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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The observability of nucleoside triphosphate (NTP) by 31P NMR spectroscopy was studied in the isolated rat liver during hypothermic perfusion and a subsequent 4-h cold ischemia. The influence of hypothermia (4 degrees C) was examined because of its delaying effects on cell injury induced by the ischemic conditions. The viability of the liver after hypothermic ischemia was assessed by measuring the recovery of the beta-NTP resonance after reperfusion. In 4-h cold ischemic liver, recovery was found to be in the range of 90-100% and consequently NTP visibility was studied under these conditions. Because the individual purine (or pyrimidine) NTPs are not distinguishable in the liver on the basis of their 31P NMR chemical shifts, the contributions of UTP and GTP were investigated by HPLC. The changes in liver NTP content measured either by NMR on isolated liver or by HPLC after perchloric acid extraction from the same organ are not significantly different. The total NTP level in normothermic perfused liver is 7.6 +/- 0.2 mumol NTP/g liver dry wt as determined by NMR. In such a liver, ATP + GTP + UTP and ATP contents measured by HPLC are, respectively, 7.9 +/- 1.0 and 6.3 +/- 0.9 mumol/g liver dry wt. This indicates that all NTP is detected by NMR and that a 20% contribution of the signal occurs from UTP + GTP. Under 4-h cold ischemic conditions, NTP visibility remains unchanged, furthermore the UTP + GTP contribution reaches 32% of the whole NTP content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Is cellular integrity responsible for the partial NMR invisibility of ATP in isolated ischemic rat liver? 181 6

Nucleotide metabolism was studied in rats during and following the induction of 10 min of forebrain ischemia (four-vessel occlusion model). Purine and pyrimidine nucleotides, nucleotides, and bases in forebrain extracts were quantitated by HPLC with an ultraviolet detector. Ischemia resulted in a severe reduction in the concentration of nucleoside triphosphates (ATP, GTP, UTP, and CTP) and an increase in the concentration of AMP, IMP, adenosine, inosine, hypoxanthine, and guanosine. During the recovery period, both the phosphocreatine level and adenylate energy charge were rapidly and completely restored to the normal range. ATP was only 78% of the control value at 180 min after ischemic reperfusion. Levels of nucleosides and bases were elevated during ischemia but decreased to values close to those of control animals following recirculation. Both the decrease in the adenine nucleotide pool and the incomplete ATP recovery were caused by insufficient reutilization of hypoxanthine via the purine salvage system. The content of cyclic AMP, which transiently accumulated during the early recirculation period, returned to the control level, paralleling the decrease of adenosine concentration, which suggested that adenylate cyclase activity during reperfusion is modulated by adenosine A2 receptors. The recovery of CTP was slow but greater than that of ATP, GTP, and UTP. The GTP/GDP ratio was higher than that of the control animals following recirculation.
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PMID:Mononucleotide metabolism in the rat brain after transient ischemia. 370 29

Extracellular ATP concentration can rise because of its release by nerve terminals and by damaged cells during ischemia. After the activation of P2-purinergic receptors, ATP induces a positive inotropic effect and increases the L-type Ca2+ current via activation of a Gs protein but without cAMP production. In addition, ATP shifts the voltage characteristics of Ca2+ current toward hyperpolarized potentials. If ATP produced similar effects on the Na+ current (INa), this compound should also affect cardiac excitability and conduction. Using the whole-cell patch-clamp to record INa in rat ventricular cells, we show that extracellular application of ATP induced hyperpolarizing shifts in the current-voltage relation and the availability of INa. The ED50 for the shifts in both conductance and availability was obtained with 0.7 mumol/L ATP. Maximal shifts in conductance and availability were respectively 9.7 +/- 0.6 and 10.6 +/- 0.7 mV. The leftward shift of the availability curve is responsible for the decrease of INa amplitude at less polarized holding potentials. These effects were not cholera toxin sensitive and thus cannot be attributed to activation of the Gs protein. At 100 mumol/L, ATP gamma S and alpha,beta-methylene ATP could induce shift, whereas UTP and beta,gamma-methylene ATP as well as ADP and adenosine were without effect. Thus, depending on the resting membrane potential, ATP should either enhance excitability or favor slow conduction and weaken cardiac electrical homogeneity and consequently favor arrhythmia.
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PMID:Effect of extracellular ATP on the Na+ current in rat ventricular myocytes. 813 6

