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The binding of nucleotides and bivalent cations to the calcium-and-magnesium ion-dependent adenosine triphosphatase from rabbit muscle sarcoplasmic reticulum.  

PubMed Central

The binding of MgATP to purified Ca2+Mg2+-dependent adenosine triphosphatase from rabbit muscle sarcoplasmic reticulum was studied by using a flow-dialysis method. Phosphoryl-enzyme formation and catalytic activity were also measured, and all three processes demonstrated negative co-operativity, with half-saturation of all three parameters at a MgATP concentration of 40-50muM, and a Hill coefficient (h) of 0.8. The variation of the binding constant with with pH was measured and showed tighter binding of MgATP with increasing pH over the range 6.8-8.5. Binding parameters for ATP analogues were also measured. The binding of Ca2+ in the presence and absence of ATP analogues gave half saturation at a Ca2+ concentration of 1.2-1.3muM. Hill plots of Ca2+-binding data gave a slope of 0.8. These results show that the binding of MgATP and Ca2+ can occur in a random manner, with neither substrate influencing the affinity of the enzyme for the other.

Yates, D W; Duance, V C



Increased renal calcium and magnesium transporter abundance in streptozotocin-induced diabetes mellitus  

Microsoft Academic Search

Diabetes is associated with renal calcium and magnesium wasting, but the molecular mechanisms of these defects are unknown. We measured renal calcium and magnesium handling and investigated the effects of diabetes on calcium and magnesium transporters in the thick ascending limb and distal convoluted tubule in streptozotocin (STZ)-induced diabetic rats. Rats were killed 2 weeks after inducing diabetes, gene expression

C-T Lee; Y-H H Lien; L-W Lai; J-B Chen; C-R Lin; H-C Chen



Effects of calcium and magnesium on strontium distribution coefficients  

Microsoft Academic Search

The effects of calcium and magnesium on the distribution of strontium between a surficial sediment and simulated wastewater\\u000a solutions were measured as part of an investigation to determine strontium transport properties of surficial sediment at the\\u000a Idaho National Engineering Laboratory (INEL), Idaho. The investigation was conducted by the U.S. Geological Survey and Idaho\\u000a State University, in cooperation with the U.S.

R. L. Bunde; J. J. Rosentreter; M. J. Liszewski; C. H. Hemming; J. Welhan



Extracellular calcium and magnesium in preeclampsia and eclampsia.  


The cause of preeclampsia remains unknown and calcium and magnesium supplement are being suggested as means of prevention. The objective of this study was to assess magnesium and calcium in the plasma and cerebrospinal fluid of Nigerian women with preeclampsia and eclampsia. Setting was University of Benin Teaching Hospital, in Nigeria. It was a cross-sectional study comprising of eleven patients and twenty-three controls. The mean, standard deviation and Standard Error of Mean (SEM) were calculated. Student 't' test method was applied. Plasma calcium was significantly lower in patients than controls (9.2 +/- 1.02 Vs 9.98 +/- 0.87mg/dl, P 0.043) "t" test. The CSF calcium and magnesium levels were lower in patients than controls, (5.66 +/- 1.22 vs 6.67 +/- 1.15 mg/ dl, P 0.043 and 1.75 +/- 0.56 vs 1.91 +/- 0.19 mg/dl, P 0. < 0.0001) respectively. There is extracellular calcium and magnesium reduction in patients with preeclampsia and eclampsia. This reduction may have a cause and effect relationship with these disorders. PMID:20690291

Idogun, E S; Imarengiaye, C O; Momoh, S M



Determination of Nitrogen, Sulphur, Phosphorus, Potassium, Sodium, Calcium, and Magnesium in Plant Material by Automatic Analysis.  

National Technical Information Service (NTIS)

Methods are proposed for the rapid determination of nitrogen, sulphur, phosphorus, potassium, sodium, calcium, and magnesium in plant material by automated chemical analysis. Phosphorus, potassium, calcium, magnesium, and sodium are determined in nitric-p...

C. H. Williams J. R. Twine



Influence of refined cellulose on human bowel function and calcium and magnesium balance13  

Microsoft Academic Search

The effect of cellulose purified from wood pulp on wet and dry stool weights, gastrointestinal transit time (TT), frequency of defecation, and calcium and magnesium balances was tested. Seven healthy women consumed a low fiber diet of constant composition (percentage of total kcal: 23% protein, 30% fat, 47% carbohydrate) and the same metabolically controlled diet to which 16 g of

J. L. Slavin; J. A. Marlett


Determination of Calcium and Magnesium in Serum, Urine, Diet, and Stool by Atomic Absorption Spectrophotometry  

Microsoft Academic Search

ATOMIC ABSORPTION was developed by Walsh and his associates (1) as an analytical technic applicable to the determination of many metals. Willis (2-4) found that this technic was applicable in particular to tile determination of calcium and magnesium in Serum and urine. These published results indicated that atomic absorption spectrophotometry would be a simple, rapid, and practical method for tile

Elizabeth G. Gimblet; Amy F. Marney; Roy W. Bonsnes


The production of calcium and magnesium during pancreatic function tests in health and disease  

PubMed Central

Duodenal calcium and magnesium concentrations after pancreatic stimulation were measured in 25 patients with and without pancreatic disease. The concentration of both ions was higher in those with pancreatic disease, and furthermore these patients showed a different secretory pattern. These findings may be relevant to the aetiology of pancreatitis and to pancreatic calcification, and might be of diagnostic value.

Nimmo, J.; Finlayson, N. D. C.; Smith, A. F.; Shearman, D. J. C.



Effect on Blood Pressure of Potassium, Calcium, and Magnesium in Women With Low Habitual Intake  

Microsoft Academic Search

In populations, dietary intakes of potassium, calcium, and magnesium each have been inversely associated with blood pressure. However, most clinical trials in normotensive populations have not found that dietary supplements of these minerals lowered blood pressure. We tested the hypothesis that normotensive persons who have low habitual intake of these minerals would be particularly responsive to supplementation. Three hundred normotensive

Frank M. Sacks; Walter C. Willett; Angela Smith; Lisa E. Brown; Bernard Rosner; Thomas J. Moore



Simultaneous determination of calcium and magnesium in water using artificial neural network spectro-photometric method  

NASA Astrophysics Data System (ADS)

A new analytical method using Back-Propagation (BP) artificial neural networks and spectrophotometry for simultaneous determination of calcium and magnesium in tap water, the Yellow River water and seawater is established. By condition experiment, the optimum analytical conditions for calcium, magnesium and Arsenazo (III) color reactions are obtained. Levenberg-Marquart (L-M) algorithm is used for calculation in BP neural network. The topological structure of three-layer BP ANN network architecture is chosen as 11-10-2 (nodes). The initial value of gradient coefficient ? is fixed at 0.001 and the increase factor and reduction factor of ? take the default values of the system. The data are processed by computers with our own programs written in MATLAB 7.0. The relative standard deviations of the calculated results for calcium and magnesium are 2.31% and 2.14%, respectively. The results of standard addition method show that the recoveries of calcium and magnesium are 103.6% and 100.8% in the tap water, 103.2% and 96.6% in the Yellow River water (Lijin district of Shandong Province), and 98.8%-103.3% and 98.43%-103.4% in seawater from Jiaozhou Bay of Qingdao. It is found that 14 common cations and anions do not interfere with the determination of calcium and magnesium under the optimum experimental conditions. The comparative experiments do not show any obvious difference between the results obtained by this new method and those obtained by the classical complexometric titration method in seawater medium. This method exhibits good reproducibility and high accuracy in the determination of calcium and magnesium and can be used for the simultaneous determination of Ca2+ and Mg2+ in tap water and natural water.

Ji, Hongwei; Li, Shuang; Xin, Huizhen; Cao, Hengxia



Simultaneous determination of calcium and magnesium by derivative spectrophotometry in pharmaceutical products  

NASA Astrophysics Data System (ADS)

First- and second-derivative spectrophotometric methods for the simultaneous determination of calcium and magnesium in their mixtures are described. The methods are based on the colored complexes formed by calcium and magnesium with bromopyrogallol red in presence of Tween 80 as a surfactant. The zero-crossing method has been utilized to measure the first- and second-derivative value of the derivative spectrum. Calcium (0.8-4.8 ?g ml -1) is determined in the presence of magnesium (0.5-3.5 ?g ml -1) at the pH 10 and vice versa at zero-crossing wavelengths of 544.5 and 570 nm in the first-derivative procedure and 574 and 531 nm in the second-derivative procedure, respectively. The detection limits achieved were 0.0575 ?g ml -1 of calcium and 0.03 ?g ml -1 of magnesium. The relative standard deviations were in all instances less than 2%. The proposed method has been applied to the simultaneous determination of calcium and magnesium in different samples: commercial multivitamin, human serum and drinking water where excellent agreement between reported and obtained results was achieved.

Benamor, M.; Aguerssif, N.



Simultaneous determination of calcium and magnesium by derivative spectrophotometry in pharmaceutical products.  


