Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.17 (adenosine deaminase)
5,206 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of adenosine for reactive hyperemia in normal and stunned myocardium was examined in 16 open-chest barbiturate-anesthetized pigs. Interstitial adenosine concentration was reduced or enhanced by intracoronary infusion of adenosine deaminase or the nucleoside transport inhibitor R 75231, respectively. In normal myocardium, adenosine deaminase reduced volume of hyperemia (Doppler flowmetry) after a 30-s left anterior descending coronary artery (LAD) occlusion by 20% (6-34%; P < 0.05), whereas R 75231 increased volume of hyperemia by 15% (2-24%; P < 0.05). Adenosine deaminase reduced volume of hyperemia after a 2-min LAD occlusion by 27% (13-37%; P < 0.001), whereas R 75231 increased volume of hyperemia by 66% (53-159%; P < 0.001). Adenosine deaminase and R 75231 did not affect maximal hyperemia. Volume of hyperemia after a 2-min LAD occlusion was reduced in stunned myocardium (%systolic segment length shortening reduced by approximately 45%, ultrasonic technique) but not further altered by either adenosine deaminase or R 75231. These findings show that adenosine contributes to reactive hyperemia after 30-120 s of ischemia in normal myocardium and indicate that the reduced reactive hyperemia in stunned myocardium is due to reduced accumulation of adenosine during ischemia.
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PMID:Role of adenosine for reactive hyperemia in normal and stunned porcine myocardium. 141 60

We have previously demonstrated that oxypurinol (40 mg/kg i.p.), a xanthine oxidase inhibitor, can reduce focal ischemic brain injury in the rat when applied pre-ischemically. By using a model of occlusion of the middle cerebral artery (MCA) in tandem with occlusion of the ipsilateral carotid artery, the present study further demonstrates that delayed (60 min) administration of oxypurinol also exhibits a protective action on ischemic damage in the stroked rat brain. Oxypurinol significantly reduced the ischemic cerebral infarct zone by preventing the development of brain damage primarily in areas distant to the central lesion core. A corresponding amelioration of brain swelling and attenuation of neurological deficits were evident. Similar protection against focal ischemic brain damage was evident when the adenosine deaminase inhibitor, deoxycoformycin (500 micrograms/kg), was administered prior to the onset of ischemia. However, with delayed (60 min) administration deoxycoformycin had no protective effect. These findings support the hypothesis that manipulation of adenosine catabolism can be an effective therapeutic approach to the prevention or treatment of brain injuries, such as those occurring during ischemic stroke or cardiac arrest.
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PMID:Deoxycoformycin and oxypurinol: protection against focal ischemic brain injury in the rat. 161 98

Cardiac microdialysis is a recently developed technique that allows intramyocardial interstitial fluid (ISF) to be sampled via the implantation and perfusion of a small, hollow dialysis fiber within the myocardium. The purpose of this paper is to describe initial studies using cardiac microdialysis in the isolated perfused heart. Microdialysis probes, constructed in the laboratory, were implanted in the left ventricular myocardium of isolated perfused rat hearts and perfused at 0.5 microliter/min with Krebs-Henseleit buffer. The effluent dialysate, assayed for adenosine, inosine, hypoxanthine, xanthine, and uric acid, was used as an index of intramyocardial levels of these purine metabolites. All metabolites were elevated initially after implantation, declined rapidly in the first 45 min, and were then stable for the next 90 min. Based on in vitro percent recovery data, baseline dialysate concentrations were extrapolated to yield estimates of intramyocardial ISF (in microM) 0.47 adenosine, 0.85 inosine, 0.29 hypoxanthine, 0.49 xanthine, and 8.6 uric acid. During global zero-flow ischemia (37 degrees C), dialysate levels of all purine metabolites were elevated, with inosine being the predominant compound. Pretreatment of the hearts with 50 microM erythro-9-(2-hydroxy-3-nonyl)adenine, an adenosine deaminase inhibitor, markedly enhanced ISF adenosine accumulation and attenuated the accumulation of inosine, hypoxanthine, and xanthine. The simplicity and versatility of cardiac microdialysis in the isolated perfused heart suggest that this technique may be a valuable adjunct to the many studies performed using this preparation.
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PMID:Cardiac microdialysis in isolated rat hearts: interstitial purine metabolites during ischemia. 162 49

