Effects of Leukotrienes and the Thromboxane A2Analogue U-46619 in Isolated Perfused Rat Liver. Metabolic, Hemodynamic and Ion-Flux Responses

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Abstract
1) Addition of leukotriene C4 to isolated perfused rat liver led to a stimulation of hepatic glucose output, a slight decrease of 14CO2 production from [1-14C] glutamate, an increase of portal pressure and an inhibition of hepatic oxygen uptake. Withdrawal of leukotriene C4 caused a transient further stimulation of hepatic glucose output. 2) These effects were accompanied by a slow net Ca2+ release from the liver, which was not completed within 8 min. Following leukotriene withdrawal there was a further Ca2+ release for about 1 min superimposing a slow reuptake of Ca2+ of about 10 min duration. 3) Leukotriene C4 induced a characteristic biphasic K+ release from the liver. Withdrawal of the leukotriene resulted in a further net K+ release for about 4 min, being followed by a K+ reuptake over more than 10 min. 4) Effects comparable to those induced with leukotriene C4 (20nM) were obtained with leukotriene D4 (20nM), were as leukotriene B4 and E4 (20nM each) were much less effective. 5) The thromboxane A2 analogue U-46619 produced ionic, metabolic and hemodynamic responses similar to leukotriene C4; however, when given at concentration yielding a comparable glucose release, the thromboxane analogue was much more vasoactive than leukotriene C4. The thromboxane A2 receptor antagonist BM-13.177 (20 microM) blocked the metabolic, hemodynamic and ion flux responses to U-46619 almost completely, but had no effect on the response to leukotriene C4. 6) Each, leukotrienes, U-46619 and UTP led to an inhibition of hepatic oxygen uptake. The extent of inhibition of oxygen uptake induced by these compounds was not exclusively explained by their effects on hepatic circulation: a 30% inhibition of oxygen uptake by leukotriene C4, U-46619 or UTP was accompanied by increases of the portal pressure of 4.9 +/- 0.4 (481 +/- 39 Pa) (n = 7), 16.0 +/- 1.9 (1570 +/- 186 Pa) (n = 7) or 11.4 +/- 0.4 (1118 +/- 39 Pa) (n = 13) cm H2O, respectively. 7) The data show that leukotrienes and possibly also thromboxanes are potent regulators of hepatic metabolism and hemodynamics, probably acting by a Ca2+ mobilizing mechanism and involving different receptor systems. The response of perfused liver to these compounds is qualitatively similar to that obtained with extracellular UTP, but different to that with prostaglandins, extracellular ATP or phenylephrine. The data further support the view that eicosanoids are important modulators of hepatic metabolism and point to a complex regulatory interaction between hepatic parenchymal and non-parenchymal cells.