First- and second-derivative spectrophotometric methods for the simultaneous determination of calcium and magnesium in their mixtures are described. The methods are based on the colored complexes formed by calcium and magnesium with bromopyrogallol red in presence of Tween 80 as a surfactant. The zero-crossing method has been utilized to measure the first- and second-derivative value of the derivative spectrum. Calcium (0.8-4.8microgml(-1)) is determined in the presence of magnesium (0.5-3.5microgml(-1)) at the pH 10 and vice versa at zero-crossing wavelengths of 544.5 and 570nm in the first-derivative procedure and 574 and 531nm in the second-derivative procedure, respectively. The detection limits achieved were 0.0575microgml(-1) of calcium and 0.03microgml(-1) of magnesium. The relative standard deviations were in all instances less than 2%. The proposed method has been applied to the simultaneous determination of calcium and magnesium in different samples: commercial multivitamin, human serum and drinking water where excellent agreement between reported and obtained results was achieved. PMID:17590390

Benamor, M; Aguerssif, N



[Simultaneous determination of calcium and magnesium in urines by flame atomic absorption spectrometry].  


The contents of calcium and magnesium in urines were simultaneously determined by flame atomic absorption spectrometry. The optimized working conditions were ascertained. For the determination of calcium, the used wavelength was 422.8 nm, and the current of HCL(Hollow Cathode Lamp) was 3 mA; for the determination of magnesium, the used wavelength was 285.2 nm, and the current of HCL (Hollow Cathode Lamp) was 4 mA. The height of burner and the air-acetylene ratio were 8 mm and 6:1, respectively, for the determination of both calcium and magnesium. In order to remove the disturbance of phosphate, sulphate and silicate on the determination of calcium, a releasing reagent can be used. Lanthanum chloride (LaCl3) was tested as a better releasing reagent than strontium chloride (SrCl2). The disturbance of urinary substrate could be avoided after the urines were diluted to 1:100 with distilled water. The concentrations of Ca and Mg in 15 urines were determined under the optimized conditions. The obtained results were consistent with the archived data. The recovery was 96%-104%, the relative standard deviation for a sample was 1.8% with P < 0.05. PMID:15766134

Bai, Yu; Ouyang, Jian-Ming; Bai, Yan; Chen, Mei-Luan



Quality of 4-hourly ejaculates--levels of calcium and magnesium.  


A four-hourly ejaculation study was conducted in which eleven normal healthy subjects participated. Five of them discontinued after submitting three samples. One alone was present for submission at the end of 16 h (fifth ejaculate), which was his last submission. Physical exhaustion was the sole reason for all participants for their discontinuation from the study. The result showed a decrease in semen volume and sperm count from first to last ejaculate. The increase in motility was probably due to reduction in exposure time to sperm motility inhibitory factors. In general, total motile spermatozoa as well as actively motile spermatozoa progressively increased from first to last ejaculate at the cost of sluggish spermatozoa. A significant increase in seminal plasma calcium and magnesium was seen as well as a significant increase in magnesium inside the cell from the first to the fourth ejaculate. Considering the quality of semen, which was good in sperm count and excellent in motility, calcium and magnesium may be helpful in cleaning motility inhibitory factors of spermatozoa. PMID:22540387

Valsa, J; Skandhan, K P; Gusani, P H; Sahab Khan, P; Amith, S



Effects of dietary vitamin D on calcium and magnesium levels in mice with abnormal calcium metabolism  

SciTech Connect

In previous studies vitamin D has been used to induce cardiac calcium overload in laboratory animals. Interrelationships between calcium and magnesium metabolism are also documented. The authors have investigated the effect of varying vitamin D in the diet on calcium and magnesium levels in plasma, kidney and heart of DBA mice which exhibit genetic abnormalities in cardiac calcium metabolism. Weanling DBA mice were maintained for 28 days on an AIN-76 diet containing either 1,000 I.U. of vitamin D{sub 3} per kg of diet (control); 4,000 I.U. of vitamin D{sub 3} per kg of diet; or no vitamin D. When compared to controls, supplemented animals showed significantly higher plasma magnesium, kidney calcium and kidney magnesium levels; animals receiving the vitamin D-deficient diet exhibited increases in cardiac calcium levels. The authors results support previous findings that vitamin D deficiency increases cardiac calcium uptake and suggest a possible role of vitamin D in magnesium metabolism.

Spurlock, B.G.; West, W.L.; Knight, E.M. (Howard Univ., Washington, DC (United States))



Calcium and Magnesium Levels in Agricultural Soil and Sewage Sludge in an Industrial Area from Southeastern Spain: Relationship with Plant (Saccharum officinarum) Disposition  

Microsoft Academic Search

This investigation was initiated to assess the following objectives: (1) to measure the total calcium and magnesium content in agricultural soil and sewage sludge from the Mediterranean coastal area of Motril (southeastern Spain); (2) to determine the pH values of indicated samples in order to evaluate first their influence on calcium and magnesium content, and second on levels of these

A. M. Jodral-Segado; M. Navarro-Alarcón; H. López-G De La Serrana; M. C. López-Martínez



Chronic dietary fiber supplementation with wheat dextrin does not inhibit calcium and magnesium absorption in premenopausal and postmenopausal women  

Technology Transfer Automated Retrieval System (TEKTRAN)

This placebo-controlled, randomized, crossover clinical study examined the effect of chronic wheat dextrin intake on calcium and magnesium absorption. Forty premenopausal and post menopausal women (mean +/- SD age 49.9 +/- 9.8 years)consumed wheat dextrin or placebo (15 g/day) for 2 weeks prior to 4...



EPA Science Inventory

Abstract A chemical equilibrium code was improved and used to show that calcium and magnesium have a large yet different effect on the aerosol size distribution in different regions of Los Angeles. In the code, a new technique of solving individual equilibrium equation...


Calcium and magnesium dietary intakes and plasma and milk concentrations of Nepalese lactating women.  


Dietary calcium and magnesium intakes of 26 Nepalese lactating women were determined from analysis of 24-h duplicate food and beverage composites. In addition, blood, urine, and milk samples were collected. The mean Ca intake of these Nepalese mothers, 482 +/- 249 mg/d, was less than half that of American lactating women yet the Ca concentration of the milk was similar for the two groups of women. The Nepalese mothers appeared to maintain milk Ca concentrations by an increase in bone resorption as demonstrated by an elevated excretion of hydroxyproline. The Nepalese women had a mean Mg intake of 353 +/- 28 mg/d. Two locally available foods considered special for lactating women, jwano and gundruk, were examined for nutrient content and found to contain high concentrations of Ca and Mg. Increased consumption of these locally grown foods could add substantially to the Ca and Mg intakes of these lactating women. PMID:3354499

Moser, P B; Reynolds, R D; Acharya, S; Howard, M P; Andon, M B



Anhydrobiosis in yeast: influence of calcium and magnesium ions on yeast resistance to dehydration-rehydration.  


The influence of calcium and magnesium ions on resistance to dehydration in the yeast, Saccharomyces cerevisiae, was investigated. Magnesium ion availability directly influenced yeast cells' resistance to dehydration and, when additionally supplemented with calcium ions, this provided further significant increase of yeast resistance to dehydration. Gradual rehydration of dry yeast cells in water vapour indicated that both magnesium and calcium may be important for the stabilization of yeast cell membranes. In particular, calcium ions were shown for the first time to increase the resistance of yeast cells to dehydration in stress-sensitive cultures from exponential growth phases. It is concluded that magnesium and calcium ion supplementations in nutrient media may increase the dehydration stress tolerance of S. cerevisiae cells significantly, and this finding is important for the production of active dry yeast preparations for food and fermentation industries. PMID:20487021

Trofimova, Yuliya; Walker, Graeme; Rapoport, Alexander



Factors modulating the pH at which calcium and magnesium phosphates precipitate from human urine.  


The factors controlling the rate at which crystalline bacterial biofilms develop on indwelling bladder catheters are poorly understood. It is known that normally the pH of voided urine (pHv) is lower than the pH at which calcium and magnesium phosphates come out of urine solution (pHn). In patients who develop infections with urease producing bacteria, however, the pHv rises above the pHn and precipitation of the phosphates occurs in the urine and the biofilm. The aim of this study was to examine ways of manipulating the pHn of urine so that more of its calcium and magnesium remain in solution under alkaline conditions. The experimental data show that pHn can be elevated by decreasing the calcium, magnesium and phosphate concentrations. Increasing the fluid intake of a human subject so that the urinary calcium fell from 120 mg/l to 25 mg/l, for example, resulted in the pHn increasing from 6.48 to 8.22. The addition of citrate to urine also produced a rise in the pHn. The daily consumption of 500 ml of fresh orange juice increased urinary citrate concentrations from 0.35 to around 1.21 mg/ml and the pHn rose from 7.24 to 8.2. The pHn of urine is thus a highly variable parameter. It can be manipulated by controlling the urinary concentrations of magnesium, calcium, phosphate and citrate ions. We suggest that increasing fluid intake with citrate containing drinks would reduce the extent of encrustation on catheters in patients infected with urease producing bacteria. PMID:15981006

Suller, M T E; Anthony, V J; Mathur, S; Feneley, R C L; Greenman, J; Stickler, D J



Pentavalent ions dependency is a conserved property of adenosine kinase from diverse sources: identification of a novel motif implicated in phosphate and magnesium ion binding and substrate inhibition.  