Adenosine (ADO) is an important endogenous protective metabolite of the heart which also exerts beneficial effects when exogenously supplied before or after ischemia. Previous studies established that after initial massive release of ADO, its endogenous production could be significantly reduced following myocardial ischemia. However, the mechanism and consequences of this phenomenon are not clear. We investigated whether this suppressed endogenous ADO production could be reversed by a transient supply of exogenous ADO during reperfusion. Furthermore, we studied the recovery of mechanical function, coronary flow and myocardial nucleotide levels after this intervention. Three concentrations of ADO were applied: 1 microM, which exerts maximal vasodilatation: 30 microM, optimal for adenylate resynthesis: and 1 mM which exerts a cardioplegic effect. Rat hearts perfused in the Langendorff mode were divided into five groups (n = 6-9 per group): all hearts had transient (30-s) ischemia at 20 min (TI-1) and 70 min (TI-3) of perfusion. Group 1 (control) had an additional transient (30-s) ischemia at 45 min (TI-2). Group 2 (ischemic control) had 10-min ischemia at 30 min: groups 3, 4 and 5 also had 10-min ischemia at 30 min but were reperfused for the initial 15 min with 1 microM, 30 microM or 1 mM ADO. Developed tension, coronary flow and coronary effluent purines and pyrimidines were measured throughout the 75-min experimental period. Nucleotide content was evaluated in freeze-clamped hearts at the end of the experiment. Endogenous ADO release to the coronary effluent increased immediately after TI-1 in all groups. This increase was similar after TI-1 and after TI-3 in control, while it was reduced to 30% in ischemic control group. In the 30 microM ADO group the increase in endogenous ADO release after TI-3 was restored and was similar to that after TI-1. A similar trend was observed with 1 mM ADO, while in 1 microM group recovery of endogenous ADO release after TI-3 was not observed. The highest recovery of developed tension (+ S.E.) occurred with 1 microM and 30 microM ADO (72 +/- 3% and 72 +/- 5% of pre-ischemic value, respectively) compared to 53 +/- 5% and 63 +/- 5% in ischemic control and 1 mM ADO groups, respectively (P <0.05). Coronary flow was restored 30 s after 10 min ischemia in hearts treated with 1 microM and 30 microM ADO, whereas more than 2 min were necessary in ischemic control or 1 mM ADO groups. Furthermore, hyperemic response after TI-3 was significantly enhanced in the 1 microM or 30 microM ADO groups. ATP content at the end of reperfusion was highest in the 30 microM ADO group (18.9 +/- 0.5 micromol/g dry wt.) as compared to ischemic control. 1 microM or 1 mM ADO groups (15.2 +/- O.6, 16.4 +/- 0.4, and 17.2 +/- 0.4 micromol/g dry wt. respectively). Concentrations of other nucleotide triphosphates (GTP, UTP and CTP) were similar in all hearts subjected to 10-min ischemia. In summary, depressed endogenous ADO production in the post-ischemic heart could be ameliorated by transient supply of exogenous ADO during reperfusion at 30 microM concentration. This effect was found to be related to the elevation of the adenine nucleotide pool. However, restoration of endogenous ADO production was not necessary for improvement in the recovery of mechanical function by exogenous ADO.
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PMID:Exogenous adenosine, supplied transiently during reperfusion, ameliorates depressed endogenous adenosine production in the post-ischemic rat heart. 904 48

A short ischemic period induced by the transient occlusion of major brain arteries induces neuronal damage in selectively vulnerable regions of the hippocampus. Adenosine is considered to be one of the major neuroprotective substances produced in the ischemic brain. It can be released from damaged cells, but it also could be generated extracellularly from released ATP via a surface-located enzyme chain. Using the rat model of global forebrain ischemia, we applied a short (10 min) transient interruption of blood flow and studied the distribution of ectonucleotidase activities in the hippocampus. Northern hybridization of mRNA isolated from hippocampi of sham-operated and ischemic animals revealed an upregulation of ectoapyrase (capable of hydrolyzing nucleoside 5'-tri- and diphosphates) and ecto-5'-nucleotidase (capable of hydrolyzing nucleoside 5'-monophosphates). A histochemical analysis that used ATP, UTP, ADP, or AMP as substrates revealed a strong and selective increase in enzyme activity in the injured areas of the hippocampus. Enhanced staining could be observed first at 2 d. Staining increased within the next days and persisted at 28 d after ischemia. The spatiotemporal development of catalytic activities was identical for all substrates. It was most pronounced in the CA1 subfield and also could be detected in the dentate hilus and to a marginal extent in CA3. The histochemical staining corresponded closely to the development of markers for reactive glia, in particular of microglia. The upregulation of ectonucleotidase activities implies increased nucleotide release from the damaged tissue and could play a role in the postischemic control of nucleotide-mediated cellular responses.
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PMID:Upregulation of the enzyme chain hydrolyzing extracellular ATP after transient forebrain ischemia in the rat. 963 55