Cerebral energy metabolism can be measured non-invasively in unanesthetized neonatal rats with 31P NMR spectroscopy. Using this technique, serial changes in high energy phosphates were determined from the right cerebral hemispheres of 7 day postnatal rat pups during a hypoxic-ischemic insult known to produce focal brain injury. During 3 h of hypoxia-ischemia the concentration of ATP dropped to 33 +/- 8% of prehypoxic (baseline) levels, phosphocreatine (PCr)/Pi decreased from 1.5 +/- 0.51 to 0.16 +/- 0.06, while pH decreased nominally by 0.2 units. After 2.5 h of recovery in air, ATP returned to 75 +/- 10% of baseline levels, PCr/Pi rose to 1.1 +/- 0.28, and pH returned to its normal value of 7.16 +/- 0.06. This model was used to test the efficacy of the adenosine deaminase inhibitor, 2-deoxycoformycin (DCF) as a potential neuroprotective drug. The data for the drug- and saline-treated populations were analyzed by integrating ATP and Pi/PCr levels over specific time intervals, expressing it relative to baseline levels, and modeling it with cubic splines. Pretreatment with 500 micrograms/kg DCF shows a small, but statistically significant, preservation of both ATP and phosphorylation potential during hypoxia and initial recovery. Brain water content (edema) at 42 h recovery was apparently associated with both mean ATP and mean Pi/PCr in the last 2 h of hypoxia-ischemia. When ATP fell below 70% of baseline, brain edema was evident at 42 h of recovery. This methodology is suitable for extension to human infants.
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PMID:31P NMR spectroscopy of perinatal hypoxic-ischemic brain damage: a model to evaluate neuroprotective drugs in immature rats. 164 72

The effects of a potent adenosine deaminase inhibitor, deoxycoformycin, on purine and amino acid neuro-transmitter release from the ischemic rat cerebral cortex were studied with the cortical cup technique. Cerebral ischemia (20 min) was elicited by four-vessel occlusion. Purine and amino acid releases were compared from control ischemic animals and deoxycoformycin-pretreated ischemic rats. Ischemia enhanced the release of glutamate, aspartate, and gamma-aminobutyric acid into cortical perfusates. The levels of adenosine, inosine, hypoxanthine, and xanthine in the same perfusates were also elevated during and following ischemia. Deoxycoformycin (500 micrograms/kg) enhanced ischemia-evoked release of adenosine, indicating a marked rise in the adenosine content of the interstitial fluid of the cerebral cortex. Inosine, hypoxanthine, and xanthine levels were depressed by deoxycoformycin. Deoxycoformycin pretreatment failed to alter the pattern of amino acid neurotransmitter release from the cerebral cortex in comparison with that observed in control ischemic animals. The failure of deoxycoformycin to attenuate amino acid neurotransmitter release, even though it markedly enhanced adenosine levels in the extracellular space, implies that the amino acid release during ischemia occurs via an adenosine-insensitive mechanism. Inhibition of excitotoxic amino acid release is unlikely to be responsible for the cerebroprotective actions of deoxycoformycin in the ischemic brain.
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PMID:Brain adenosine and transmitter amino acid release from the ischemic rat cerebral cortex: effects of the adenosine deaminase inhibitor deoxycoformycin. 167 Oct 90