The catalytic activity of adenosine kinase (AK) from mammalian sources has previously been shown to exhibit a marked dependency upon the presence of pentavalent ions (PVI), such as phosphate (PO4), arsenate, or vanadate. We now show that the activity of AK from diverse sources, including plant, yeast, and protist species, is also markedly enhanced in the presence of PVI. In all cases, PO4 or other PVI exerted their effects primarily by decreasing the Km for adenosine and alleviating the inhibition caused by high concentrations of substrates. These results provide evidence that PVI dependency is a conserved property of AK and perhaps of the PfkB family of carbohydrate kinases which includes AK. On the basis of sequence alignments, we have identified a conserved motif NXXE within the PfkB family. The N and E of this motif make close contacts with Mg2+ and PO4 ions in the crystal structures of AK and bacterial ribokinase (another PfkB member which shows PVI dependency), implicating these residues in their binding. Site-directed mutagenesis of these residues in Chinese hamster AK have resulted in active proteins with greatly altered phosphate stimulation and substrate inhibition characteristics. The N239Q mutation leads to the formation of an active protein whose activity was not stimulated by PO4 or inhibited by high concentrations of adenosine or ATP. The activity of the E242D mutant protein was also not significantly altered in the presence of phosphate. Although PO4 had no effect on the KmAdenosine for this mutant, the KmATP, K(i)Adenosine, and K(i)ATP were significantly decreased. In contrast to these mutations, N239L or E242L mutant proteins showed greatly decreased activity with an altered Mg2+ requirement. These observations support the view that N239 and E242 play an important role in the binding of PO4 and Mg2+ ions required for the catalytic activity of adenosine kinase. PMID:11900549

Maj, Mary C; Singh, Bhag; Gupta, Radhey S



Lack of blood pressure effect with calcium and magnesium supplementation in adults with high-normal blood pressure  

Microsoft Academic Search

Phase I of the Trials of Hypertension Prevention (TOHP) was a randomized, multicenter investigation that included double-blind, placebo-controlled testing of calcium and magnesium supplementation among 698 healthy adults (10.5% blacks and 31% women) aged 30 to 54 years with high-normal diastolic blood pressure (DBP) (80 to 89 mm Hg). Very high compliance (94 to 96% by pill counts) with daily

Monica E. Yamamoto; William B. Applegate; Michael J. Klag; Nemat O. Borhani; Jerome D. Cohen; Kent A. Kirchner; Edward Lakatos; Frank M. Sacks; James O. Taylor; Charles H. Hennekens



Calcium and magnesium in exocrine secretion--an X-ray microanalytical study  

SciTech Connect

Calcium and magnesium distribution in mammalian exocrine glands under resting, stimulated and pathological conditions was investigated by X-ray microanalysis of thick and ultrathin cryosections. Ultrathin sections were cut from tissue frozen in the presence of a polymer cryoprotectant, dextran. The effect of this treatment on isolated rabbit pancreas. Dextran caused a disturbance in water and ion transport, partly due to an osmotic effect and the impermeability of the pancreatic epithelium to dextran; this does, however, not necessarily invalidate intracellular measurements on frozen-dried sections. Cholinergic stimulation of the rat pancreas caused a change of Ca distribution from the basal to the apical part of the cell; this may be a component of the secretory Ca flux. Kinetic considerations make a significant Ca movement via the ER-Golgi endomembrane space less likely. The mitochondrial Ca concentration is low, and not significantly changed by cholinergic stimulation. X-ray microanalysis was carried out on submandibular glands of rats after chronic treatment with reserpin and/or isoproterenol (an animal model for cystic fibrosis, CF). The acinar cells had elevated Mg and Ca and lowered K concentrations. Analysis of ultrathin cryosections showed high levels of Ca and Mg in secretory granules, mucus globules and the ER. Ca and Mg in the ER may be transported intracellularly with secretory proteins to secretion granules or mucus globules. The decrease in cell K may be due to efflux of K caused by elevated cytoplasmic Ca levels. A similar decrease in cell K was caused by incubation of rat salivary glands with diluted serum from CF patients, a treatment which has been reported to mimic the effect of a rise in cytoplasmic Ca.

Roomans, G.M.; Barnard, T.



5-bromo-2'-deoxyuridine-stimulated calcium ion- or magnesium ion-dependent ecto-(adenosine triphosphatase) activity of cultured hamster cardiac cells.  

PubMed Central

1. Treatment of hamster heart cells in primary culture with 5-bromo-2'-deoxyuridine resulted in the greatly increased activity of a particulate Ca2+- or Mg2+-dependent ATPase (adenosine triphosphatase). 2. 5-Bromo-2'-deoxyuridine exerted these effects only when it was incorporated into cellular DNA, and then in a concentration-dependent manner. 3. Serially replated cells contained less of the activity (expressed as a function of total cell protein) than did the primary cultures, but the stimulation caused by 5-bromo-2'-deoxyuridine addition was much greater. 4. The affected enzyme was apparently localized in the plasma membrane of the cells with its active centre exposed to the outer environment [ecto-(ATPase) dependent on Ca2+ or Mg2+].5. The activity was unaffected by treatment with p-chloromercuriphenylsulphonate, ouabain andverapamil. 6. Ecto (5'-nucleotidase) activity was not increased by 5-bromo-2'-deoxyuridine treatment of cells, and ecto-(p-nitrophenyl phosphatase) activity was only slightly enhanced. Images PLATE 1

Coetzee, G A; Gevers, W



Nationwide data on municipal drinking water and hip fracture: Could calcium and magnesium be protective? A NOREPOS study.  


Norway has a high incidence of hip fractures, and the incidence varies by degree of urbanization. This variation may reflect a difference in underlying environmental factors, perhaps variations in the concentration of calcium and magnesium in municipal drinking water. A trace metal survey (1986-1991) in 556 waterworks (supplying 64% of the Norwegian population) was linked geographically to hip fractures from hospitals throughout the country (1994-2000). In all, 5472 men and 13,604 women aged 50-85years suffered a hip fracture. Poisson regression models were fitted, adjusting for age, urbanization degree, region of residence, type of water source, and pH. The concentrations of calcium and magnesium in drinking water were generally low. An inverse association was found between concentration of magnesium and risk of hip fracture in both genders (IRR men highest vs. lowest tertile=0.80, 95% CI: 0.74, 0.87; IRR women highest vs. lowest tertile=0.90, 95% CI: 0.85, 0.95), but no consistent association between calcium and hip fracture risk was observed. The highest tertile of urbanization degree (city), compared to the lowest (rural), was related to a 23 and 24% increase in hip fracture risk in men and women, respectively. The association between magnesium and hip fracture did not explain the variation in hip fracture risk between city and rural areas. Magnesium in drinking water may have a protective role against hip fractures; however this association should be further investigated. PMID:23831379

Dahl, Cecilie; Sřgaard, Anne Johanne; Tell, Grethe S; Flaten, Trond Peder; Hongve, Dag; Omsland, Tone Kristin; Holvik, Kristin; Meyer, Haakon E; Aamodt, Geir



Comparison of Calcium and Magnesium Contents in Cruciferous Vegetables Grown in Areas around Steelworks, on Organic Farms, and Those Available in Retail  

Microsoft Academic Search

The aim of the present study was to compare calcium and magnesium contents in cruciferous vegetables grown under diversified ecological conditions for three consecutive years, independently of the climatic and agrotechnical conditions. The metal contents were determined using validated Atomic Absorption Spectrometry with atomization in the flame (FAAS method; spectrometer: AA240FS Varian). The dry mass of various vegetable species cultivated

Joanna Kapusta-Duch; Teresa Leszczy?ska; Adam Florkiewicz; Agnieszka Filipiak-Florkiewicz



Effects of lanthanum on calcium and magnesium contents and cytoplasmic streaming of internodal cells of Chara corallina.  


Biological and environmental effects of lanthanide series of elements have received much attention recently due to their wide applications. In this study, effects of La(3+) treatments on calcium and magnesium concentrations as well as cytoplasmic streaming of internodal cells of Chara corallina were investigated. At all treatment concentrations (10, 100, and 1,000 ?M), La(3+) significantly decreased calcium concentrations in the cell-wall fractions after 5-h treatments. Calcium concentrations in the cell contents and magnesium concentrations in the cell-wall fractions were reduced by 100 and 1,000 ?M La(3+) treatments. However, cytoplasmic streaming as an indicator of [Ca(2+)](cyt) was only inhibited at the highest La(3+) concentration (1,000 ?M). The results suggest that La(3+) may affect cellular calcium homeostasis by actions other than as a simple Ca(2+) antagonist. La(3+) could partially compensate for calcium deficiency at certain concentrations. PMID:20862562

Li, Zijie; Zhang, Zhiyong; Yu, Ming; Zhou, Yunlong; Zhao, Yuliang



Chronic dietary fiber supplementation with wheat dextrin does not inhibit calcium and magnesium absorption in premenopausal and postmenopausal women.  


