Rat livers were perfused at constant pressure via the portal vein with media containing 5 mM glucose, 2 mM lactate and 0.2 mM pyruvate.1. Leukotrienes C4 and D4 enhanced glucose and lactate output and reduced perfusion flow to the same extent and with essentially identical kinetics. They both caused half-maximal alterations (area under the curve) of carbohydrate metabolism at a concentration of about 1 nM and of flow at about 5 nM. The leukotrine-C4/D4 antagonist CGP 35949 B inhibited the metabolic and hemodynamic effects of 5 nM leukotrienes C4 and D4 with the same efficiency, causing 50% inhibition at about 0.1 pM.2. Leukotriene C4 elicited the same metabolic and hemodynamic alterations with the same kinetics as leukotriene D4 in livers from rats pretreated with the y-glutamyltransferase inhibitor, acivicin.3. The calcium antagonist, nifedipine, at a concentration of 50 pM did not affect the metabolic and hemodynamic changes caused by 5 nM leukotriene D4. The smooth-muscle relaxant, nitroprussiate, at a concentration of 10 pM reduced flow changes, without significantly affecting the metabolic alterations.4. Leukotriene D4 not only reduced flow; it also caused an intrahepatic redistribution of flow, restricting some areas from perfusion. Thus, leukotrienes increased glucose and lactate output directly in the accessible parenchyma and, in addition, indirectly by washout from restricted areas during their reopening upon termination of application.5. The phospholipase A2 inhibitor, bromophenacyl bromide, but not the cyclooxygenase inhibitor, indomethacin, at a concentration of 20 pM reduced the metabolic and hemodynamic effects of 5 mM leukotriene D4.6. Stimulation of the sympathetic hepatic nerves with 2-ms rectangular pulses at 20 Hz and infusion of 1 pM noradrenaliiie increased glucose and lactate output and decreased flow, similar to 10 nM leukotrienes C4 and D4, The kinetics of the metabolic and hemodynamic changes caused by the leukotrienes differed, however, from those due to nerve stimulation and noradrenaline.7. The leukotriene-C4/D4 antagonist, CGP 35949 B, even at very high concentrations (20 pM) inhibited the metabolic and hemodynamic alterations caused by nerve stimulation or noradrenaline infusion only slightly and unspecificall y.The present results suggest that (a) leukotriene C4 and leukotriene D4 modulate hepatic metabolism and hemodynamics with equal kinetics and efficiencies specifically, via leukotriene C4/D4 receptors; (b) they act without being dependent upon calcium uptake via slow calcium channels, in part indirectly, by stimulating the formation of other phospholipase A2 produts and (c) they do not have a major role in the actions of sympathetic hepatic nerves and circulating noradrenaline. Metabolic regulation by leukotrienes, which are formed only in non-parenchymal cells, constitutes another example of a complex intra-organ cell -cell communication between non-parenchymal and parenchymal cells.