Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intravenous injection of murine recombinant tumor necrosis factor alpha(TNF-alpha) to male NMRI albino mice in doses greater than 4 micrograms/kg (specific activity 4 x 10(7) U/mg) resulted in a fulminant hepatitis when animals had been sensitized 1 hr before by intraperitoneal administration of 700 mg/kg galactosamine. Liver injury was assessed by measurement of serum transaminases as well as sorbitol dehydrogenase activity 8 hr after administration of TNF-alpha. Pretreatment with either galactosamine or 40 micrograms/kg TNF-alpha alone did not cause hepatitis. Pretreatment of galactosamine/TNF-alpha-injured mice with 800 mg/kg uridine or with 6 mg/kg calmidazolium fully protected the animals, while administration of either verapamil or nifedipine (100 mg/kg, respectively) had no significant effect. The following inhibitors of generation or action of leukotriene D4, which were previously shown to block galactosamine/endotoxin-induced hepatitis in mice, failed to protect against galactosamine/TNF-alpha-induced intoxication: 200 micrograms/kg dexamethasone, 174 mg/kg BW 755 C or 13 x 10 mg/kg FPL 55712. In addition, unlike in the galactosamine/endotoxin model no prevention was achieved by pretreatment of galactosamine/TNF-alpha-injured animals with the following substances blocking the development of an ischemia/reperfusion syndrome: 2 x 100 mg/kg allopurinol, 3.3 x 10(4) U/kg superoxide dismutase, 10(6) U/kg catalase or 10 micrograms/kg iloprost. We conclude from our results that tumor necrosis factor alpha is likely to act as a final mediator of endotoxin action in a sequence of events which includes formation of leukotriene D4 and reactive oxygen species.
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PMID:Tumor necrosis factor is a terminal mediator in galactosamine/endotoxin-induced hepatitis in mice. 246 8

Using isolated hemoglobin-free perfused rat livers we studied the effect of low oxygen supply on ethanol hepatotoxicity in two models. In the first model resembling low blood supply, perfusion rate was lowered from 60 to 10 ml/min after a 30 min-equilibration phase and kept low for 60 min. As a consequence, oxygen consumption fell from 1.76 +/- 0.15 mumol/min/g to 0.51 +/- 0.02 mumol/min/g. In the second model, total ischemia was accomplished by interruption of the perfusion for 30 min and was followed by reperfusion at a perfusion rate of 60 ml/min for a further 30 min. In this model, oxygen consumption returned immediately to normal values upon reperfusion. In both models, low oxygen supply had no toxic effects of its own on livers from fed rats. While ethanol (3 g/l) given under normoxic conditions led to a moderate hepatotoxicity, its application in both models of partial as well as total ischemia and reperfusion resulted in a marked liver damage as evidenced by a strong release of sorbitol dehydrogenase, glutamate-pyruvate-transaminase, lactate dehydrogenase and glutathione, as well as by an increase in hepatic calcium content. Inhibition of ethanol metabolism by 4-methylpyrazol prevented liver damage in both models indicating that metabolism of ethanol is a prerequisite for its toxicity to occur. Also, hepatotoxicity was inhibited partially by catalase and superoxide dismutase and nearly totally by deferrioxamine and allopurinol. Thus, reactive oxygen species which are produced during ethanol metabolism as well as under conditions of low oxygen supply are mediators of hepatic damage in both models employed.
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PMID:Enhancement of acute ethanol hepatotoxicity under conditions of low oxygen supply and ischemia/reperfusion. The role of oxygen radicals. 281 46

This report describes a new method for producing Sertoli cell-only testes in the Lewis rat using 90 min of hypothermic testicular ischemia. The method employs selective occlusion of the testicular blood supply using atraumatic microclips applied with the aid of an operating microscope. The testis is packed in ice-cold saline throughout the ischemic interval, and the deferential artery and vein are ligated. Twelve weeks after the ischemic insult, the testes weigh half that of control testes while there were no differences in prostate or seminal vesicle weights. Microscopic examination of the ischemic damaged testes revealed normal-appearing Leydig and Sertoli cells, but complete absence of germ cells. Assays of testicular enzyme activities indicated that lactic dehydrogenase and sorbitol dehydrogenase were reduced, while alpha-glutamyl transpeptidase activity was normal, consistent with the marked reduction of germ cells. Serum androgen binding protein (rABP) levels were elevated relative to nonischemic controls. By contrast, serum concentrations of testosterone, LH, and FSH were normal. In addition, LHRH elicited identical LH and testosterone responses in control and experimental animals. Testicular blood flow measured with 133Xenon was slightly decreased in Sertoli-cell-only testes. Intratesticular temperatures was normal in all groups. These observations in rats with ischemia-induced Sertoli-cell-only testes are strikingly different from those induced by radiation or genetic defects. Animals with these latter disorders have elevated FSH levels, evidence of altered Leydig cell function as evidenced by elevated LH or abnormal response to LHRH; and normal or low serum rABP levels. We conclude that 1) ischemia produces no abnormalities of the pituitary testicular axis in spite of marked germ cell depletion and 2) Sertoli-cell-only testes of different etiologies can have varied patterns of hormone and rABP secretion.
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PMID:Sertoli cell-only syndrome produced by cold testicular ischemia. 312 37