This placebo-controlled, randomized, crossover clinical study examined the effect of chronic wheat dextrin intake on calcium and magnesium absorption. Forty premenopausal and post menopausal women (mean ± SD age 49.9 ± 9.8 years) consumed wheat dextrin or placebo (15 g/day) for 2 weeks prior to (45)calcium ((45)Ca) and (26)magnesium ((26)Mg) absorption testing. After a standardized breakfast, serial blood and urine samples were obtained. The mean ± SD area under the curve from 0 to 9 h for (45)Ca specific activity was 0.81 ± 0.21 for wheat dextrin and 0.82 ± 0.22 for placebo, showing that wheat dextrin had no effect on calcium absorption. The mean ± SD percentage excess of (26)Mg/(24)Mg was 7.8% ± 2.1% for wheat dextrin and 7.9% ± 2.6% for placebo, showing that wheat dextrin had no effect on magnesium absorption. In conclusion, chronic wheat dextrin consumption did not inhibit calcium or magnesium absorption from the gastrointestinal tract in women. PMID:22117983

Armas, L A G; Rafferty, K; Hospattankar, A; Abrams, S A; Heaney, R P



Effects of calcium and magnesium on acute and chronic neurotoxicity caused by oxaliplatin: A meta-analysis  

PubMed Central

The primary toxicity of oxaliplatin is neurotoxicity. Calcium and magnesium (Ca/Mg) are reported to be beneficial in protecting against this adverse effect. However, the results obtained from clinical trials are not definitive. The aim of this study was to evaluate whether Ca/Mg alleviates the neurotoxicity of oxaliplatin by performing a meta-analysis of the literature involving available randomized controlled trials. Systematic searches for trials were undertaken from the Cochrane Library, MEDLINE, CENTRAL, Embase, CBMdisc and CNKI databases without language limitations. The primary outcome was severe chronic neurotoxicity and the secondary outcome was acute neurotoxicity. Four randomized double-blind trials met the search criteria. The odds ratio (OR) comparing Ca/Mg treatment with placebo was 0.44 (0.23–0.85, P=0.01) for severe chronic neurotoxicity of oxaliplatin (grade ?2) and 0.41 (0.11–1.49, P=0.18) for acute neurotoxicity. In conclusion, Ca/Mg treatment does not reduce the incidence of acute neurotoxicity of oxaliplatin, but does reduce the incidence of severe chronic neurotoxicity (grade ?2). No differences were observed in the outcomes of chemotherapy. Thus, Ca/Mg treatment is recommended for use as an adjunct with oxaliplatin.




The role of calcium and magnesium ions in uptake of beta-amyloid peptides by microglial cells.  


Amyloid peptides 1-40 and 1-42 (Abeta 1-40 and Abeta 1-42) are major components of diffuse and neuritic senile plaques present in the brain of patients with Alzheimers disease. Their interaction with microglial cells was studied using a system partly mimicking these plaques, which consisted in heat-killed yeast particles coated with either Abeta 1-40 or Abeta 1-42. Using these particles, it has been shown in our laboratory that LRP is involved mainly in the elimination of Abeta 1-42-coated heat-killed yeast particles and partly in that of Abeta 1-40-coated heat-killed yeast particles by microglial cells in culture. We show here that in the presence of calcium and magnesium ions extracellular chelators, namely EDTA (for both ions) and EGTA (for calcium ions), the internalization of coated heat-killed particles was impaired. In the presence of BAPTA-AM, an intracellular chelator of calcium ions and thapsigargin, an inhibitor of the endoplasmic reticulum calcium pump, no effect was observed on the phagocytosis of Abeta 1-40-coated heat-killed yeast particles, whereas that of Abeta 1-42-coated heat-killed yeast particles was affected. These results suggest that different signaling mechanisms are involved after the internalization of Abeta 1-40 and Abeta 1-42. PMID:17026853

Choucair, N; Laporte, V; Levy, R; Tranchant, C; Gies, J-P; Poindron, P; Lombard, Y


Effect of calcium and magnesium on the antimicrobial action of enterocin LR/6 produced by Enterococcus faecium LR/6.  


Enterococci are well-known producers of antimicrobial peptides (enterocins) that possess potential as biopreservatives in food. In this study, divalent cations and release of intracellular potassium were used to assess the mechanism of interaction and killing of enterocin LR/6 produced by Enterococcus faecium LR/6 on three target Gram-positive and Gram-negative bacteria, namely Micrococcus luteus, Enterococcus sp. strain LR/3 and Escherichia coli K-12. Whilst treatment with enterocin LR/6 in all cases led to a significant loss of viability, suggesting a bactericidal mode of action, E. coli K-12 showed better tolerance than the other two strains. Bacteriocins have generally been reported to create pores in the membrane of sensitive cells and this function is diminished by divalent cations. In this study it was shown that Ca(2+) and Mg(2+) markedly improved the viability of enterocin LR/6-treated cells in a concentration-dependent manner. K(+) release as a sign of membrane leakiness was higher in M. luteus compared with the other two test strains. In agreement with the viability response, pre-exposure to Ca(2+) and Mg(2+) substantially reduced the amount of K(+) leakage by M. luteus and Enterococcus sp.; in the case of E. coli K-12, no leakage of K(+) was recorded. These results suggest that enterocin LR/6, which possesses good antibacterial potential, may not be very effective as a preservative in foods containing high concentrations of calcium and magnesium. PMID:21411293

Kumar, Manoj; Srivastava, Sheela



The nature and properties of the inducible sodium-plus-potassium ion-dependent adenosine triphosphatase in the gills of eels (Anguilla anguilla) adapted to fresh water and sea water  

PubMed Central

1. Gill tissue from eels adapted to fresh water or to sea water was disrupted in 0.32m-sucrose containing 0.1% (w/v) sodium deoxycholate and the subcellular distribution of (Na++K+)-dependent adenosine triphosphatase was determined. 2. About 70% of the recovered enzyme was in a fraction sedimenting between 225000gav.-min and 6000000gav.-min; the specific activities of enzymes from tissues of freshwater and seawater eels were 16 and 51 ?mol of phosphate/h per mg of protein respectively. 3. The enzymes from gills of freshwater and seawater eels were indistinguishable on the basis of a number of parameters. These included phosphorylation by [?-32P]ATP, the binding of [3H]ouabain, the extent to which bound [3H]ouabain was displaced by increasing concentrations of KCl and pH optima. 4. Electrophoresis on polyacrylamide gels in sodium dodecyl sulphate showed that enzyme preparations from both sources had an identical number of protein components. 5. The higher specific activity of (Na++K+)-dependent adenosine triphosphatase from tissue of seawater eels was accompanied by increased amounts of two protein components. One of these proteins retained 32P after treatment of the enzyme with [?-32P]ATP and had mol.wt. 97000; the other component was a glycoprotein with mol.wt. approx. 46000. 6. The results are discussed in terms of the nature of the transepithelial NaCl pumps in the gills of freshwater and seawater fish.

Sargent, John R.; Thomson, Alison J.



Effects of low calcium and magnesium dietary intake on the central nervous system tissues of rats and calcium-magnesium related disorders in the amyotrophic lateral sclerosis focus in the Kii Peninsula of Japan.  


Current epidemiological investigations in the Western Pacific including the Kii Peninsula of Japan, have suggested that environmental factors contribute to the pathogenetic process of amyotrophic lateral sclerosis (ALS) and parkinsonism dementia (PD). The condition of unbalanced minerals (a low content of calcium and magnesium, and a high content of aluminum) found in soil and drinking water in all three ALS foci was experimentally mimicked in our studies using rats. In rat groups maintained on unbalanced mineral diets, the calcium and magnesium contents of bones were lower than those fed a standard diet. In addition, the calcium content of CNS tissues showed higher values in the unbalanced diet groups (especially in the spinal cord of the low calcium and magnesium plus high aluminum diet group) than those in the standard diet group. The calcium content of other soft tissues as well as the CNS of rats fed unbalanced mineral diets was also higher than those on the standard diet. The magnesium content of soft tissues and spinal cord of rats was markedly lower in the low calcium and magnesium plus high aluminum diet group than in the other groups. Examination of tissues from six Kii Peninsula patients with ALS showed an average magnesium concentration in 26 CNS regions (cortical gray matter, white matter, basal ganglia, brain stem, spinal cord) significantly lower than that for five neurologically normal controls. The average calcium concentration in gray matter of ALS cases was significantly higher than that of controls. Interestingly, only 120 cases of calcification of spinal ligaments have been reported worldwide, and of these, 26 of 28 cases of calcification of spinal in the Kii Peninsula have been found to overlap the same geographic focal region as ALS. We analyzed the magnesium content of seven spinal vertebrae and 10 spinal ligaments of patients with calcification of spinal ligaments and the calcium content of five spinal bones compared with controls. The calcification of spinal ligaments patients had lower values for magnesium contents of bones and ligaments compared to controls and the calcium content of bones in these patients was significantly lower than that of controls. These data suggest that low dietary intake of calcium and magnesium over an extended period of time may contribute to the pathogenesis of patients with ALS and calcification of spinal ligaments. PMID:9339837

