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)

The adhesion of leukocytes to the endothelium of postcapillary venules hallmarks a key event in ischemia-reperfusion injury. Adenosine has been shown to protect from postischemic reperfusion injury, presumably through inhibition of postischemic leukocyte-endothelial interaction. This study was performed to investigate in vivo by which receptors the effect of adenosine on postischemic leukocyte-endothelium interaction is mediated. The hamster dorsal skinfold model and fluorescence microscopy were used for intravital investigation of red cell velocity, vessel diameter, and leukocyte-endothelium interaction in postcapillary venules of a thin striated skin muscle. Leukocytes were stained in vivo with acridine orange (0.5 mg kg-1 min-1 i.v.). Parameters were assessed prior to induction of 4 h ischemia to the muscle tissue and 0.5 h, 2 h, and 24 h after reperfusion. Adenosine, the adenosine A1-selective agonist 2-chloro-N6-cyclopentyladenosine (CCPA), the A2-selective agonist CGS 21,680, the non-selective adenosine receptor antagonist xanthine amine congener (XAC), and the adenosine uptake blocker S-(p-nitrobenzyl)-6-thioinosine (NBTI) were infused via jugular vein starting 15 min prior to release of ischemia until 0.5 h after reperfusion. Adenosine and CGS 21,680 significantly reduced postischemic leukocyte-endothelium interaction 0.5 h after reperfusion (p less than 0.01), while no inhibitory effect was observed with CCPA. Coadministration of XAC blocked the inhibitory effects of adenosine. Infusion of NBTI alone effectively decreased postischemic leukocyte-endothelium interaction. These findings indicate that adenosine reduces post-ischemic leukocyte-endothelium interaction via A2 receptor and suggest a protective role of endogenous adenosine during ischemia-reperfusion.
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PMID:Reduction of postischemic leukocyte-endothelium interaction by adenosine via A2 receptor. 144 86

Recent experimental data indicate a probable role of adenosine as an endogenous neuroprotective substance in brain ischemia. This nucleoside is rapidly formed during ischemia as a result of intracellular breakdown of ATP and it is subsequently transported into the extracellular space. With use of microdialysis and other techniques, a massive increase of interstitial adenosine has been measured during ischemia in different brain areas. Adenosine acts through two subtypes of receptors, A1 and A2, which are located on neurons, glial cells, blood vessels, platelets, and leukocytes and are linked via G-proteins to different effector systems such as adenylate cyclase and membrane ion channels. There is a very high density of A1-receptors in the hippocampus, an area with specific vulnerability to ischemia. In different in vivo and in vitro models of brain ischemia, the pharmacological manipulation of the adenosine system by adenosine receptor antagonists tended to aggravate ischemic brain damage, whereas the reinforcement of adenosine action by receptor agonists or inhibitors of cellular reuptake and inactivation showed neuroprotection. The up-regulation of adenosine A1-receptor number and affinity by chronic preadministration of the competitive antagonist caffeine also attenuated ischemic brain damage. The mechanisms underlying the neuroprotective effects of adenosine seem to involve both types of adenosine receptors, A1 and A2, but the A1-mediated pre- and postsynaptic neuromodulation may be of special importance. By inhibiting neuronal Ca2+ influx, adenosine counteracts the presynaptic release of the potentially excitotoxic neurotransmitters glutamate and aspartate, which may impair intracellular Ca2+ homeostasis via metabotrophic glutamate receptors or induce uncontrolled membrane depolarization via ion channel-linked glutamate receptors, especially of the N-methyl-D-aspartate (NMDA) type. In addition, adenosine directly stabilizes the neuronal membrane potential by increasing the conductance for K+ and Cl- ions, thereby counteracting excessive membrane depolarization. The latter triggers a number of pathological events including blockade of voltage-sensitive K+ currents, increase of NMDA receptor-mediated Ca2+ influx, and presumably also impairment of glutamate uptake by astrocytes. In the way of a vicious cycle, all these factors again tend to enhance extracellular glutamate levels and membrane depolarization, finally leading to cytotoxic calcium loading and neuronal cell death. In addition to its important neuromodulatory effects, which tend to reduce energy demand of the brain, adenosine acting via A2-receptors in brain vessels, platelets, and neutrophilic granulocytes may improve the cerebral microcirculation and thus oxygen and substrate supply to the tissue. There is evidence that the functional state of adenosine receptors is impaired during ischemia, limiting the time window of the adenosine action.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adenosine and brain ischemia. 148 19