On the basis of chronic weight loss, bilateral asymmetric abdominal distention, ballottement of a large abomasum, hypochloremic metabolic alkalosis, and high rumen chloride concentration, an adult Suffolk ewe was diagnosed as having an abomasal emptying defect. In this ewe, and in 4 of 7 other sheep diagnosed as having abomasal emptying defects, aspartate transaminase and sorbitol dehydrogenase activities were high, and histopathologic evidence of hepatic congestion and ischemia was found. It was theorized that increased intra-abdominal pressure from abomasal distention may be the cause of the hepatic abnormalities. These changes have not been previously associated with ovine abomasal emptying defect, the pathogenic mechanism of which remains unclear.
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PMID:Abomasal dilatation and emptying defect in a ewe. 335 94

Simultaneous intraperitoneal administration of 700 mg/kg galactosamine and 33 micrograms/kg Salmonella abortus equi endotoxin to male NMRI albino mice resulted in fulminant hepatitis as assessed after nine hours by measurement of serum transaminases as well as sorbitol dehydrogenase activities. Intraperitoneal pretreatment of animals with 2 X 100 mg/kg allopurinol, or intravenous pretreatment with 33 kU superoxide dismutase or 1 MU catalase fully prevented hepatitis. Administration of 10 micrograms/kg of the prostacyclin analogue iloprost antagonized liver injury when given simultaneously with galactosamine/endotoxin but did not protect when given 90 min later. Tocopherol or desferal pretreatment of the animals had no significant protective effect. Together with our recent finding that hepatic leukotriene D4 production is likely to be responsible for galactosamine/endotoxin-induced hepatitis we interpret these results as evidence for a leukotriene-induced hepatic ischemia followed by a reperfusion syndrome.
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PMID:Evidence for the involvement of a reperfusion injury in galactosamine/endotoxin-induced hepatitis in mice. 360 63

In liver transplantation, activation of NFkappaB occurs upon reperfusion, yet few data exist regarding NFkappaB activation during cold ischemia. We hypothesized that activation of NFkappaB may initially occur during cold ischemia, prior to reperfusion, and serve as an important determinant of postreperfusion function. To test this hypothesis, serial biopsies during porcine liver harvest were obtained immediately upon laparotomy, upon completion of dissection, after 45 and 120 min of cold ischemia, and 60 and 180 min after reperfusion. Nuclear extracts were isolated for Western blot analysis of NFkappaB. Hepatic function was assessed through bile output and sorbitol dehydrogenase (SDH) activity. NFkappaB expression was maximal at 45 min of cold ischemia and decreased by 120 min. The expression at 120 min of cold ischemia correlated with markers of postreperfusion function, namely bile flow and SDH activity. During reperfusion a second distinct peak occurred at 180 min. Increased expression of NFkappaB at 180 min of reperfusion correlated directly with prior expression at 120 min during cold ischemia and with increased SDH activity. These data indicate that nuclear expression of NFkappaB demonstrate two distinct peaks of activity, one during cold ischemia and one after reperfusion. Enhanced expression of NFkappaB during cold ischemia not only correlates directly with NFkappaB expression during reperfusion, but also correlates inversely with postreperfusion graft function.
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PMID:NFkappaB expression during cold ischemia correlates with postreperfusion graft function. 1094 41

Endothelin is a potent hepatic vasoconstrictor. We evaluated the role of an endothelin antagonist in hepatic ischemia/reperfusion injury. Bosentan, a novel endothelin receptor antagonist, was infused directly into the portal vein prior to cold ischemia and immediately on reperfusion, in five porcine livers. Five other pigs underwent routine liver harvest and reperfusion without bosentan treatment. Hepatic vascular resistance and liver tissue blood flow, as measured by thermistor flow probes, were determined following reperfusion. Hepatocellular damage was assessed through hepatic venous levels of sorbitol dehydrogenase and lactate dehydrogenase. Endothelial cell damage was determined in sections immuno-stained for factor VIII. Graft function was determined through oxygen consumption, bile production, and response to bile acid challenge. Organs treated with bosentan demonstrated lower vascular resistance and enhanced tissue blood flow (P < 0.05) as compared to untreated organs. Portal vein inflow to hepatic tissue was significantly enhanced (4.4-fold) in the bosentan-treated organs (P < 0.05). No difference was observed in hepatocellular damage. Pathology scores for factor VIII immunohistochemical staining were 2.3-fold higher in the bosentan-treated livers as compared to untreated livers (P < 0.05). The bosentan-treated livers also demonstrated enhanced oxygen consumption, increased bile production, and augmented biliary response to a bile acid challenge (P < 0.05). These results indicate that administration of bosentan before and after ischemia/reperfusion reduces hepatic circulatory disturbances, diminishes endothelial cell damage, and augments hepatic graft function.
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PMID:Bosentan, an endothelin antagonist, augments hepatic graft function by reducing graft circulatory impairment following ischemia/reperfusion injury. 1136 57

