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 objective of this study was to determine if augmentation of myocardial adenosine levels during global ischemia improves functional recovery after reperfusion. Isolated adult rabbit hearts were subjected to 120 minutes of mildly hypothermic ischemia (34 degrees C) with modified St. Thomas' Hospital cardioplegic solution used to provide myocardial protection. Myocardial adenosine levels were augmented during ischemia by providing exogenous adenosine in the cardioplegic solution or by inhibiting adenosine degradation with 2-deoxycoformycin, a noncompetitive inhibitor of adenosine deaminase. Four groups of hearts were studied: (1) control (n = 23)--cardioplegia alone; (2) adenosine group (n = 10)--adenosine 200 mumol/L added to the cardioplegic solution; (3) 2-deoxycoformycin group (n = 8)--2-deoxycoformycin 1 mumol/L added to the cardioplegic solution; and (4) a combined adenosine/deoxycoformycin group (n = 10). Recovery of developed pressure 45 minutes after reperfusion in the control group averaged only 38% +/- 4% of baseline values. Significantly better recovery was evident in the adenosine (66% +/- 7%), deoxycoformycin (59% +/- 2%), and adenosine/deoxycoformycin (75% +/- 2%) groups. The slope of the relationship between end-diastolic pressure and volume was used as an index of diastolic stiffness. The slope averaged 85 +/- 2 mm Hg/ml in the control group 45 minutes after reperfusion, significantly higher than that in the adenosine (31 +/- 6), deoxycoformycin (75 +/- 5), and adenosine/deoxycoformycin (58 +/- 5) groups; this suggests better diastolic function in the adenosine-augmented groups. During ischemia, adenosine levels were significantly elevated in the adenosine-augmented groups, whereas adenosine triphosphate decreased equally in all four groups, which indicates that augmenting myocardial adenosine had no effect on depletion of adenosine triphosphate during ischemia. After reperfusion, adenosine triphosphate levels were depressed in the control group but increased in the other groups above baseline values, which suggests that improvement in functional recovery was due to accelerated repletion of adenine nucleotide stores in the adenosine-augmented groups.
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PMID:Augmenting intracellular adenosine improves myocardial recovery. 230 64

Adenosine is known to induce rapid cardioplegic arrest and to improve postischemic recovery in the isolated rat heart. Long exposures to high doses of adenosine impair postischemic recovery, however. In this paper we tested the combination of low-dose adenosine (1 mmol/L) with potassium (26 mmol/L), with the aim of achieving rapid arrest (as with high-dose adenosine) but eliminating the need for postarrest washout of adenosine. Cardioplegic solutions studied were (1) Krebs-Henseleit potassium (26 mmol/L) (K); (2) K plus adenosine (1 mmol/L) (KA); (3) K plus an adenosine deaminase inhibitor [erythro-9-(2-hydroxy-3-nonyl)adenine] (0.1 mmol/L) (KE); and as control (4) Krebs-Henseleit potassium (6 mmol/L) (C). We induced cardiac arrest in Langendorff-perfused rat hearts by infusing the cardioplegic solution for 3 minutes at 3 ml/min. Total ischemia lasted 20 minutes at 37 degrees C, followed by reperfusion for 30 minutes. High potassium decreased the arrest time from 260 +/- 16 seconds (group C, mean values +/- standard error of the mean) to 22 +/- 4 seconds (group K). A further decrease to 10 +/- 2 seconds was observed with KA (p = 0.016 versus K). KE, which increased endogenous adenosine, gave intermediate effects. All hearts recovered during reperfusion; the product of developed tension and heart rate (grams per minute) was superior in KA hearts (6250 +/- 740 versus K hearts 4380 +/- 390; p = 0.050). KE gave an intermediate result (5290 +/- 900), while C showed the worst recovery (3180 +/- 830). Our electrophysiologic studies with sinus node and atrial tissue suggest that adenosine induced hyperpolarization and an increase in potassium permeability, thereby arresting the sinus node before depolarization of the membrane by potassium (26 mmol/L). We conclude that low-dose adenosine as an adjunct to potassium shortens the arrest time in this model and improves postischemic recovery.
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PMID:Adenosine as adjunct to potassium cardioplegia: effect on function, energy metabolism, and electrophysiology. 239 80