Yasui, M; Ota, K; Yoshida, M



Adenosine Information  

Center for Drug Evaluation (CDER)

... FDA Drug Safety Communication: Connection problems involving certain needleless pre-filled glass syringes containing adenosine and ... More results from


The influence of calcium and magnesium in drinking water and diet on cardiovascular risk factors in individuals living in hard and soft water areas with differences in cardiovascular mortality  

PubMed Central

Background The role of water hardness as a risk factor for cardiovascular disease has been widely investigated and evaluated as regards regional differences in cardiovascular disease. This study was performed to evaluate the relation between calcium and magnesium in drinking water and diet and risk factors for cardiovascular disease in individuals living in hard and soft water areas with considerable differences in cardiovascular mortality. Methods A random sample of 207 individuals living in two municipalities characterised by differences in cardiovascular mortality and water hardness was invited for an examination including a questionnaire about health, social and living conditions and diet. Intake of magnesium and calcium was calculated from the diet questionnaire with special consideration to the use of local water. Household water samples were delivered by each individual and were analysed for magnesium and calcium. Results In the total sample, there were positive correlations between the calcium content in household water and systolic blood pressure (SBP) and negative correlations with s-cholesterol and s-LDL-cholesterol. No correlation was seen with magnesium content in household water to any of the risk factors. Calcium content in diet showed no correlation to cardiovascular risk factors. Magnesium in diet was positively correlated to diastolic blood pressure (DBP). In regression analyses controlled for age and sex 18.5% of the variation in SBP was explained by the variation in BMI, HbA1c and calcium content in water. Some 27.9% of the variation in s-cholesterol could be explained by the variation in s-triglycerides (TG), and calcium content in water. Conclusions This study of individuals living in soft and hard water areas showed significant correlations between the content of calcium in water and major cardiovascular risk factors. This was not found for magnesium in water or calcium or magnesium in diet. Regression analyses indicated that calcium content in water could be a factor in the complexity of relationships and importance of cardiovascular risk factors. From these results it is not possible to conclude any definite causal relation and further research is needed.

Nerbrand, Christina; Agreus, Lars; Lenner, Ragnhild Arvidsson; Nyberg, Per; Svardsudd, Kurt



Abnormalities of serum calcium and magnesium  

Technology Transfer Automated Retrieval System (TEKTRAN)

Neonatal hypocalcemia is defined as a total serum calcium concentration of <7 mg/dL or an ionized calcium concentration of <4 mg/dL (1mmol/L). In very low birth weight (VLBW) infants, ionized calcium values of 0.8 to 1 mmol/L are common and not usually associated with clinical symptoms. In larger in...


Adenosine dysfunction in epilepsy  

PubMed Central

Extracellular levels of the brain’s endogenous anticonvulsant and neuroprotectant adenosine largely depend on an astrocyte-based adenosine cycle, comprised of ATP release, rapid degradation of ATP into adenosine, and metabolic reuptake of adenosine through equilibrative nucleoside transporters and phosphorylation by adenosine kinase (ADK). Changes in ADK expression and activity therefore rapidly translate into changes of extracellular adenosine, which exerts its potent anticonvulsive and neuroprotective effects by activation of pre- and postsynaptic adenosine A1 receptors. Increases in ADK increase neuronal excitability, whereas decreases in ADK render the brain resistant to seizures and injury. Importantly, ADK was found to be overexpressed and associated with astrogliosis and spontaneous seizures in rodent models of epilepsy, as well as in human specimen resected from patients with hippocampal sclerosis and temporal lobe epilepsy. Several lines of evidence indicate that overexpression of astroglial ADK and adenosine deficiency are pathological hallmarks of the epileptic brain. Consequently, adenosine augmentation therapies constitute a powerful approach for seizure prevention, which is effective in models of epilepsy that are resistant to conventional antiepileptic drugs. The adenosine kinase hypothesis of epileptogenesis suggests that adenosine dysfunction in epilepsy undergoes a biphasic response: An acute surge of adenosine that can be triggered by any type of injury might contribute to the development of astrogliosis via adenosine receptor –dependent and –independent mechanisms. Astrogliosis in turn is associated with overexpression of ADK, which was shown to be sufficient to trigger spontaneous recurrent electrographic seizures. Thus, ADK emerges as a promising target for the prediction and prevention of epilepsy.

Boison, Detlev



Adenosine and blood platelets  

Microsoft Academic Search

Adenosine is an important regulatory metabolite and an inhibitor of platelet activation. Adenosine released from different\\u000a cells or generated through the activity of cell-surface ectoenzymes exerts its effects through the binding of four different\\u000a G-protein-coupled adenosine receptors. In platelets, binding of A2 subtypes (A2A or A2B) leads to consequent elevation of intracellular cyclic adenosine monophosphate, an inhibitor of platelet activation.

Hillary A. Johnston-Cox; Katya Ravid


Adenosine in exercise adaptation.  

PubMed Central

By influencing the regulation of the mechanisms of angiogenesis, erythropoietin production, blood flow, myocardial glucose uptake, glycogenolysis, systolic blood pressure, respiration, plasma norepinephrine and epinephrine levels, adenosine may exert a significant effect on the body's adaptation response to exercise. However, adenosine's possible influence over the vasodilatory response to exercise in skeletal muscle is controversial and more research is required to resolve this issue. Various popular exercise training methods, such as cyclic training, interval training, and the 'warm down' from training may increase adenosine levels and thereby might enhance the response of adenosine-influenced adaptive mechanisms. Among the several classes of drugs which may enhance extracellular adenosine levels and thereby might augment adenosine-influenced adaptive mechanisms, are the anabolic steroidal and some readily available non-steroidal anti-inflammatory drugs (NSAIDs).

Simpson, R E; Phillis, J W



Adenosine and neuronal plasticity  

Microsoft Academic Search

Adenosine is considered an important neuromodulator of the nervous system acting at pre-, post- and non-synaptic levels. In the present review we describe how adenosine modifies paired-pulse facilitation (PPF), posttetanic depression (PTD), long-term potentiation (LTP), long-term depression (LTD) and depotentiation at the hippocampus, and therefore how this nucleoside modulates synaptic plasticity.

Alexandre de Mendonça; J. A. Ribeiro



Adenosine receptor activation and nociception  

Microsoft Academic Search

Adenosine and ATP exert multiple influences on pain transmission at peripheral and spinal sites. At peripheral nerve terminals in rodents, adenosine A1 receptor activation produces antinociception by decreasing, while adenosine A2 receptor activation produces pronociceptive or pain enhancing properties by increasing, cyclic AMP levels in the sensory nerve terminal. Adenosine A3 receptor activation produces pain behaviours due to the release

Jana Sawynok



Metal Ion Dependence of Cooperative Collapse Transitions in RNA  

SciTech Connect

Positively charged counterions drive RNA molecules into compact configurations that lead to their biologically active structures. To understand how the valence and size of the cations influences the collapse transition in RNA, small-angle X-ray scattering was used to follow the decrease in the radius of gyration (R{sub g}) of the Azoarcus and Tetrahymena ribozymes in different cations. Small, multivalent cations induced the collapse of both ribozymes more efficiently than did monovalent ions. Thus, the cooperativity of the collapse transition depends on the counterion charge density. Singular value decomposition of the scattering curves showed that folding of the smaller and more thermostable Azoarcus ribozyme is well described by two components, whereas collapse of the larger Tetrahymena ribozyme involves at least one intermediate. The ion-dependent persistence length, extracted from the distance distribution of the scattering vectors, shows that the Azoarcus ribozyme is less flexible at the midpoint of transition in low-charge-density ions than in high-charge-density ions. We conclude that the formation of sequence-specific tertiary interactions in the Azoarcus ribozyme overlaps with neutralization of the phosphate charge, while tertiary folding of the Tetrahymena ribozyme requires additional counterions. Thus, the stability of the RNA structure determines its sensitivity to the valence and size of the counterions.

Moghaddam, Sarvin; Caliskan, Gokhan; Chauhan, Seema; Hyeon, Changbong; Briber, R.M.; Thirumalai, D.; Woodson, Sarah A.; (Chung-Ang); (JHU); (Maryland)



Biogeochemistry cycling of calcium and magnesium by Ceanothus and chamise  

SciTech Connect

Vegetation has long been recognized as a fundamental factor in soil formation, but vegetation and soils commonly covary in response to other environmental factors, confounding the specific effects of vegetation on soil properties. The lysimeter installation at the San Dimas Experimental Forest in southern California offers a rarely found opportunity for quantifying cation-cycling processes in a setting where all factors except vegetation are kept constant. The lysimeters were filled in 1937 with homogenized, fine sandy loam and planted in 1946 with chamise (Adenostoma fasciculatum Hook, and Arn.) and ceanothus (Ceanothus crassifolius Torr.). Comparison of the chamise and ceanothus lysimeters was best achieved by using the Ca/Mg ration of the different cation pools and fluxes as an index. In 1987, the ceanothus exchangeable soil pool contained proportionally more Ca than Mg compared with chamise; that is, the Ca/Mg ratio in the ceanothus exchangeable soil pool was higher than that in chamise. Strong evidence supports vegetation influence on intra-system fluxes (weathering and biocycling) as the basis for these differences. First, more Ca than Mg was released by weathering under ceanothus than under chamise. Second, the ceanothus aboveground biomass exhibited a higher Ca/Mg ration that the chamise. Third, differences between vegetation types widened with time since construction of the lysimeter installation in both the aboveground biomass and exchangeable soil pools. Differences in cation storage measured for the lysimeter chamise and ceanothus stands appear representative of natural chaparral communities throughout California, and may result in distinct Ca and Mg biogeochemical processes in associated ecosystems.