The aldose reductase pathway has been demonstrated to be a key component of myocardial ischemia reperfusion injury. Previously, we demonstrated that increased lactate/pyruvate ratio, a measure of cytosolic NADH/NAD+, is an important change that drives the metabolic cascade mediating ischemic injury. This study investigated signaling mechanisms by which the aldose reductase pathway mediates myocardial ischemic injury. Specifically, the influence of the aldose reductase pathway flux on JAK-STAT signaling was examined in perfused hearts. Induction of global ischemia in rats resulted in JAK2 activation followed by STAT5 activation. Pharmacological inhibition of aldose reductase or sorbitol dehydrogenase blocked JAK2 and STAT5 activation and was associated with lower lactate/pyruvate ratio and lower protein kinase C activity. Niacin, known to lower cytosolic NADH/NAD+ ratio independent of the aldose reductase pathway inhibition, also blocked JAK2 and STAT5 activation. Inhibition of protein kinase C also blocked JAK2 and STAT5 activation. Transgenic mice overexpressing human aldose reductase exhibited increased JAK2 and STAT5 activation. Pharmacological inhibition of JAK2 reduced ischemic injury and improved functional recovery similar to that observed in aldose reductase pathway inhibited mice hearts. These data, for the first time, demonstrate JAK-STAT signaling by the aldose reductase pathway in ischemic hearts and is, in part, due to changes in cytosolic redox state.
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PMID:Aldose reductase pathway mediates JAK-STAT signaling: a novel axis in myocardial ischemic injury. 1574 88

Previously, we reported that transgenic mice overexpressing endothelin-1 in astrocytes showed more severe neurological deficits and increased infarct after transient focal ischemia. In those studies, we also observed increased level of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which has been implicated in osmotic and oxidative stress. To further understand the involvement of the polyol pathway, the mice with deletion of enzymes in the polyol pathway, AR, and sorbitol dehydrogenase (SD), which is the second enzyme in this pathway, were challenged with similar cerebral ischemic injury. Deletion of AR-protected animals from severe neurological deficits and large infarct, whereas similar protection was not observed in mice with SD deficiency. Most interestingly, AR(-/-) brains showed lowered expression of transferrin and transferrin receptor with less iron deposition and nitrotyrosine accumulation. The protection against oxidative stress in AR(-/-) brain was also associated with less poly(adenosine diphosphate-ribose) polymerase (PARP) and caspase-3 activation. Pharmacological inhibition of AR by Fidarestat also protected animals against cerebral ischemic injury. These findings are the first to show that AR contributes to iron- and transferrin-related oxidative stress associated with cerebral ischemic injury, suggesting that inhibition of AR but not SD may have therapeutic potential against cerebral ischemic injury.
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PMID:Deletion of aldose reductase leads to protection against cerebral ischemic injury. 1729 45

Retinal ischemic injury is common in patients with diabetes, atherosclerosis, hypertension, transient ischemia attack and amaurosis fugax. Previously, signs of ischemic stress, such as pericyte loss, blood-retinal barrier breakdown and neovascularization, which can lead to occlusion of retinal vessels, have been prevented in diabetic db/db mice with aldose reductase (AR) null mutation. To determine the role in retinal ischemic injury of AR and sorbitol dehydrogenase (SDH), the first and second enzymes in the polyol pathway, mice with deletion of AR (AR(-/-)) or SDH-mutation (SDH(-/-)), or C57BL/6N mice treated with AR or SDH inhibitors were subjected to transient retinal artery occlusion (2h of occlusion and 22h of reperfusion) by the intraluminal suture method. Neuronal loss and edema observed in wildtype (AR(+/+)) retinas after transient ischemia were prevented in the retinas of AR(-/-) mice or C57BL/6N mice treated with an AR inhibitor, Fidarestat. Fewer TUNEL-positive cells and smaller accumulations of nitrotyrosine and poly(ADP-ribose) were also observed in the retinas of AR(-/-) mice. However, SDH(-/-) mice and C57BL/6N mice treated with SDH inhibitor, CP-470,711, were not protected against ischemia-induced retinal damage. Taken together, AR contributes to retinal ischemic injury through increased edema and free radical accumulation. Therefore, AR inhibition should be considered for the treatment of retinal ischemic injury often observed in diabetic patients.
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PMID:Gene deletion and pharmacological inhibition of aldose reductase protect against retinal ischemic injury. 1772 43


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