Mechanism of action of cysteinyl leukotrienes on glucose and lactate balance and on flow in perfused rat liver

Rat livers were perfused at constant pressure via the portal vein with media containing 5 mM glucose, 2mM lactate and 0.2 mM pyruvate.1 Leukotrienes C 4 and D 4 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‐C 4 /D 4 antagonist CGP 35949 B inhibited the metabolic and hemodynamic effects of 5 nM leukotrienes C 4 and D 4 with the same efficiency, causing 50% inhibition at about 0.1 μM. 2 Leukotriene C 4 elicited the same metabolic and hemodynamic alterations with the same kinetics as leukotriene D 4 in livers from rats pretreated with the γ‐glutamyltransferase inhibitor, acivicin. 3 The calcium antagonist, nifedipine, at a concentration of 50 μM did not affect the metabolic and hemodynamic changes caused by 5 nM leukotriene D 4 . The smooth‐muscle relaxant, nitroprussiate, at a concentration of 10 μM reduced flow changes, without significantly affecting the metabolic alterations. 4 Leukotriene D 4 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 A 2 inhibitor, bromophenacyl bromide, but not the cyclooxygenase inhibitor, indomethacin, at a concentration of 20 μM reduced the metabolic and hemodynamic effects of 5 mM leukotriene D 4 . 6 Stimulation of the sympathetic hepatic nerves with 2‐ms rectangular pulses at 20 Hz and infusion of 1 μM noradrenaline increased glucose and lactate output and decreased flow, similar to 10 nM leukotrienes C 4 and D 4 . 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‐C 4 /D 4 antagonist, CGP 35949 B, even at very high concentrations (20 μM) inhibited the metabolic and hemodynamic alterations caused by nerve stimulation or noradrenaline infusion only slightly and unspecifically.The present results suggest that (a) leukotriene C 4 and leukotriene D 4 modulate hepatic metabolism and hemodynamics with equal kinetics and efficiencies specifically, via leukotriene C 4 /D 4 receptors; (b) they act without being dependent upon calcium uptake via slow calcium channels, in part indirectly, by stimulating the formation of other phospholipase A 2 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.