In vivo administration of low doses of lipopolysaccharide (LPS) to rodents can protect these animals from subsequently administrated, usually lethal doses of endotoxin or LPS. In this study we tested the effects of LPS pretreatment on ischemia/reperfusion injury in the kidney. Male C57/B1 mice were pretreated with different doses of LPS or phosphate-buffered saline on days -4 and -3. The right kidney was removed, and the vessels of the left kidney were clamped for 30 or 45 minutes on day 0. Creatinine levels and survival of animals were monitored. To test the involvement of cytokines, additional animals were harvested before ("time 0") and 15 minutes, 1, 2, 8, and 16 hours after reperfusion for histology, immunohistochemistry, terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay, and reverse transcriptase-polymerase chain reaction analysis (including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, inducible nitric oxide synthase (iNOS), and interferon (IFN)-gamma messenger RNA (mRNA)). In controls, renal ischemia of 30 minutes was nonlethal, whereas 73% of the animals died within 48 +/- 18 hours, after 45 minutes of ischemia. All different doses of LPS protected the animals from lethal renal ischemia/reperfusion injury. Starting at similar levels, serum creatinine increased significantly in controls but not in LPS-pretreated animals over time. As early as 2 hours after reperfusion, tubular cell damage was significantly more pronounced in controls than in LPS-treated mice. In controls, tubules deteriorated progressively until 8 hours of reperfusion. At this time, more than 50% of tubular cells were destroyed. This destruction was accompanied by a pronounced leukocytic infiltration, predominantly by macrophages. In contrast, LPS pretreatment prevented the destruction of kidney tissue and infiltration by leukocytes. The terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay revealed significantly more apoptotic cells in controls compared with LPS-pretreated animals. IL-1, IFN-gamma, and iNOS mRNA expression did not differ between the groups throughout the time points examined. However, the expression of TNF-alpha mRNA was significantly increased at 2 hours and IL-6 mRNA was significantly down-regulated before ischemia and shortly after reperfusion in the LPS-pretreated kidneys. Therefore, we found that sublethal doses of LPS induced cross-tolerance to renal ischemia/reperfusion injury. Our data suggest that increased TNF-alpha and reduced IL-6 mRNA expression might be responsible. However, more studies are needed to decipher the exact mechanism.
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PMID:Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury : possible connection to an interleukin-6-dependent pathway. 1062 77

1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.
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PMID:Inflammatory mediators and modulation of blood-brain barrier permeability. 1069 6

In the last decade, the field of purinergic pharmacology has continued to grow as the complexity of the receptor families and the various enzymes involved in purine metabolism have been defined in molecular terms. A major theme that has emerged from these studies is the functional complexity of the interactions between P1 and P2 receptors, based upon the dynamic interrelationship between ATP and adenosine as extracellular signaling molecules. It is now clear that ATP and its degradation products (particularly ADP and adenosine) form a complex cascade for the regulation of cell-to-cell communication that can function to attenuate the consequences of tissue trauma (e.g. ischemia) that involve alterations in cellular energy charge and depletion of ATP stores. In addition to the P2 receptor family, alterations in cellular ATP stores can also affect the function of other receptors, e.g. K(ATP) channels, and mitochondrial function. The discovery of pyrimidine-preferring (UTP/UDP) P2Y receptors has also raised the possibility that the corresponding nucleoside, uracil, may function as a signaling molecule.
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PMID:Purinergic and pyrimidinergic receptors as potential drug targets. 1073 18

Birth asphyxia can cause moderate to severe brain injury. It is unclear to what degree apoptotic or necrotic mechanisms of cell death account for damage after neonatal hypoxia-ischemia (HI). In a 7-d-old rat HI model, we determined the contributions of apoptosis and necrosis to neuronal injury in adjacent Nissl-stained, hematoxylin and eosin-stained, and terminal deoxynucleotidyl transferase-mediated UTP nick end-labeled sections. We found an apoptotic-necrotic continuum in the morphology of injured neurons in all regions examined. Eosinophilic necrotic neurons, typical in adult models, were rarely observed in neonatal HI. Electron microscopic analysis showed "classic" apoptotic and necrotic neurons and "hybrid" cells with intermediate characteristics. The time course of apoptotic injury varied regionally. In CA3, dentate gyrus, medial habenula, and laterodorsal thalamus, the density of apoptotic cells was highest at 24-72 hr after HI and then declined. In contrast, densities remained elevated from 12 hr to 7 d after HI in most cortical areas and in the basal ganglia. Temporal and regional patterns of neuronal death were compared with expression of caspase-3, a cysteine protease involved in the execution phase of apoptosis. Immunocytochemical and Western blot analyses showed increased caspase-3 expression in damaged hemispheres 24 hr to 7 d after HI. A p17 peptide fragment, which results from the proteolytic activation of the caspase-3 precursor, was detected in hippocampus, thalamus, and striatum but not in cerebral cortex. The continued expression of activated caspase-3 and the persistence of cells with an apoptotic morphology for days after HI suggests a prolonged role for apoptosis in neonatal hypoxic ischemic brain injury.
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PMID:Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. 1105 Jan 20

The implication of low affinity nerve growth factor receptor (p75NGFR), which is believed to play a pro-apoptotic role, in delayed neuronal death (DND) after ischemia in the gerbil hippocampus was investigated. Immunohistochemistry and Western blot analysis revealed that the presence of p75 NGFR immunoreactivity (IR) was negligible in the hippocampus of the sham control gerbil but appeared clearly in CA1 neurons 3 and 4 days after 5-min transient ischemia. Terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL) positive nuclei appeared when the level of p75NGFR IR increased. Furthermore, almost all TUNEL-positive CA1 neurons also costained for p75NGFR. These results suggest that p75NGFR contributes to DND after ischemia by an apoptotic mechanism.
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PMID:The contribution of low affinity NGF receptor (p75NGFR) to delayed neuronal death after ischemia in the gerbil hippocampus. 1124 73


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