The concentrations of purine catabolites in the cerebral interstitial fluid during progression of and recovery from ischemia were studied using brain microdialysis and high-performance liquid chromatography. Sealed 0.5-mm hollow dialysis fibers were stereotactically implanted into either the cerebral cortex or hippocampus of ketamine anesthetized gerbils and perfused with artificial cerebrospinal fluid at 2 microliters/min. Cerebral ischemia was induced by occlusion of the bilateral common carotid arteries. The reflectance spectra of oxy- and deoxyhemoglobin at the brain surface were monitored over the scalp to assess ischemia and confirm recirculation. Ischemia caused a rapid, 4.8-fold increase in the extracellular concentration of adenosine. The progressive increase in the concentration of adenosine, inosine, and hypoxanthine soon after recirculation is particularly interesting. The subsequent decrease in purine compound concentration was rapid for adenosine but more gradual for inosine and hypoxanthine. Calculated K values for adenosine deaminase and purine nucleoside phosphorylase were 0.045/min and 0.016/min, respectively. However, no xanthine, uric acid, or purine nucleotides were found in the perfusate. These observations indicated the presence of purine catabolites in the cerebral interstitial space as well as consecutive degradation and recycling involving the interconversion of purine compounds by biochemical metabolic pathways.
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PMID:Purine catabolites in cerebral interstitial fluid during progression of and recovery from ischemia. 171 45

Cultured chick heart muscle cells degrade ATP during metabolic inhibition via ADP to AMP. Whether AMP is primarily deaminated to IMP or dephosphorylated to adenosine depends on the 'metabolic block' (glycolysis vs. oxidative phosphorylation). Inhibition of glycolysis (deoxyglucose) results in an inosine/adenosine ratio greater than 1 in the supernatant, whereas the nucleoside ratio is less than or equal to 1 during inhibition of oxidative phosphorylation (hypoxia, rotenone). EHNA, a blocker of adenosine deaminase, has little effect on inosine release during metabolic inhibition, consistent with the reported low activity of adenosine deaminase in cardiac muscle cells. The amount of adenosine and inosine released can be largely attenuated by two nucleoside carrier inhibitors, nitrobenzyl-thioinosine and dipyridamole, which suggests that nucleosides are produced intracellularly and subsequently released. These results indicate that the amount of inosine or adenosine released from the cardiomyocyte during impaired energy metabolism (e.g. ischemia) can be controlled by the metabolic state of the cell.
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PMID:Adenine nucleotide degradation in cultured chick heart muscle cells. 179 25

Reversible myocardial dysfunction associated with transient ischemia has been termed the stunned myocardium. Because exogenous adenosine has been shown to protect the ischemic myocardium, we hypothesized that augmentation of endogenous adenosine levels would attenuate myocardial stunning. To induce stunning, anesthetized dogs were subjected to 15 minutes of ischemia (left anterior descending artery occlusion) followed by 60 minutes of reperfusion. Erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; 5 mg/kg/hr), an adenosine deaminase inhibitor, was used to augment adenosine levels. The effect of EHNA on interstitial fluid (ISF) adenosine levels, coronary blood flow, and regional systolic wall thickening was compared with that of an untreated group (n = 8). EHNA increased preischemia ISF adenosine levels threefold and was associated with a corresponding increase in coronary blood flow. EHNA administration did not alter preischemia systolic wall thickening. Although ISF adenosine increased fourfold during ischemia in the untreated group, ISF adenosine increased nearly sixtyfold above preischemia values in the EHNA-treated group and remained elevated throughout reperfusion. Postischemic regional function was enhanced significantly in the group treated with EHNA. These data show that adenosine deaminase inhibition increased ISF adenosine levels and attenuated myocardial stunning. Metabolic manipulation of myocardial ISF nucleoside levels may be beneficial in limiting postischemic myocardial dysfunction.
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PMID:Enhanced interstitial fluid adenosine attenuates myocardial stunning. 185 25

