endothelin-1 and Liver-Failure--Acute

Secondary activation of the endothelin system is thought to be involved in toxic liver injury. This study tested the hypothesis that dual endothelin-converting enzyme / neutral endopeptidase blockade might be able to attenuate acute toxic liver injury. - Male Sprague-Dawley rats were implanted with subcutaneous minipumps to deliver the novel compound SLV338 (10 mg/kg*d) or vehicle. Four days later they received two intraperitoneal injections of D-galactosamine (1.3 g/kg each) or vehicle at an interval of 12 hours. The animals were sacrificed 48 hours after the first injection. - Injection of D-galactosamine resulted in very severe liver injury, reflected by strongly elevated plasma liver enzymes, hepatic necrosis and inflammation, and a mortality rate of 42.9 %. SLV338 treatment did not show any significant effect on the extent of acute liver injury as judged from plasma parameters, hepatic histology and mortality. Plasma measurements of SLV338 confirmed adequate drug delivery. Plasma concentrations of big endothelin-1 and endothelin-1 were significantly elevated in animals with liver injury (5-fold and 62-fold, respectively). Plasma endothelin-1 was significantly correlated with several markers of liver injury. SLV338 completely prevented the rise of plasma big endothelin-1 (p<0.05) and markedly attenuated the rise of endothelin-1 (p = 0.055). - In conclusion, dual endothelin-converting enzyme / neutral endopeptidase blockade by SLV338 did not significantly attenuate D-galactosamine-induced acute liver injury, although it largely prevented the activation of the endothelin system. An evaluation of SLV338 in a less severe model of liver injury would be of interest, since very severe intoxication might not be relevantly amenable to pharmacological interventions.

Topics: Animals; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Galactosamine; Liver Failure, Acute; Male; Metalloendopeptidases; Neprilysin; Protease Inhibitors; Rats; Rats, Sprague-Dawley

Topics: Adrenomedullin; Albumins; Arginine; Biomarkers; Cohort Studies; Dialysis; Endothelin-1; Female; Humans; Liver Failure, Acute; Male; Protein Precursors; Sensitivity and Specificity; Treatment Outcome; Vasopressins

To study the effect of alprostadil lipid microballoons (lipo PGE1) on the function and morphous of livers from brain-dead rats.. Twenty-four SD rats were randomly assigned into 4 groups: a control group(Group C),a brain-dead group (Group B) and 2 lipo PGE1 protection groups (Group L1 and Group L2). Brain-dead models were established in Group B,L1 and L2.There was no inflation of Fogarty balloon in Group C, while other operations were the same as Group B. Lipo PGE1 [20 ng/(kg.min) and 40 ng/(kg.min)] was injected via the femoral vein in Group L1 and Group L2 immediately after the establishment of the brain-dead model. The serum levels of alanine aminotransferase (ALT), aspartate amino transferase (AST), endothelin (ET)-1, and tumor necrosis factor (TNF)-α were detected by radioimmunological analyzer. Liver tissues were observed by HE staining 6 h after the brain death.. At the time of brain death, the level of ALT, AST, ET-1, and TNF-α in Group B, L1 and L2 was significantly different compared with that in Group C. That in Group L1 and L2 was significantly lower than in Group B(P<0.05). There was no significant difference between Group L1 and L2(P>0.05).. Brain death can cause damage to the liver of rats. Lipo PGE1 can relieve the injury of brain death donors.The protective mechanism of Lipo PGE1 is to decrease the release of serum inflammatory mediators.

Topics: Alprostadil; Animals; Brain Death; Endothelin-1; Female; Liver Failure, Acute; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

To investigate the protective effect of stronger neo-minophafen C (SNMC) on fulminant hepatic failure (FHF) and its underlying mechanism.. A mouse model of FHF was established by intraperitoneal injection of galactosamine (D-Gal N) and lipopolysaccharide (LPS). The survival rate, liver function, inflammatory factor and liver pathological change were obtained with and without SNMC treatment. Hepatocyte survival was estimated by observing the stained mitochondria structure with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate fluorescence nick end labeling (TUNEL) method and antibodies against cytochrome C (Cyt-C) and caspase-3.. The levels of plasma tumor necrosis factor alpha (TNF-alpha), nitric oxide (NO), ET-1, interleukin-6 (IL-6), and the degree of hepatic tissue injury were decreased in the SNMC-treated groups compared with those in the model group (P < 0.01). However, there were no differences after different dosages administered at different time points. There was a significant difference in survival rates between the SNMC-treated groups and the model group (P < 0.01). The apoptosis index was 32.3% at 6 h after a low dose of SNMC, which was considerably decreased from 32.3% +/- 4.7% vs 5% +/- 2.83% (P < 0.05) to 5% on d 7. The expression of Cyt-C and caspase-3 decreased with the prolongation of therapeutic time. Typical hepatocyte apoptosis was obviously ameliorated under electron microscope with the prolongation of therapeutic time.. SNMC can effectively protect liver against FHF induced by LPS/D-Gal N. SNMC can prevent hepatocyte apoptosis by inhibiting inflammatory reaction and stabilizing mitochondria membrane to suppress the release of Cyt-C and sequent activation of caspase-3.

Topics: Alanine Transaminase; Albumins; Animals; Apoptosis; Bilirubin; Caspase 3; Cysteine; Cytochromes c; Drug Combinations; Endothelin-1; Female; Glycine; Glycyrrhetinic Acid; Interleukin-6; Liver; Liver Failure, Acute; Mice; Microscopy, Electron; Tumor Necrosis Factor-alpha

Liver failure represents a major therapeutic challenge, and yet basic pathophysiological questions about hepatic perfusion and oxygenation in this condition have been poorly investigated. In this study, hepatic blood flow (HBF) and splanchnic oxygen delivery (DO2, sp) and oxygen consumption (VO2,sp) were assessed in patients with liver failure defined as hepatic encephalopathy grade II or more. Measurements were repeated after high-volume plasmapheresis (HVP) with exchange of 8 to 10 L of plasma. HBF was estimated by use of constant infusion of D-sorbitol and calculated according to Fick's principle from peripheral artery and hepatic vein concentrations. In 14 patients with acute liver failure (ALF), HBF (1.78 +/- 0.78 L/min) and VO2,sp (3.9 +/- 0.9 mmol/min) were higher than in 11 patients without liver disease (1.07 +/- 0.19 L/min, P <.01) and (2.3 +/- 0.7 mmol/min, P <.001). In 9 patients with acute on chronic liver disease (AOCLD), HBF (1.96 +/- 1.19 L/min) and VO2,sp (3.9 +/- 2.3 mmol/min) were higher than in 18 patients with stable cirrhosis (1.00 +/- 0.36 L/min, P <.005; and 2.0 +/- 0.6 mmol/min, P <.005). During HVP, HBF increased from 1.67 +/- 0.72 to 2.07 +/- 1.11 L/min (n=11) in ALF, and from 1.89 +/- 1.32 to 2.34 +/- 1.54 L/min (n=7) in AOCLD, P <.05 in both cases. In patients with ALF, cardiac output (thermodilution) was unchanged (6.7 +/- 2.5 vs. 6.6 +/- 2.2 L/min, NS) during HVP. Blood flow was redirected to the liver as the systemic vascular resistance index increased (1,587 +/- 650 vs. 2, 020 +/- 806 Dyne. s. cm-5. m2, P <.01) whereas splanchnic vascular resistance was unchanged. In AOCLD, neither systemic nor splanchnic vascular resistance was affected by HVP, but as cardiac output increased from 9.1 +/- 2.8 to 10.1 +/- 2.9 L/min (P <.01) more blood was directed to the splanchnic region. In all liver failure patients treated with HVP (n=18), DO2,sp increased by 15% (P <.05) whereas VO2,sp was unchanged. Endothelin-1 (ET-1) and ET-3 were determined before and after HVP. Changes of ET-1 were positively correlated with changes in HBF (P <.005) and VO2,sp (P <.05), indicating a role for ET-1 in splanchnic circulation and oxygenation. ET-3 was negatively correlated with systemic vascular resistance index before HVP (P <.05) but changes during HVP did not correlate. Our data suggest that liver failure is associated with increased HBF and VO2, sp. HVP further increased HBF and DO2,sp but VO2,sp was unchanged, indicating that splanchnic hypoxia

Topics: Acute Disease; Adult; Blood Flow Velocity; Chronic Disease; Endothelin-1; Endothelin-3; Female; Hepatic Encephalopathy; Humans; Liver Circulation; Liver Diseases; Liver Failure; Liver Failure, Acute; Male; Middle Aged; Oxygen Consumption; Plasmapheresis; Splanchnic Circulation