To test the hypothesis that 5'-nucleotidase activity during ischemia is attenuated by oxygen-derived free radicals, we measured ischemia-induced reactive hyperemic flow, adenosine release, and 5'-nucleotidase activity in dogs (n = 62). A 1-minute occlusion of the coronary artery caused reactive hyperemic flow (307 +/- 5 versus 92 +/- 1 ml.100 g-1.min-1 at baseline) with increased release of adenosine (14.4 +/- 1.4 versus 0.4 +/- 0.1 nmol.100 g-1.min-1 at baseline). Superoxide dismutase augmented (p less than 0.001) both peak coronary blood flow (333 +/- 6 ml.100 g-1.min-1) and repayment (436 +/- 12 versus 320 +/- 7 ml/100 g in the untreated group). Adenosine release during reperfusion was augmented (22.7 +/- 1.9 nmol.100 g-1.min-1, p less than 0.001), and 8-phenyltheophylline completely abolished the enhanced reactive hyperemia. Enzymatic assay of 5'-nucleotidase activity revealed that the administration of superoxide dismutase increases ecto-5'-nucleotidase activity in ischemic myocardium. When an inhibitor of ecto-5'-nucleotidase, alpha, beta-methyleneadenosine 5'-diphosphate, was administered, the effects of superoxide dismutase were completely abolished. Thus, we conclude that 1) the augmentation of reactive hyperemic flow caused by superoxide dismutase is attributed to the enhanced release of adenosine and 2) the enhanced release of adenosine over the untreated controls is attributed to the protection of ecto-5'-nucleotidase activity during ischemia.
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PMID:Superoxide dismutase enhances ischemia-induced reactive hyperemic flow and adenosine release in dogs. A role of 5'-nucleotidase activity. 149 5

Adenosine participates in the coupling of cerebral blood flow to oxygen consumption in the brain during such stimuli as hypoxia, ischemia, and seizures. It has been suggested that it also participates in the regulation of cerebral blood flow during somatosensory stimulation, a condition during which cerebral blood flow and oxygen consumption appear to be uncoupled. Interstitial adenosine was estimated by the microdialysis technique and cerebral blood flow was measured by hydrogen clearance in the hindlimb sensory-motor cortex during sciatic nerve stimulation. Cerebral blood flow increased from 102 to 188 ml min-1 100 g-1 (p less than 0.001) in the cortex contralateral to the stimulated leg without an associated increase in interstitial adenosine (baseline 0.624 microM, stimulation 0.583 microM). Infusion of the adenosine antagonist 8-sulfophenyltheophylline failed to block an increase in cerebral blood flow during central sciatic nerve stimulation, but decreased basal cerebral blood flow (69 ml min-1 100 g-1). These results suggest that adenosine does not mediate changes in cerebral blood flow during somatosensory stimulation, but may participate in the regulation of cerebral blood flow in the basal state.
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PMID:Sciatic nerve stimulation does not increase endogenous adenosine production in sensory-motor cortex. 959 50

We hypothesized that either through local myocardial or systemic effects, adenosine could be used to control hypotension during ischemia. Therefore, we compared the effects of systemic with intracoronary infusion of adenosine on myocardial hemodynamics and metabolism during ischemia in 27 dogs. Left anterior descending artery (LADa) flow was measured and the LADa constricted by a micrometer to restrict resting flow by 50%, 75%, and 100%. Adenosine was infused either systemically (n = 9), to maintain mean aortic pressure at 50-60 mm Hg, or directly into the LADa (n = 9), to create maximal coronary hyperperfusion; no adenosine was infused in the control group (n = 9). With systemic adenosine, during each constriction aortic pressure, left ventricular first derivative (LV dP/dt), and heart rate (HR) decreased: aortic pressure by 56.1% +/- 2.9% (mean +/- SEM), LV dP/dt by 36.2% +/- 2.2%, systemic resistance by 42.7% +/- 5%, and HR by 38.7% +/- 3% during 50% constriction (P less than 0.05 for each variable). Intracoronary adenosine decreased only aortic pressure, LV dP/dt, and HR, all to a lesser extent: aortic pressure by 5% +/- 2.8%, LV dP/dt by 15% +/- 1.2%, and HR by 4.6% +/- 1.7% (P less than 0.05, compared with systemic adenosine for each variable). With systemic adenosine only in the nonischemic area, regional myocardial blood flow increased and remained high, from 224.6 +/- 65.2 to 342 +/- 46.2 mL.min-1.100 g-1 during 50% constriction (P less than 0.05); with intracoronary adenosine, ischemic zone regional myocardial blood flow increased, but not consistently. In the ischemic area, O2 consumption was less with than without systemic adenosine; also, lactate flux production was less positive (-60.2 +/- 37.6 compared with 80.3 +/- 20.2 mmol.min-1.100 g-1 x 10(-3) during 50% constriction; P less than 0.05). Systemic infusion of adenosine during coronary hypoperfusion improves regional metabolism during ischemia and, thus, may mitigate myocardial ischemia. The mechanism by which systemic infusion improves metabolic status may be by decreases in both systemic pressure and systemic vascular resistance.
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PMID:Adenosine for controlled hypotension: systemic compared with intracoronary infusion in dogs. 151 Feb 51

Adenosine is released from the myocardium in response to a decrease in the oxygen supply/demand ratio, as is seen in myocardial ischemia; its protective role is manifested by coronary and collateral vessel vasodilation that increase oxygen supply and by multiple effects that act in concert to decrease myocardial oxygen demand (i.e., negative inotropism, chronotropism, and dromotropism). During periods of oxygen deprivation, adenosine enhances energy production via increased glycolytic flux and can act as a substrate for purine salvage to restore cellular energy charge during reperfusion. Adenosine limits the degree of vascular injury during ischemia and reperfusion by inhibition of oxygen radical release from activated neutrophils, thereby preventing endothelial cell damage, and by inhibition of platelet aggregation. These effects help to preserve endothelial cell function and microvascular perfusion. Long-term exposure to adenosine may also induce coronary angiogenesis.
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PMID:Protective effects of adenosine in myocardial ischemia. 153 25

In vivo 31P nuclear magnetic resonance (NMR) spectroscopy of the right ventricular (RV) free wall was employed to determine (a) whether phosphorus energy metabolites vary reciprocally with workload in the RV and (b) the mechanisms that limit RV contractile function in acute pressure overload. In 20 open-chest pigs, phosphocreatine (PCr)/ATP ratio (an index of energy metabolism inversely related to free ADP concentration), myocardial blood flow (microspheres), and segment shortening (sonomicrometry, n = 14) were measured at control (RV systolic pressure 31 +/- 1 mm Hg), and with pulmonary artery constriction to produce moderate pressure overload (RV systolic pressure 45 +/- 1 mm Hg), and maximal pressure overload before overt RV failure and systemic hypotension (RV systolic pressure 60 +/- 1 mm Hg). With moderate pressure overload, PCr/ATP declined to 89% of control (P = 0.01), while contractile function increased. Adenosine (n = 10, mean dose 0.16 mg/kg-min) increased RV blood flow by an additional 41% without increasing PCr/ATP, indicating that coronary reserve was not depleted and that the decrease in PCr/ATP from control was not due to ischemia. With maximal pressure overload and incipient RV failure, PCr/ATP fell further to 81% of control and RV blood flow did not increase further, even with adenosine. Thus: (a) The decline in PCr/ATP with moderate RV pressure overload, without evident ischemia or contractile dysfunction, supports the positive regulation of oxidative phosphorylation by ATP hydrolysis products. (b) Depletion of RV coronary flow reserve accompanies the onset of RV failure at maximal pressure overload.
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PMID:Energetics of acute pressure overload of the porcine right ventricle. In vivo 31P nuclear magnetic resonance. 154 81

The objective of this study was to determine the effect of adenosine on overall myocardial substrate utilization and mechanical function in isolated working rat hearts. Hearts were perfused with Krebs-Henseleit buffer containing 11 mM glucose (no fat) or with 11 mM glucose and 0.4 mM palmitate (normal fat). Steady-state rates of glycolysis, glucose oxidation, and fatty acid oxidation were measured by determination of quantitative 3H2O and 14CO2 production from radiolabeled substrates. The ratio of glycolysis (6.07 +/- 0.57 mumol.min-1.g dry wt-1) to glucose oxidation (3.12 +/- 0.28 mumol.min-1.g dry wt-1) under no fat conditions was 2:1. The addition of palmitate per se decreased glucose oxidation (to 0.81 +/- 0.09 mumol.min-1.g dry wt-1) and increased the glycolysis-to-glucose oxidation ratio to 6:1. Adenosine (100 microM) reduced this ratio to 3:1 by decreasing glycolysis (to 3.75 +/- 0.32 mumol.min-1.g dry wt-1) and increasing glucose oxidation (to 1.28 +/- 0.18 mumol.min-1.g dry wt-1) in the presence of palmitate. Steady-state palmitate oxidation rates were not altered by adenosine. Adenosine increased efficiency (work performed per unit O2 consumed) of spontaneously beating hearts but had no effect in paced hearts. These effects of adenosine on glucose metabolism may explain the beneficial actions of adenosine during reperfusion post ischemia.
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PMID:Adenosine modification of energy substrate use in isolated hearts perfused with fatty acids. 159 Apr 54

Adenosine is released from renal cells, and extracellular adenosine may influence the effects of ischemia on medullary tubule segments by altering ion transport or renal hemodynamics. While adenosine release and excretion are enhanced during renal ischemia, the specific sites of renal adenosine production have not been completely elucidated. In the present study, extracellular adenosine concentrations in suspensions of renal outer medulla and thick ascending limb segments were quantitated by reversed-phase high performance liquid chromatography. Media from other medullary (OM) suspensions incubated for 8 and 15 minutes at 0% oxygen contained significantly greater amounts of adenosine (1.404 +/- 0.21 and 2.034 +/- 0.27 ng/micrograms protein, respectively), when compared to values obtained from media of suspensions incubated for equivalent periods under non-hypoxic conditions (8, 20, and 95% oxygen), 0.78 +/- 0.05 (8 min) and 1.37 +/- 0.21 ng/micrograms protein (15 min). Similarly, adenosine release was greater in medullary thick ascending limb (mTAL) suspensions incubated for 8 minutes at 0% versus 8% oxygen (0.81 +/- 0.17 vs. 0.20 +/- 0.12 ng/micrograms protein, respectively). Moreover, the observed increase in adenosine release by thick ascending limbs at 0% oxygen could be inhibited completely by either furosemide or ouabain. These studies demonstrate that: 1) the renal medulla and medullary thick ascending limb are sites of adenosine release; 2) adenosine release by the mTAL is enhanced significantly during hypoxic conditions; and 3) the increased release of adenosine during hypoxia appears to be related to ion transport and oxidative metabolism, as the increased release was prevented by two disparate inhibitors of transport in this segment.
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PMID:Effects of graded oxygen tension on adenosine release by renal medullary and thick ascending limb suspensions. 164 43

Hyperkalaemia-induced hypopolarization of the sarcolemnal membrane during standard crystalloid cardioplegic arrest potentiates calcium influx during reperfusion and is associated with depletion of high-energy phosphate reserves. Adenosine has been shown to induce fast cardiac arrest whilst preserving membrane hyperpolarization in an isolated rat heart model. In this study we compared the efficacy of adenosine, both as an arresting agent and as an ultrastructural, haemodynamic and high-energy phosphate preserving agent, in an in situ global ischemia model in the baboon with St. Thomas' Hospital solution No. 2 (ST2; n = 8) and with Krebs-Henseleit buffer (KHB; n = 7). The addition of 10 mM adenosine to the non-cardioplegic KHB (ADO; n = 8) improved haemodynamic recovery significantly in terms of cardiac index (91.6% +/- 7.2 vs 59.9% +/- 9.9) and stroke volume index (101.6% +/- 8.9 vs 55.6 +/- 10.0) and was not statistically distinguishable from the ST2 with regard to cardiac index (91.6% +/- 7.2 vs 94.8% +/- 5.8), stroke volume index (101.6% +/- 8.9 vs 114.0% +/- 8.3) or left ventricular dP/dt (73.1% +/- 9.9 vs 87.0% +/- 12.4). Adenosine triphosphate was best preserved with ADO (103.5% +/- 21.1 vs 67.9% +/- 9.3 and 48.5% +/- 8.7) although this was not statistically significant. This suggests therefore that the mechanism of cardioprotection by adenosine occurs by means other than its role as high-energy phosphate precursor.
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PMID:Adenosine cardioplegia: reducing reperfusion injury of the ischaemic myocardium? 175 47


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