[Effect of hypoxia on nitric oxide formation and leukotriene metabolism in the perfused rat liver].
Endotoxinaemia stimulates the generation of cysteinyl leukotrienes (LT), potent mediators of inflammation which are preferentially eliminated into the bile. Nitric oxide (NO) is a mediator molecule that has a possible protective role in liver injury. As sepsis and shock often lead to the development of hypoxic regions in the liver, the influence of hypoxia on the metabolism of cysteinyl leukotrienes and the hepatic production of NO were investigated in the isolated perfused rat liver. Livers were perfused in a non-recirculating haemoglobin-free system from the portal to the caval vein. Perfusion medium was equilibrated with 95% O2/5% CO2. In hypoxia experiments, gassing was changed to 95% N2/5% CO2 for 20 min. Tritiated leukotrienes were infused to the portal vein and metabolites in effluent and bile were measured by HPLC. Hypoxia did not influence the uptake of 3H-LTC4 and 3H-LTE4 but biliary elimination was reduced by 50-60% compared to normoxic control experiments. In hypoxia, the metabolite pattern in bile was also significantly changed with a decrease of omega-oxidation products. Following reoxygenation larger amounts of leukotrienes were excreted from the liver into the bile. To induce NO synthase in the liver, rats were injected intraperitoneally with endotoxin 6 hours before livers were isolated for perfusion. In contrast to nontreated livers, nitrite and nitrate, the oxidation products of NO, were detectable in the effluent perfusate. Basal NO2(-)+NO3- release was 5.3 (1.2) nmol/g liver/min. NO2(-)+NO3- release was stimulated by L-arginine infusion, whereas hypoxia resulted in an almost complete inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Wettstein
M
M
Medizinische Klinik II, Albert-Ludwigs-Universität Freiburg.
Häussinger
D
D
D000594:Amino Acid Oxidoreductases / Q000502:physiology; D000818:Animals; D001646:Bile / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D007511:Ischemia / Q000503:physiopathology*; D017997:Leukotriene C4 / Q000378:metabolism; D017998:Leukotriene D4 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism*; D008099:Liver / Q000098:blood supply*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000503:physiopathology*
D015289:Leukotrienes; D017997:Leukotriene C4; D009569:Nitric Oxide; D017998:Leukotriene D4; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases