Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of ischemic preconditioning on rat liver integrity, as well as the implication of nitric oxide (NO) and adenosine in this process, has been evaluated. Preconditioning before ischemia-reperfusion prevented the increases in alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels, but did not modify blood flow. Adenosine or NO administration previous to hepatic ischemia-reperfusion simulated the effect of preconditioning, whereas inhibition of adenosine or NO synthesis abolished the protective effect of hepatic preconditioning. Nevertheless, inhibition of adenosine and simultaneous administration of NO in preconditioned animals offered similar results to those found in the preconditioned group, indicating that, in the absence of adenosine, NO is able to maintain the preconditioning benefits. It is suggested that, in preconditioning, adenosine stimulates NO production to protect against the injury associated with ischemia-reperfusion.
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PMID:Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: role of nitric oxide and adenosine. 909

The present study was designed to investigate if TAK-044, a novel endothelin (ET) ETA/ETB receptor antagonist, inhibits ischemia-reperfusion liver injury. The initial study showed the presence of both ETA and ETB receptors in canine hepatic membrane fractions using the specific binding assay of labeled ET-1 with ET isomers and TAK-044. The nonselective ETA/ETB receptor antagonist TAK-044 inhibited the specific binding of ET-1 to the receptors in a concentration-dependent manner. In subsequent studies using a canine 70% partial liver ischemic model (60 minutes), we found that an intravenous injection of TAK-044 (3 mg/kg) before ischemia significantly inhibited the release of serum liver enzymes (aspartate transaminase, alanine transaminase, mitochondrial glutamic oxaloacetic transaminase, and an increase of indocyanine green retention rate after reperfusion, compared with the control group. Elevation of the portal venous pressure was also suppressed significantly during the portal triad occlusion, and a rapid restoration of oxygen pressure in the liver tissue after reperfusion was observed in the TAK-044-treated group. Morphometric analysis revealed that the hepatocyte swelling and sinusoidal contraction 1 hour after reperfusion were significantly less severe in the treated group than in the control group. The sludging of erythrocytes in the sinusoidal lumens was also minimal in the treated group. In conclusion, the significant suppression of hepatic microcirculatory disturbance and tissue injury after ischemia-reperfusion were shown in the TAK-044-treated group. This finding indicates that the pretreatment of TAK-044 is useful as a hepatoprotective agent against ischemia-reperfusion injury, which is otherwise produced by a pathway involving ET-1.
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PMID:Hepatoprotective effect of the endothelin receptor antagonist TAK-044 against ischemia-reperfusion injury in the canine liver. 909 1

Recent studies suggest a major role played by sodium in the pathogenesis of ischemic liver injury: in these studies, sodium-free media have been shown to offer protection against hypoxic injury to isolated hepatocytes. As sodium-free perfusions of the isolated rat liver proved impossible because of extensive vasoconstriction, we assessed the effects of two inhibitors of the Na+-K+-2Cl- cotransporter, the loop diuretics furosemide and bumetanide, on ischemic liver injury. In untreated control livers lactate dehydrogenase (LDH) efflux immediately after reperfusion after 60 minutes of ischemia at 37 degrees C was 1666 +/- 473 U/L. When livers were pretreated with furosemide or bumetanide before the ischemic period, LDH efflux was only 773 +/- 292 U/L and 702 +/- 183 U/L respectively (P < .01). LDH activity in the effluent of the pretreated livers remained significantly below the values of ischemic control livers for the whole reperfusion period of 90 minutes. Bile flow in the postischemic phase was improved by pretreatment with furosemide or bumetanide. The increase in intracellular sodium, as measured by 23Na-NMR, was attenuated from 193% +/- 71% during 60 minutes of ischemia in controls to 148% +/- 80% after bumetanide application (P < .05). Also, after 120 minutes of warm ischemia, LDH and aspartate aminotransferase release were significantly decreased and bile flow increased by pretreatment with bumetanide. Thus, both furosemide and bumetanide showed a clear benificial effect on rat livers subjected to warm ischemia. These data suggest that one means by which sodium ions are accumulated during liver ischemia might be the Na+-K+-2Cl- cotransporter, which is blocked by furosemide and bumetanide.
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PMID:Decrease of ischemic injury to the isolated perfused rat liver by loop diuretics. 918 63

Plasma L-arginine is usually deficient immediately after hepatic reperfusion in orthotopic liver transplantation, which may also contribute to the occurrence of either hepatic ischemia-reperfusion injury or pulmonary hypertension. In this study, exogenous L-arginine was thus experimentally used to reverse the deficient status of the L-arginine/NO pathway. An in vivo model of 1 hr hepatic ischemia and reperfusion was thus tested in both rats (Experiment A) and pigs (Experiment B). In Experiment A, 10 mg/kg of L-arginine (group 1, n = 7), D-arginine (group 2, n = 7), or saline (group 3, n = 7) was administered through the portal vein. The hepatic tissue blood flow, at 20 min after reperfusion, improved in group 1 (70.7 +/- 7.0% of the preclamp levels) compared to groups 2 and 3. The serum glutamate oxaloacetate transaminase levels at 24 hr after reperfusion were also lower in group 1 (320 +/- 22.2 IU/L) than in either group 2 or group 3. The intrahepatic NO levels showed a temporal burst (> 15,000 pA current) after reperfusion only in group 1. In Experiment B, 10 mg/kg of L-arginine (group 4, n = 5), D-arginine (group 5, n = 5), or 10 ml of saline (group 6, n = 5) was administered through the portal vein. In group 4, the MPAP (mean pulmonary arterial pressure)/MAP (mean arterial pressure) was lower than that observed in groups 5 and 6. In conclusion, exogenous L-arginine administered from the portal vein was thus found to be effective in mitigating both portal hypertension and reperfusion injury by producing an increased amount of NO immediately after reperfusion.
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PMID:Role of exogenous L-arginine in hepatic ischemia-reperfusion injury. 922 19

Proteases as well as alterations in intracellular calcium have important roles in hepatic preservation-reperfusion injury, and increased calpain activity recently has been demonstrated in liver allografts. Experiments were designed to evaluate (i) hepatic cytosolic calpain activity during different periods of cold ischemia (CI), rewarming, or reperfusion, and (ii) effects of inhibition of calpain on liver graft function using the isolated perfused rat liver and arterialized orthotopic liver transplantation models. Calpain activity was assayed using the fluorogenic substrate Suc-Leu-Leu-Val-Tyr-7-amino-4-methyl coumarin (AMC) and expressed as mean +/- SD pmol AMC released/min per mg of cytosolic protein. Calpain activity rose significantly after 24 hr of CI in University of Wisconsin solution and further increased with longer preservation. Activity also increased within 30 min of rewarming, peaking at 120 min. Increased durations of CI preceding rewarming resulted in significantly higher activity (P < 0.01). Calpain activity increased rapidly upon reperfusion and was significantly enhanced by previous CI (P < 0.01). Calpain inhibition with Cbz-Val-Phe methyl ester significantly decreased aspartate aminotransferase released in the isolated perfused rat liver perfusate (P < 0.05). Duration of survival after orthotopic liver transplantation using livers cold-preserved for 40 hr was also significantly increased (P < 0.05) with calpain inhibitor. In conclusion, calpain proteases are activated during each phase of transplantation and are likely to play an important role in the mechanisms of preservation-reperfusion injury.
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PMID:Calpain is a mediator of preservation-reperfusion injury in rat liver transplantation. 925 86

Centrilobular necrosis (CLN) is a histological finding often encountered after orthotopic liver transplantation, but its pathogenesis is still unknown. In this study, the significance of CLN was assessed in a series of 227 consecutive liver transplantations performed between January 1989, and December 1991. Seventy-one patients (30.9%) showed CLN on at least one biopsy result, which were obtained because of an increase of aspartate aminotransferase activity. Their liver specimens were reviewed, and 19 histological features were recorded with particular attention given to lobular changes in acinar zone 3, to features commonly attributed to cellular and ductopenic rejection, and to changes suggestive of ischemia. CLN could first be observed either soon (within 4 days) or late (up to 3 years) after transplantation. Only 23 (32.4%) specimens had centrilobular necrosis affecting more than 75% of acinar zones 3. In 60 cases (84.5%) the lesion was limited to acinar zone 3. An important associated feature was sinusoidal congestion in 73.2% of cases. Fifty-one of 71 patients (71.8%) had histological features of cellular rejection before or at the time of CLN, and 13 of these progressed to ductopenic rejection versus 3 of the 156 patients without CLN (P < .0001). Nine patients had a recurrence of CLN, of whom 2 progressed to ductopenic rejection, a recurrence rate of 16.7% in this series. The survival of patients with CLN is worsened by associated ductopenic portal tracts compared with those without ductopenia (P = .0189-Mantel-Cox). This histological combination, irrespective of the serum bilirubin level, may warrant an early conversion to FK506-based immunosuppression.
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PMID:Centrilobular necrosis after orthotopic liver transplantation: a longitudinal clinicopathologic study in 71 patients. 934 84

The role of true cold ischemia times (CIT) and rewarming ischemia times (WIT) in determining outcome after liver transplantation was investigated in 230 adult recipients. Using multivariate analysis, WIT (time from the start of implantation until restoration of arterial and portal blood supply) and donor intensive care stay (P = .04 and .0004, respectively) but not CIT (the time from donor portal vein flushing until the graft was removed from University of Wisconsin solution; P > .30) emerged as independent determinants of graft survival. In the small number of patients with a WIT of greater than 180 minutes, there were reductions in graft survival (58% v 80% for WIT greater than 180 minutes) but these just failed to reach significance (P = .055). CIT had no influence on graft survival using cut-offs of 12 or 18 hours. A WIT of greater than 180 minutes was associated with an increased median area under the curve of day 1 through 7 serum bilirubin (1,370 v 915 mumol/L.day; P = .048) and trends towards an increased incidence of primary graft nonfunction or dysfunction (22.2% v 6.2% for WIT of less than 180 minutes; P = .065) and the day 1 through 7 area under the curve of serum aspartate aminotransferase (3,310 v 1,440 IU/L.day; P = .092). A prolonged CIT (greater than 18 hours) led to a prolonged hospital stay (69 v 31 days; P = .03), an increased area under the curve of day 8 through 14 serum bilirubin (2,500 v 995 mumol/L.day; P = .003), and a trend towards an increased incidence of initial poor graft function (33.3% v 6.3% for less than 18 hours; P = .092). The incidence of acute rejection increased (to 64.3% from 53.4%; P = .04) in patients with preservation injury (serum aspartate aminotransferase greater than 1,500 IU/L during the first 2 postoperative days). True CIT and WIT are important determinants of outcome after liver transplantation.
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PMID:Contribution of true cold and rewarming ischemia times to factors determining outcome after orthotopic liver transplantation. 934 86

To evaluate the safety of temporary hepatic inflow occlusion during major liver resection, we reviewed 71 consecutive noncirrhotic patients who underwent elective liver resection using this technique. There were 27 males and 44 females (mean age, 54.4 years), the majority of whom had hepatic malignancies. There were 31 right hepatectomies, 21 left hepatectomies, and 19 extended right hepatectomies. Ischemic injury of the liver was assessed using changes in postoperative liver function tests and patient outcome was assessed using morbidity and mortality rates. After preliminary ligation of the blood supply to the lobe to be removed, global hepatic ischemia was produced by temporary occlusion of the main portal vein and hepatic artery proper while the liver parenchyma was divided. The average duration of inflow occlusion was 59 minutes (range, 25 to 90 minutes). There was no operative mortality, and no patient developed liver failure. The liver enzymes reached their peak on the first postoperative day (mean aspartate aminotransferase [AST] level, 283 +/- 227 IU/L; mean alanine aminotransferase [ALT] level, 269 +/- 238 IU/L) and they returned to normal by 7 days. The most common postoperative complications were related to the chest, wound, and urinary tract. The mean intraoperative transfusion was 3.4 +/- 2.6 U of packed red blood cells, and 0.94 +/- 2.13 U of fresh frozen plasma. We conclude that continuous hepatic inflow occlusion for periods of 1 hour during major liver resection is safe and well-tolerated when there is no underlying parenchymal liver disease.
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PMID:The safety of continuous hepatic inflow occlusion during major liver resection. 934 33

Little is known about the possible contribution of apoptosis to ischemia-reperfusion injury in human liver transplantation. Therefore, we studied postreperfusion surgical biopsy specimens of 16 human liver allografts using the TUNEL assay for in situ demonstration of apoptotic cells. In all patients, a variable proportion of hepatocytes and sinusoidal endothelial cells presented labeled nuclei. The mean +/- standard deviation percentages of positive hepatocytes were 18.7% +/- 12.2% in the whole section, 30.4% +/- 18.7% in the subcapsular region, 14.5% +/- 13.5% in the centrilobular zones, and 10.3% +/- 9.5% in the periportal zones. The percentage of positive hepatocytes were not correlated with the duration of cold ischemia but was higher in grafts harvested from donors with elevated preoperative aspartate aminotransferase (AST) levels. The percentage of positive hepatocytes was correlated with postoperative serum levels of AST (P = .015) and inversely correlated with postoperative serum levels of factor V (P = .019). Apoptotic biliary epithelial cells were detected in only 3 cases. In conclusion, apoptosis is a frequent event in postreperfusion biopsy specimens of liver allografts and probably contributes to preservation injury of hepatocytes.
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PMID:Apoptosis after ischemia-reperfusion in human liver allografts. 934 71

Donor pretreatment is a new concept in organ preservation. Pentoxifylline (PTX) has been reported to suppress the activation of Kupffer cells and to decrease injury to the hepatic graft after rat liver transplantation. We evaluated the efficiency of PTX pretreatment on the donor against hepatic injury following cold ischemia (CI) or warm ischemia (WI) using the rat liver transplantation model. Dose dependency: every rat was injected intraperitoneally with PTX (30, 50, or 80 mg/kg) or saline. One hour later, the portal vein (PV) and the hepatic artery (HA) were clamped for 30 min. Transplantation: the donor rat was injected intraperitoneally with 50 mg/kg PTX or saline, 1 hr before laparotomy. Animals were divided into two groups. In the CI group, grafts were preserved for 12 hr in University of Wisconsin solution at 4 degrees C and transplanted. In the WI group, the PV and the HA in the donor were clamped for 30 min before donor surgery, and the grafts were transplanted. Serum levels of tumor necrosis factor-alpha (TNF-alpha), glutathione S-transferase-alpha (GST-alpha), and aspartate transaminase (AST) were measured at 30 min, 3 hr, and 24 hr after reperfusion of the PV. Compared with those of a control group, the serum levels of TNF-alpha, GST-alpha, and AST in the PTX-pretreated groups were significantly lower after both CI and WI at 30 min and further suppressed in the WI group at 24 hr. These results indicate that PTX pretreatment on the donor is effective for suppression of hepatic injury after both CI and WI.
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PMID:Efficiency of pentoxifylline in donor pretreatment in rat liver transplantation. 935 39


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