Although cardioplegia reduces myocardial metabolism during ischemia, adenosine triphosphate (ATP) depletion occurs, which may contribute to poor functional recovery after reperfusion. Augmenting myocardial adenosine during ischemia is successful in improving ATP repletion and myocardial recovery following ischemia. If adenosine is an important determinant of ischemic tolerance, then depletion or elimination of myocardial adenosine should lead to poor functional and metabolic recovery after ischemia. To test this hypothesis, isolated, perfused rabbit hearts were subjected to 120 min of 34 degrees C ischemia. Hearts received St. Thomas cardioplegia alone or cardioplegia containing 200 microM adenosine, or cardioplegia containing 15, 5, 2.5, or 0.025 micrograms/ml adenosine deaminase (ADA), which catalyzes the breakdown of adenosine to inosine, making adenosine unavailable as an ATP precursor. Functional recovery was determined and myocardial nucleotide levels were measured before, during, and after ischemia. Following ischemia and reperfusion, control hearts recovered to 51 +/- 3% of preischemic developed pressure (DP). There was significantly better recovery in adenosine-augmented hearts (68 +/- 7%), while ADA hearts had significantly worse recovery. Hearts treated with 0.025 microgram/ml ADA recovered to only 29 +/- 5% of DP and higher dose ADA hearts failed to demonstrate any recovery of systolic function. Furthermore, adenosine enhanced metabolic recovery, whereas ADA resulted in greatly depleted ATP and precursor reserves. Postischemic developed pressure closely paralleled the availability of myocardial adenosine, consistent with the hypothesis that myocardial adenosine levels at end ischemia and early reperfusion are important determinants of functional recovery after global ischemia.
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PMID:ATP precursor depletion and postischemic myocardial recovery. 205 74

The aim of this study was to determine the dual role of ATP as an energy substrate and as a major source of oxygen-derived free-radical-mediated reperfusion injury by using adenine nucleoside blocker, p-nitrobenzylthioinosine (NBMPR), and adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). In a randomized study, 16 dogs were instrumented with minor-axis LTZ-piezoelectric crystals and intraventricular pressure transducers to monitor, off bypass, left ventricular performance by using a sensitive and load-independent index of contractility (slope of the stroke work-end-diastolic length relation). Hearts were subjected to 60 minutes of normothermic global ischemia and 120 minutes of reperfusion. Normal saline without (Group 1, n = 8) or with (Group 2, n = 8) NBMPR and EHNA was infused in three boluses into the cardiopulmonary bypass reservoir before ischemia and reperfusion. Transmural serial biopsies were obtained before and during ischemia and reperfusion and analyzed for myocardial adenine nucleotide pool intermediates by using high-performance liquid chromatography. In the control group, three hearts developed ischemic contracture and another three hearts exhibited cardiogenic shock during reperfusion. In the EHNA/NBMPR-treated group, left ventricular performance recovered within 30 minutes of reperfusion (p less than 0.05 vs. control). Myocardial ATP was depleted to 20% of normal in both groups by the end of ischemia (p less than 0.05). Intramyocardial adenosine in the EHNA/NBMPR-treated group was 12-fold greater (15.09 +/- 1.6 nmol/mg protein) than the control group at the end of the ischemic period (p less than 0.05). Inosine was about fourfold higher in the control group (19.07 +/- 1.50 nmol/mg protein) compared with the drug-treated group (p less than 0.05). During reperfusion, myocardial ATP levels increased to approximately 50% of normal in the EHNA/NBMPR group while remaining depressed (20% of normal) in the control group. Thus, despite the dramatic loss of myocardial ATP during ischemia, complete recovery of ventricular performance and significant repletion of ATP during reperfusion were observed when adenosine transport and deamination were modulated during ischemia and reperfusion. These results suggest that 1) the myocardium may have more ATP than is needed for basic cardiac functions and 2) washout of ATP diffusible catabolites is detrimental to ventricular performance during reperfusion. Specific blockade of nucleoside transport resulted in complete functional recovery despite low but critical ATP levels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Is adenosine 5'-triphosphate derangement or free-radical-mediated injury the major cause of ventricular dysfunction during reperfusion? Role of adenine nucleoside transport in myocardial reperfusion injury. 193 94


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