Hemodynamic and metabolic responses to leukotriene C4 in isolated perfused rat liver

Krell, Herbert; Dietze, Eberhard

doi:10.1002/hep.1840100308

Cited by 21 publications

(14 citation statements)

References 24 publications

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“…On the other hand, the small extent of hepatic LTB4 extraction ( Fig. 1; Tables 1 and 2) corresponds to the minor responsiveness of the liver to this LT [38,39] as compared with the respective effects of cysteinyl LTs [33,[38][39][40][41].…”

Section: Discussionmentioning

confidence: 97%

Hepatic uptake and metabolic disposition of leukotriene B4 in rats

Hagmann

Körte

1990

Biochemical Journal

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1. In isolated perfused rat liver and in vivo, up to 25 % of [3H]leukotriene B4 was eliminated from the circulation via hepatic uptake and biliary excretion within 1 h. Total body recovery of 3H amounted to about 60 % of infused [3H]leukotriene B4. 2. Hepatobiliary excretion of leukotriene B4 and its metabolites exceeded renal elimination by about 4-fold and depended, in contrast with excretion of cysteinyl leukotriene E4, upon continuous taurocholate supply. 3. Analyses of bile, liver and recirculated perfusate using h.p.l.c. indicated that the liver metabolized leukotriene B4 extensively to wocarboxyleukotriene B4 and its f-oxidized derivatives, and no unmetabolized leukotriene B4 appeared in bile. These results substantiate the important contribution of the hepatobiliary system with respect to the metabolic fate of leukotriene B4.

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Section: Discussionmentioning

confidence: 97%

Hepatic uptake and metabolic disposition of leukotriene B4 in rats

Hagmann

Körte

1990

Biochemical Journal

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“…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. Antiarrhythmic drugs were reported to reduce biliary secretion [23].…”

Section: Discussionmentioning

confidence: 98%

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

et al. 1997

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The specific cholecystokinin (CCK) receptor antagonist loxiglumide has been used in several human and animal studies to investigate the role of CCK in gastrointestinal physiology. In the present study, the interference of this CCK receptor antagonist with hepatic transport processes was characterized in the perfused rat liver. Indocyanine green, an organic dye which is secreted into bile without being metabolized, was taken up in control experiments at a rate of 68.1 +/- 7.7%. The CCK receptor antagonist lowered the extraction to 0.5 +/- 2.6% (P < 0.001). The compound diminished the hepatic extraction of CCK-8 from 90.95 +/- 2.60% to 4.90 +/- 1.95% (P < 0.001) and of gastrin from 22.2 +/- 1.1% to 8.2 +/- 1.9% (P < 0.001). The hepatic extraction of lidocaine, which is metabolized by the cytochrome P450 system, was only slightly altered. For leukotrienes and taurocholate, the rate-limiting step for transport into bile is secretion across the canalicular membrane; the hepatic extraction of leukotriene D4 was markedly diminished by loxiglumide whereas the transport of taurocholate was only slightly inhibited. The present study demonstrates that the specific CCK receptor antagonist loxiglumide diminished the hepatic extraction of various substances, including peptides and organic anions. It did not interfere with the cytochrome P450 system. The pronounced reduction of hepatic uptake of indocyanine green and leukotriene may be due to an interference with the transport system of these substances in the liver.

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“…In addition, it is known that the elimination of Cys-LTs is altered in some pathological conditions. 6 Different mechanisms of Cys-LT-related liver injury have been identified; the two major postulated mechanisms are intrahepatic vasoconstriction leading to hypoxia [7][8][9] and inflammatory cell damage. 8,10 Furthermore, Kupffer cells (KCs) have an important role in Cys-LT-mediated necroinflammatory liver injury.…”

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confidence: 99%

Role of cysteinyl-leukotrienes for portal pressure regulation and liver damage in cholestatic rat livers

Winkel

Gmelin

Schewe

et al. 2013

Laboratory Investigation

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Kupffer cells (KCs) have a major role in liver injury, and cysteinyl-leukotrienes (Cys-LTs) are known to be involved as well. The KC-mediated pathways for the production and secretion of Cys-LT in cholestatic liver injury have not yet been elucidated. Here, we hypothesized that KC activation by Toll-like receptor ligands results in Cys-LT-mediated microcirculatory alterations and liver injury in acute cholestasis. We hypothesized further that this situation is associated with changes in the secretion and production of Cys-LT. One week after bile duct ligation (BDL), livers showed typical histological signs of cholestatic liver injury. Associated microcirculatory disturbances caused increased basal and maximal portal pressure following KC activation. These differences were determined in BDL livers compared with shamoperated livers in vivo (KC activation by LPS 4 mg/kg b.w.) and in isolated perfused organs (KC activation by Zymosan A, 150 mg/ml). Treatment with the 5-lipoxygenase inhibitor MK-886 alone did not alter portal perfusion pressure, lactate dehydrogenase (LDH) efflux, or bile duct proliferation in BDL animals. Following KC activation, portal perfusion pressure increased. The degree of cell injury was attenuated by MK-886 (3 mM) treatment as estimated by LDH efflux. In normal rats, a large amount of Cys-LT efflux was found in the bile. Only a minor amount was found in the effluent perfusate. In BDL livers, the KC-mediated Cys-LT efflux into the sinusoidal system increased, although the absolute Cys-LT level was still grossly lower than the biliary excretion in sham-operated livers. In conclusion, our results indicate that treatment with Cys-LT inhibitors might be a relevant target for attenuating cholestatic liver damage.

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Hemodynamic and metabolic responses to leukotriene C4 in isolated perfused rat liver

Cited by 21 publications

References 24 publications

Hepatic uptake and metabolic disposition of leukotriene B4 in rats

Hepatic uptake and metabolic disposition of leukotriene B4 in rats

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

Role of cysteinyl-leukotrienes for portal pressure regulation and liver damage in cholestatic rat livers

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