects are mediated by specific purinoceptors which respond to ATP or other nucleotides present in the extracellular millieu (Gordon, 1986).…”

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.…”

“…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). It must be noted, however, that if some effects are shared among the adenine nucleotide family, others appear to be specific (12,14,18), suggesting that different signaling pathways may be involved.…”