We tested the effect of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenosine (EHNA) on ischemia-reperfusion injury in isolated perfused rat heart. In the ischemia-reperfusion group (n = 10), ventricular fibrillation occurred within 3 min of reperfusion after the 40-min ischemic period. The incidence of ventricular fibrillation was 90% with a mean duration of 3.15 +/- 0.97 (SE) min. Resting tension increased significantly. By contrast, the incidence of ventricular fibrillation after reperfusion in the EHNA-treated (5 microM) group (n = 10) was 20% (P less than 0.01), and the duration was 0.30 +/- 0.21 min (P less than 0.01). Resting tension was significantly lower and around the normal level in the EHNA-treated group (P less than 0.01). Contraction amplitude and heart rate recovered to nearly normal compared with the ischemia-reperfusion group (P less than 0.01). Coronary flow was greater in the EHNA-treated group (P less than 0.01). It is concluded that EHNA protects the heart, possibly by accumulation of adenosine that benefits the hearts and by blocking the xanthine oxidase pathway for free radical generation.
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PMID:Protective effects of an adenosine deaminase inhibitor on ischemia-reperfusion injury in isolated perfused rat heart. 239 91

Ischaemia rapidly increases the concentration of cAMP in the brain by mechanism(s) which still remain undefined. In the present study significant enhancement of cAMP generation was found in vitro after brain ischaemia induced by decapitation or cardiac arrest. The particulate fraction from ischaemic brain accumulated considerably more cAMP and responded more effectively to stimulation by noradrenaline (NE), histamine (Hi) and adenosine than that prepared from normoxic controls. The most pronounced effect was observed immediately after ischaemic insult and proceeded to normalize during 24 hours of postischaemic recovery. The activation of cAMP production by NE and Hi, but not 2-chloradenosine (2-CA), was totally dependent on the presence of endogenous adenosine and calcium. The synergism of 2-CA with NE or Hi on cAMP accumulation was observed. Its disappearance after adenosine deaminase treatment indicates that the postischaemic activation of adenosine A2 receptors may be positively modulated by NE and Hi. These results strongly suggest that primary functional changes in the cell-membrane signalling system had been induced by the ischaemic insult.
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PMID:Rapid enhancement of cAMP accumulation in rat brain particulate fraction after ischaemia. 255 46

Adenosine has been proposed as a metabolic factor involved in the regulation of cerebral blood flow. The evidence in support of this hypothesis, presented in this review, includes information on the adenosine receptors associated with cerebral blood vessels, the synthesis and metabolism of adenosine, and the release of adenosine from the brain. Adenosine dilates cerebral blood vessels, acting at an A2 receptor. The critical evidence implicating an involvement of adenosine in cerebrovascular regulation is derived from experiments with adenosine antagonists and potentiators. The antagonists include methylxanthine adenosine receptor antagonists and the enzyme adenosine deaminase. Potentiators include transport inhibitors, enzyme inhibitors, and adenosine precursors. Adenosine has been implicated in vascular regulation during hypoxia/ischemia, hypercapnia, seizures, severe hypotension, and hypoglycemia. Adenosine possesses a number of properties that can be used to minimize neuronal degeneration during cerebral insults, such as ischemia, including vasodilatation, reduction of excitatory transmitter release, reduction of membrane calcium permeability, inhibition of platelets, and neutrophil aggregation. Several recent studies have demonstrated that manipulation of central adenosine tone can alter the extent of cerebral ischemic damage, indicating a potential new therapeutic approach for the treatment of stroke.
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PMID:Adenosine in the control of the cerebral circulation. 270 69

Deoxycoformycin, a potent and specific adenosine deaminase antagonist, reduced ischemic hippocampal damage and the associated hypermotility in Mongolian gerbils. Cerebral ischemia was induced by a bilateral 5 min occlusion of the carotid arteries. Deoxycoformycin (500 micrograms/kg IP), administered 15 min prior to ischemia, prevented the increase in locomotor activity normally observed with this model and significantly reduced the ischemia-induced damage to CA1 hippocampal neurons. The results suggest that deoxycoformycin may be useful in the prevention of brain damage due to cerebral ischemia.
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PMID:Deoxycoformycin antagonizes ischemia-induced neuronal degeneration. 278 31

