Actions of extracellular UTP and ATP in perfused rat liver. A comparative study

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 microM. Whereas ATP (up to 100 microM) 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 microM) 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 beta- and gamma-thio substituted ATP, whereas beta,gamma-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 beta,gamma-methylene derivative, pointing to additive effects. 5. ATP (20 microM) 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 microM each) were 70 nmol and 30 nmol g-1 min-1. 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 P2 receptor, whereas the ATP action involves predominantly the P2Y purinoceptor subtype.