Quideau, S.A.; Graham, R.C.; Chadwick, O.A.; Wood, H.B.



Tropical Andean forest derives calcium and magnesium from Saharan dust  

Microsoft Academic Search

We quantified base metal deposition to Amazonian montane rain forest in Ecuador between May 1998 and April 2003 and assessed the response of the base metal budget of three forested microcatchments (8–13 ha). There was a strong interannual variation in deposition of Ca [4.4–29 kg ha?1 a?1], Mg [1.6–12], and K [9.8–30]). High deposition changed the Ca and Mg budgets

Jens Boy; Wolfgang Wilcke



The taste of calcium and magnesium salts and anionic modifications  

Microsoft Academic Search

Taste properties of divalent salts are complex. The first study examined the taste profiles of calcium chloride, magnesium chloride and magnesium sulfate. These divalent cation salts were characterized primarily by bitter taste, with additional sensations described as salty, metallic, astringent, sour and sweet, generally in decreasing order of intensity. A second study examined the taste properties of calcium salts other

Harry T. Lawless; Frank Rapacki; John Horne; April Hayes



Calcium and Magnesium ATPase Activities in Women with Varying BMIs  

Microsoft Academic Search

Objective: Intracellular calcium (Ca) is increased in obese humans, and magnesium (Mg)-ATPase activity is increased in monosodium glutamate-induced obese rats. The aims of this study were to test the hypotheses that Ca-ATPase activity is negatively correlated with BMI, and that Mg-ATPase activity is positively correlated with BMI and Ca-ATPase activity in obese women.Research Methods and Procedures: Thirty healthy adult women,

Jennifer A. Nasser; Sami A. Hashim; Paul A. Lachance



Purification of some Calcium and Magnesium Waste by Hydrodynamics Classification  

Microsoft Academic Search

In the manufacturing process of magnesium carbonate and oxide from dolomites by carbon dioxide leach ing are evacuated calcium carbonate waste, on one hand and on the other hand, in the carbide industry could be obtained calcium carbonate by practical application of some subsized lime fractions-containing waste. In order to obtai n calcium carbonate in different sorts as final products

L. M. Taubert; M. Milos; L. Sayti


Adenosine promotes tumor metastasis.  


An early step in tumor metastasis is a reduction in cell-cell adhesion to enable cell scattering. Contacts between cells are stabilized by accumulation in the plasma membrane of the small guanosine triphosphatase (GTPase) Rap1B. The membrane localization of Rap1B is increased when it is posttranslationally modified by prenylation of its C-terminal Cys-Ala-Ala-X motif. A new study shows that Rap1B prenylation and plasma membrane localization were reduced when Rap1B was phosphorylated by protein kinase A (PKA). In some tumors, high adenosine production and an abundance of G(s)-coupled adenosine A(2B) receptors would be expected to cause persistent PKA signaling and reduced Rap1B prenylation. These findings suggest that adenosine signaling reduces prenylation and plasma membrane localization of Rap1B, resulting in enhanced tumor cell scattering and invasiveness. PMID:23716715

Linden, Joel



Regulation of Inflammation by Adenosine  

PubMed Central

Adenosine, a purine nucleoside generated by the dephosphorylation of adenine nucleotides, is a potent endogenous physiologic and pharmacologic regulator of many functions. Adenosine was first reported to inhibit the inflammatory actions of neutrophils nearly 30?years ago and since then the role of adenosine and its receptors as feedback regulators of inflammation has been well established. Here we review the effects of adenosine, acting at its receptors, on neutrophil and monocyte/macrophage function in inflammation. Moreover, we review the role of adenosine in mediating the anti-inflammatory effects of methotrexate, the anchor drug in the treatment of Rheumatoid Arthritis and other inflammatory disorders.

Hasko, Gyorgy; Cronstein, Bruce



Adenosine and sleep  

SciTech Connect

Behavioral and biochemical approaches have been used to determine the relative contribution of endogenous adenosine and adenosine receptors to the sleep-wake cycle in the rat. Adenosine concentrations in specific areas of the rat brain were not affected by 24 hours of total sleep deprivation, or by 24 or 48 hours of REM sleep deprivation. In order to assess the effect of REM sleep deprivation on adenosine A/sub 1/ receptors, /sup 3/H-L-PIA binding was measured. The Bmax values for /sup 3/H-L-PIA binding to membrane preparations of the cortices and corpus striata from 48 hour REM sleep-deprived animals were increased 14.8% and 23%, respectively. These increases were not maintained following the cessation of sleep deprivation and recovered within 2 hours. The results of a 96 hour REM deprivation experiment were similar to those of the 48 hour REM sleep deprivation experiment. However, these increases were not evident in similar structures taken from stress control animals, and conclusively demonstrated that the changes in /sup 3/H-L-PIA binding resulted from REM sleep deprivation and not from stress.

Yanik, G.M. Jr.



Rat cardiac myocyte adenosine transport and metabolism  

SciTech Connect

Based on the importance of myocardial adenosine and adenine nucleotide metabolism, the adenosine salvage pathway in ventricular myocytes was studied. Accurate estimates of transport rates, separate from metabolic fllux, were determined. Adenosine influx was constant between 3 and 60 s. Adenosine metabolism maintained intracellular adenosine concentrations < 10% of the extracellular adenosine concentrations and thus unidirectional influx could be measured. Myocytes transported adenosine via saturable and nonsaturable processes. A minimum estimate of the V/sub max/ of myocytic adenosine kinase indicated the saturable component of adenosine influx was independent of adenosine kinase activity. Saturable transport was inhibited by nitrobenzylthioinosine and verapamil. Extracellular adenosine taken up myocytes was rapidly phosphorylated to adenine taken up by myocytes was rapidly phosphorylated to adenine nucleotides. Not all extracellular adenosine, though, was phosphorylated on entering myocytes, since free, as opposed to protein-bound, intracellular adenosine was detected after digitonin extraction of cells in the presence of 1 mM ethylene-diaminetetraacetic acid.

Ford, D.A.; Rovetto, M.J.



Regulation of adenosine receptor engagement by ecto-adenosine deaminase  

Microsoft Academic Search

Adenosine deaminase (ADA) can localize to the cell surface through its interaction with CD26. Using CD26-transfected cells, we demonstrate that cell surface ADA (ecto-ADA) can regulate adenosine receptor engagement by degrading extracellular adenosine (Ado) to inosine. This ability was dependent upon CD26 expression, the extent of CD26 saturation with ecto-ADA, and the kinetics of the cAMP response. Thus, the cAMP

Tomoko Hashikawa; Scott W. Hooker; Jerzy G. Maj; Christopher J. Knott-Craig; Masahide Takedachi; Shinya Murakami; Linda F. Thompson



Adenosine, mast cells and asthma  

Microsoft Academic Search

The aim of this article is to review the interplay between adenosine and mast cells in asthma. Adenosine is an endogenous nucleoside released from metabolically active cells and generated extracellularly via the degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types including platelets, neutrophils and mast cells via action at specific

P. Forsythe; M. Ennis



Caffeine alters plasma adenosine levels  

Microsoft Academic Search

Since the delights of tea were discovered by Emperor Shen Nung in 2737 BC, methylxanthines have been common in the human diet. Today, the methylxanthine caffeineis the most commonly consumed drug in the world, with actions mediated primarily by adenosine receptor blockade. We now report that caffeine increases plasma adenosine concentration in a manner that is dose-related, saturable, and mimicked

Lydia A. Conlay; Jeffrey A. Conant; Fred Debros; Richard Wurtman



Emerging adenosine receptor agonists.  


Adenosine receptors (ARs) are a four-member subfamily of G protein-coupled receptors and are major targets of caffeine and theophylline. There are four subtypes of ARs, designated as A1, A2A, A2B and A3. Selective agonists are now available for all four subtypes. Over a dozen of these selective agonists are now in clinical trials for various conditions, although none has received regulatory approval except for the endogenous AR agonist adenosine itself. A1AR agonists are in clinical trials for cardiac arrhythmias and neuropathic pain. A2AAR agonists are now in trials for myocardial perfusion imaging and as anti-inflammatory agents. A2BAR agonists are under preclinical scrutiny for potential treatment of cardiac ischemia. A3AR agonists are in clinical trials for the treatment of rheumatoid arthritis and colorectal cancer. The present review will mainly cover the agonists that are presently in clinical trials for various conditions and only a brief introduction will be given to major chemical classes of AR agonists presently under investigation. PMID:17874974

Gao, Zhan-Guo; Jacobson, Kenneth A



Adenosine, inflammation and asthma – a review  

Microsoft Academic Search

Adenosine is a ubiquitous molecule present in every cell of the human body. It has a wide range of physiological functions mediated predominantly through specific cell surface adenosine receptors. Adenosine has both pro- and anti-inflammatory effects and acts on inflammatory and resident immune cells and antioxidant enzymes. The elevation of adenosine in the bronchoalveolar lavage (BAL) fluid of asthmatics combined

M. Livingston; L. G. Heaney; M. Ennis



Purine Metabolism in Adenosine Deaminase Deficiency  

Microsoft Academic Search

Purine and pyrimidine metabolites were measured in erythrocytes, plasma, and urine of a 5-month-old infant with adenosine deaminase (adenosine aminohydrolase, EC deficiency. Adenosine and adenine were measured using newly devised ion exchange separation techniques and a sensitive fluorescence assay. Plasma adenosine levels were increased, whereas adenosine was normal in erythrocytes and not detectable in urine. Increased amounts of adenine

Gordon C. Mills; Frank C. Schmalstieg; K. Bryan Trimmer; Armond S. Goldman; Randall M. Goldblum



Functions of neuronal adenosine receptors  

Microsoft Academic Search

Endogenous adenosine in nervous tissue, a central link between energy metabolism and neuronal activity, varies according to behavioral state and (patho)physiological conditions; it may be the major sleep propensity substance. The functional consequences of activation of the four known adenosine receptors, A1, A2A, A2B and A3, are considered here. The mechanisms and electrophysiological actions, mainly those of the A1-receptor, have

Helmut L. Haas; Oliver Selbach



Subclasses of External Adenosine Receptors  

Microsoft Academic Search

Cell surface adenosine receptors mediate either stimulation or inhibition of adenylate cyclase activity [ATP pyrophosphate-lyase (cyclizing), EC], and the receptors that mediate these different responses can be discriminated with selected adenosine analogs. 5'-N-Ethylcarboxamideadenosine is a more potent agonist at stimulatory receptors (Ra) than is N6-phenylisopropyladenosine, whereas the reverse potency order is seen with inhibitory receptors (Ri). The potency of

Constantine Londos; Dermot M. F. Cooper; J. Wolff



Resveratrol inhibits metal ion-dependent and independent peroxidation of porcine low-density lipoproteins  

Microsoft Academic Search

Resveratrol, a phytoalexin (3, 4?, 5, trihydroxystilbene) present in some red wines, has been reported to inhibit copper-mediated low-density lipoprotein (LDL) oxidation. In this study, we examined the efficiency of this compound in inhibiting metal ion-dependent and independent peroxidation of porcine LDL. At 0.5, 1, or 1.5 ?M, transresveratrol prolonged the lag time preceding the onset of conjugated diene formation

Leila Belguendouz; Lucie Fremont; Alain Linard



Extracellular guanosine regulates extracellular adenosine levels.  


The aim of this investigation was to test the hypothesis that extracellular guanosine regulates extracellular adenosine levels. Rat preglomerular vascular smooth muscle cells were incubated with adenosine, guanosine, or both. Guanosine (30 ?mol/l) per se had little effect on extracellular adenosine levels. Extracellular adenosine levels 1 h after addition of adenosine (3 ?mol/l) were 0.125 ± 0.020 ?mol/l, indicating rapid disposition of extracellular adenosine. Extracellular adenosine levels 1 h after addition of adenosine (3 ?mol/l) plus guanosine (30 ?mol/l) were 1.173 ± 0.061 ?mol/l, indicating slow disposition of extracellular adenosine. Cell injury increased extracellular levels of endogenous adenosine and guanosine, and the effects of cell injury on endogenous extracellular adenosine were modulated by altering the levels of endogenous extracellular guanosine with exogenous purine nucleoside phosphorylase (converts guanosine to guanine) or 8-aminoguanosine (inhibits purine nucleoside phosphorylase). Extracellular guanosine also slowed the disposition of extracellular adenosine in rat preglomerular vascular endothelial cells, mesangial cells, cardiac fibroblasts, and kidney epithelial cells and in human aortic and coronary artery vascular smooth muscle cells and coronary artery endothelial cells. The effects of guanosine on adenosine levels were not mimicked or attenuated by 5-iodotubericidin (adenosine kinase inhibitor), erythro-9-(2-hydroxy-3-nonyl)-adenine (adenosine deaminase inhibitor), 5-aminoimidazole-4-carboxamide (guanine deaminase inhibitor), aristeromycin (S-adenosylhomocysteine hydrolase inhibitor), low sodium (inhibits concentrative nucleoside transporters), S-(4-nitrobenzyl)-6-thioinosine [inhibits equilibrative nucleoside transporter (ENT) type 1], zidovudine (inhibits ENT type 2), or acadesine (known modulator of adenosine levels). Guanosine also increases extracellular inosine, uridine, thymidine, and cytidine, yet decreases extracellular uric acid. In conclusion, extracellular guanosine regulates extracellular adenosine levels. PMID:23242185

Jackson, Edwin K; Cheng, Dongmei; Jackson, Travis C; Verrier, Jonathan D; Gillespie, Delbert G



Characterisation of central adenosine A 1 receptors and adenosine transporters in mice lacking the adenosine A 2a receptor  

Microsoft Academic Search

The present study was designed to assess whether adenosine A2a receptor knockout mice exhibit altered purine utilisation in brain nuclei. Specifically, the properties of adenosine transporters and adenosine A1 receptors were characterised in brain membranes and on slide-mounted sections. The BMAX for [3H]nitrobenzylthioinosine ([3H]NBTI) binding (adenosine transporter density) was significantly reduced in brainstem membranes of homozygotes (560±52 fmol\\/mg protein, n=5,

Broughton J Snell; Jennifer L Short; John Drago; Catherine Ledent; Andrew J Lawrence



Endogenous adenosine and adenosine receptors localized to ganglion cells of the retina  

Microsoft Academic Search

Using specific sensitive antisera against adenosine, we have immunocytochemically localized endogenous adenosine to specific layers of rat, guinea pig, monkey, and human retina. Highest adenosine immunoreactivity was observed in ganglion cells and their processes in the optic nerve fiber layer. Substantial staining was also found throughout the inner plexiform layer and in select cells in the inner nuclear layer. Adenosine

K. M. Braas; M. A. Zarbin; S. H. Snyder



Allosteric modulation of adenosine receptors  

PubMed Central

Allosteric modulators for adenosine receptors may have potential therapeutic advantage over orthosteric ligands. Allosteric enhancers at the adenosine A1 receptor have been linked to antiarrhythmic and antilipolytic activity. They may also have therapeutic potential as analgesics and neuroprotective agents. A3 allosteric enhancers are postulated to be useful against ischemic conditions or as antitumor agents. In this review, we address recent developments regarding the medicinal chemistry of such compounds. Most efforts have been and are directed toward adenosine A1 and A3 receptors, whereas limited or no information is available for A2A and A2B receptors. We also discuss some findings, mostly receptor mutation studies, regarding localization of the allosteric binding sites on the receptors.

Goblyos, Aniko



Adenosine in the airways: Implications and applications  

Microsoft Academic Search

Adenosine in a signaling nucleoside eliciting many physiological responses. Elevated levels of adenosine have been found in bronchoalveolar lavage, blood and exhaled breath condensate of patients with asthma a condition characterized by chronic airway inflammation. In addition, inhaled adenosine-5?-monophosphate induces bronchoconstriction in asthmatics but not in normal subjects. Studies on animals and humans have shown that bronchoconstriction is most likely

Lucia Spicuzza; Giuseppe Di Maria; Riccardo Polosa



Activation of Adenosine Receptor on Gingival Fibroblasts  

PubMed Central

CD73 (ecto-5?-nucleotidase) on human gingival fibroblasts plays a role in the regulation of intracellular cAMP levels through the generation of adenosine, which subsequently activates adenosine receptors. In this study, we examined the involvement of ecto-adenosine deaminase, which can be anchored to CD26 on human gingival fibroblasts, in metabolizing adenosine generated by CD73, and thus attenuating adenosine receptor activation. Ecto-adenosine deaminase expression on fibroblasts could be increased by pre-treatment with a lysate of Jurkat cells, a cell line rich in cytoplasmic adenosine deaminase. Interestingly, the cAMP response to adenosine generated from 5?-AMP via CD73 and the ability of 5?-AMP to induce hyaluronan synthase 1 mRNA were significantly decreased by the pre-treatment of fibroblasts with Jurkat cell lysate. This inhibitory effect was reversed by the specific adenosine deaminase inhibitor. These results suggest that ecto-adenosine deaminase metabolizes CD73-generated adenosine and regulates adenosine receptor activation.

