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

Abstract

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.

The cytosolic concentration of phosphate determines the maximal rate of glycogenolysis in perfused rat liver

“…Control of hepatic phosphorvlase a activity by phosphate (Iwai & Jungermann, 1989 (Unkefer & London, 1984;Murphy et al, 1988;Hutson et al, 1989). However, isolated mitochondria contain a large amount of Pi, which is at least partially n.m.r.…”

Impairment of hepatic transport processes in perfused rat liver by the specific CCK receptor antagonist loxiglumide

“…Leukotrienes are known to have vasoconstrictive effects in a variety of organs [20]. In the perfused rat liver, these compounds stimulate glucose and lactate release [17]. Krell and Dietze [22] reported strong evidence that the changes in carbohydrate metabolism and bile secretion are due to the microcirculatory redistribution of perfusate flow.…”

Isolation and some properties of dioxygenase and co-oxidase activities of adult human liver cytosolic lipoxygenase

“…The data obtained using the isolated and perfused rat liver technique led Haussinger and co-workers (6) to suggest that LTs play a modulatory role in hepatic metabolism and hemodynamics. Using a similar experimental approach, Iwai and Jungermann (7) observed an enhanced glucose and lactate output and reduced perfusion flow in the rat liver by LTC 4 and LTD 4 . Quiroga et al (8) noted that nordihydroguaiaretic acid, BW755c, and eicosatetraynoic acid, inhibitors of LO, impair the glycocolic acid efflux from isolated rat hepatocytes.…”