The loss of the catabolic products of adenosine triphosphate in the form of purine nucleosides and oxypurines during ischemia and subsequent reperfusion may limit adenine nucleotide regeneration. This study compared the effects of infusion of inhibitors of the major reactions involved in the degradation of adenosine triphosphate to inosine on the postischemic recovery of high energy phosphate and myocardial function. Inhibitors of adenylate kinase, 5'nucleotidase, adenosine translocase and adenosine deaminase were studied. Following 30 minutes of ischemia, only hearts infused with alpha, beta, methylene adenosine diphosphate (5' nucleotidase inhibitor) recovered significantly better ventricular function than control (p less than 0.05), but all hearts had increased adenosine triphosphate regeneration (p less than 0.05). The formation and washout of greater than 30% of the total adenine pool metabolites was not prevented by any drug. Nevertheless all manipulations of adenine metabolism resulted in recruitment of high energy phosphate during preischemic infusion.
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PMID:The influence of inhibitors of the ATP degradative pathway on recovery of function and high energy phosphate after transient ischemia in the rat heart. 302 47

The loss of the catabolic products of adenosine triphosphate in the form of purine nucleosides and oxypurines during ischemia and subsequent reperfusion may limit adenine nucleotide regeneration. This study compared the effects of infusion of inhibitors of the major reactions involved in the degradation of adenosine triphosphate to inosine on the postischemic recovery of high energy phosphate and myocardial function. Isolated rat hearts were made totally ischemic after a 5-min infusion of p1,p5-diadenosine pentaphosphate, alpha, beta-methylene adenosine diphosphate, nitrobenzyl-6-thioinosine, or erythro-9-(2-hydroxy-3-nonyl) adenine, which are inhibitors of adenylate kinase, 5'-nucleotidase, adenosine translocase, and adenosine deaminase, respectively. Following 30 min of ischemia, only hearts infused with alpha, beta-methylene adenosine diphosphate recovered significantly better ventricular function than did the control (P less than 0.05), but all hearts had increased adenosine triphosphate and creatine phosphate regeneration (P less than 0.05). The formation and washout of greater than 30% of the total adenine pool metabolites were not prevented by any drug. Nevertheless all manipulations of adenine metabolism resulted in recruitment of high energy phosphate during preischemic infusion which may have potential benefits in elective ischemic arrest.
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PMID:Influence of inhibitors of ATP catabolism on myocardial recovery after ischemia. 304 Nov 5

The effects of the adenosine deaminase inhibitor, deoxycoformycin, on purine release from the rat cerebral cortex were studied with the cortical cup technique. Deoxycoformycin (5 and 500 micrograms/kg i.v.) enhanced the hypoxia/ischemia-evoked release of adenosine from the cerebral cortex, indicating a marked rise in the adenosine content of interstitial fluid in the cerebral cortex. Inosine and hypoxanthine release were attenuated at the higher dose of deoxycoformycin. Uric acid release into the cortical perfusates was enhanced at the higher dose level. These results demonstrate that low doses of deoxycoformycin can be used to elevate interstitial levels of adenosine in the brain during hypoxia, and to depress the formation of some of its metabolites. The elevation of hypoxia/ischemia-evoked adenosine levels can account for the previously reported potentiation of hypoxia-evoked increases in rat cerebral blood flow after deoxycoformycin administration. The potential therapeutic utility of these findings is discussed.
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PMID:Effects of deoxycoformycin on adenosine, inosine, hypoxanthine, xanthine, and uric acid release from the hypoxemic rat cerebral cortex. 326 16

The concentrations of renal ATP have been measured by 31P-nuclear magnetic resonance (NMR) before, during, and after bilateral renal artery occlusion. Using in vivo NMR, the initial postischemic recovery of ATP increased with the magnitude of the residual nucleotide pool at the end of ischemia. ATP levels after 120 min of reflow correlated with functional recovery at 24 h. In the present study the effect of blocking the degradation of ATP during ischemia upon the postischemic restoration of ATP was investigated. Inhibition of adenosine deaminase by 80% with the tight-binding inhibitor 2'-deoxycoformycin led to a 20% increase in the residual adenine nucleotide pool. This increased the ATP initial recovery after 45 min of ischemia from 52% (in controls) to 62% (in the treated animals), as compared to the basal levels. The inhibition also caused an accelerated postischemic restoration of cellular ATP so that at 120 min it was 83% in treated rats vs. 63% in untreated animals. There was a corresponding improvement in the functional recovery from the insult (increase of 33% in inulin clearance 24 h after the injury). Inhibition of adenosine deaminase during ischemia results in a injury similar to that seen after a shorter period of insult.
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PMID:Metabolic and functional consequences of inhibiting adenosine deaminase during renal ischemia in rats. 326 96


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