Actions of extracellular UTP and ATP in perfused rat liver

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 50μM. Whereas ATP (up to 100 μM) 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 μM) 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 β‐and γ‐thio substituted ATP, whereas β, γ‐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 β,γ‐methylene derivative, pointing to additive effects. 5. ATP (20 μM) led to a net Ca 2+ release (50–60 nmol/g liver) within 2–3 min. When the extracellular Ca 2+ concentration was lowered from 1.25 mM to 0.3 mM, this Ca 2+ release was increased to about 110 nmol/g liver whereby its time course remained largely unchanged. With 1.25 mM Ca 2+ , UTP induced Ca 2+ movements only near the detection level (i.e. below 10–20 nmol/g liver); however, with 0.3 mM Ca 2+ in influent perfusate, there was a slow Ca 2+ release (not completed within 5–6 min). The maximal rates of Ca 2+ efflux following ATP and UTP (20 μM each) were 70 nmol and 30 nmol g −1 min −1 . Withdrawal of UTP led to a short Ca 2+ release supcrimposing a phase of net Ca 2+ 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 P 2 receptor, whereas the ATP action involves predominantly the P 2Y purinoceptor subtype.