Hashikawa, T.; Takedachi, M.; Terakura, M.; Yamada, S.; Thompson, L.F.; Shimabukuro, Y.; Murakami, S.



Potassium ion-dependent trehalose phosphorylase from halophilic Bacillus selenitireducens MLS10.  


We discovered a potassium ion-dependent trehalose phosphorylase (Bsel_1207) belonging to glycoside hydrolase family 65 from halophilic Bacillus selenitireducens MLS10. Under high potassium ion concentrations, the recombinant Bsel_1207 produced in Escherichia coli existed as an active dimeric form that catalyzed the reversible phosphorolysis of trehalose in a typical sequential bi bi mechanism releasing ?-d-glucose 1-phosphate and d-glucose. Decreasing potassium ion concentrations significantly reduced thermal and pH stabilities, leading to formation of inactive monomeric Bsel_1207. PMID:24021648

Nihira, Takanori; Saito, Yuka; Chiku, Kazuhiro; Kitaoka, Motomitsu; Ohtsubo, Ken'ichi; Nakai, Hiroyuki



Adenosine Receptors and Cancer  

PubMed Central

The A1, A2A, A2B and A3 G-protein-coupled cell surface adenosine receptors (ARs) are found to be upregulated in various tumor cells. Activation of the receptors by specific ligands, agonists or antagonists, modulates tumor growth via a range of signaling pathways. The A1AR was found to play a role in preventing the development of glioblastomas. This antitumor effect of the A1AR is mediated via tumor-associated microglial cells. Activation of the A2AAR results in inhibition of the immune response to tumors via suppression of T regulatory cell function and inhibition of natural killer cell cytotoxicity and tumor-specific CD4+/CD8+ activity. Therefore, it is suggested that pharmacological inhibition by specific antagonists may enhance immunotherapeutics in cancer therapy. Activation of the A2BAR plays a role in the development of tumors via upregulation of the expression levels of angiogenic factors in microvascular endothelial cells. In contrast, it was evident that activation of A2BAR results in inhibition of ERK1/2 phosphorylation and MAP kinase activity, which are involved in tumor cell growth signals. Finally, A3AR was found to be highly expressed in tumor cells and tissues while low expression levels were noted in normal cells or adjacent tissue. Receptor expression in the tumor tissues was directly correlated to disease severity. The high receptor expression in the tumors was attributed to overexpression of NF-?B, known to act as an A3AR transcription factor. Interestingly, high A3AR expression levels were found in peripheral blood mononuclear cells (PBMCs) derived from tumor-bearing animals and cancer patients, reflecting receptor status in the tumors. A3AR agonists were found to induce tumor growth inhibition, both in vitro and in vivo, via modulation of the Wnt and the NF-?B signaling pathways. Taken together, A3ARs that are abundantly expressed in tumor cells may be targeted by specific A3AR agonists, leading to tumor growth inhibition. The unique characteristics of these A3AR agonists make them attractive as drug candidates.

Fishman, P.; Bar-Yehuda, S.; Synowitz, M.; Powell, J.D.; Klotz, K.N.; Gessi, S.; Borea, P.A.



Adenosine receptors as therapeutic targets  

Microsoft Academic Search

Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of

Zhan-Guo Gao; Kenneth A. Jacobson



Adenosine decreases neurotransmitter release at central synapses.  

PubMed Central

Adenosine, at concentrations ranging from 5 to 100 microM, decreases the efficacy of transmission at the perforant path synapses on dentate granule cells. We have used whole cell recording from these cells in slices to determine the mechanism of the reduced synaptic strength. We find that size of miniature excitatory postsynaptic currents (mepscs) is unaffected by adenosine at concentrations up to 100 microM, an observation that indicates adenosine's mode of action is not through a decreased postsynaptic sensitivity to neurotransmitter. A quantal analysis indicates, however, that the quantity of neurotransmitter released is sufficiently diminished by adenosine to account entirely for the adenosine-produced decrease in synaptic strength. Application of 3-isobutyl-1-methylxanthine (IBMX), a drug that antagonizes the effects of endogenous adenosine, produces an increase in synaptic strength. This observation suggests that the resting level of adenosine in our slices is appreciable, and an analysis of the adenosine dose-response relation is consistent with endogenous adenosine levels of about 10 microM. IBMX application produces only slight changes in the amplitude of mepscs, whereas a quantal analysis demonstrates that the drug significantly increases the amount of neurotransmitter released. Thus IBMX acts as an "anti-adenosine" in our experiments. In some experiments we have been able to record excitatory and inhibitory synaptic currents produced by the same perforant path stimulus. In these instances we find that inhibitory transmission is unaffected by concentrations of adenosine that produce a marked decrease in the strength of excitatory synapses.

Prince, D A; Stevens, C F



Adenosine-induced activation of esophageal nociceptors  

PubMed Central

Clinical studies implicate adenosine acting on esophageal nociceptive pathways in the pathogenesis of noncardiac chest pain originating from the esophagus. However, the effect of adenosine on esophageal afferent nerve subtypes is incompletely understood. We addressed the hypothesis that adenosine selectively activates esophageal nociceptors. Whole cell perforated patch-clamp recordings and single-cell RT-PCR analysis were performed on the primary afferent neurons retrogradely labeled from the esophagus in the guinea pig. Extracellular recordings were made from the isolated innervated esophagus. In patch-clamp studies, adenosine evoked activation (inward current) in a majority of putative nociceptive (capsaicin-sensitive) vagal nodose, vagal jugular, and spinal dorsal root ganglia (DRG) neurons innervating the esophagus. Single-cell RT-PCR analysis indicated that the majority of the putative nociceptive (transient receptor potential V1-positive) neurons innervating the esophagus express the adenosine receptors. The neural crest-derived (spinal DRG and vagal jugular) esophageal nociceptors expressed predominantly the adenosine A1 receptor while the placodes-derived vagal nodose nociceptors expressed the adenosine A1 and/or A2A receptors. Consistent with the studies in the cell bodies, adenosine evoked activation (overt action potential discharge) in esophageal nociceptive nerve terminals. Furthermore, the neural crest-derived jugular nociceptors were activated by the selective A1 receptor agonist CCPA, and the placodes-derived nodose nociceptors were activated by CCPA and/or the selective adenosine A2A receptor CGS-21680. In contrast to esophageal nociceptors, adenosine failed to stimulate the vagal esophageal low-threshold (tension) mechanosensors. We conclude that adenosine selectively activates esophageal nociceptors. Our data indicate that the esophageal neural crest-derived nociceptors can be activated via the adenosine A1 receptor while the placodes-derived esophageal nociceptors can be activated via A1 and/or A2A receptors. Direct activation of esophageal nociceptors via adenosine receptors may contribute to the symptoms in esophageal diseases.

Ru, F.; Surdenikova, L.; Brozmanova, M.



Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat  

Microsoft Academic Search

The present study examined the spinal antinociceptive effects of adenosine analogs and inhibitors of adenosine kinase and adenosine deaminase in the carrageenan-induced thermal hyperalgesia model in the rat. The possible enhancement of the antinociceptive effects of adenosine kinase inhibitors by an adenosine deaminase inhibitor also was investigated. Unilateral hindpaw inflammation was induced by an intraplantar injection of lambda carrageenan (2

Anthony Poon; Jana Sawynok



Vascular adenosine receptors; potential clinical applications.  


Adenosine is an endogenous purine nucleoside that is an important metabolic sensing molecule. It is released during conditions of low oxygen delivery to tissues and organs to activate a range of effects in vascular tissues. Adenosine has a role in the vasculature by mediating vasodilation, vessel remodelling, cell proliferation as well as antiplatelet and inflammatory responses. Also, adenosine stimulates vasculogenesis and angiogenesis during wound healing and tumour growth. Currently, the clinical uses of adenosine are limited to treatment of supraventricular tachycardia or as a coronary vasodilator during radionuclide myocardial perfusion imaging. Due to the involvement of adenosine in various pathological conditions, the targeting of specific adenosine receptor (ADOR) subtypes in the vasculature using selective ADOR agonists or antagonists could have potential therapeutic benefit. However, the distribution of the receptors differs between species. Therefore, cross-species testing is essential to validate drug function. PMID:22724462

Ho, Ming-Fen; Rose'Meyer, Roselyn B



Sensitive radioimmunoassay for adenosine in biological samples  

SciTech Connect

A simple, sensitive, specific, and reproducible radioimmunoassay for the measurement of adenosine in biological materials has been developed. Adenosine antibody was obtained by immunizing rabbits with an immunogen prepared by conjugating 2',3'-disuccinyladenosine to human serum albumin. By succinylating adenosine in samples at the 2'- and 3'-O positions with a premixed reagent consisting of succinic anhydride, triethylamine, and dioxane, the assay became sensitive enough to detect less than picomole amounts of adenosine in minute quantities of tissues. The cross-reactivity of structurally related compounds with the antibody was mostly negligible except for 2'-deoxyadenosine, whose usual concentration was very low. The use of this method made it possible to measure adenosine without any prior purification procedure. The immunoreactive materials in various biological samples disappeared during incubation of the samples with adenosine deaminase.

Sato, T. (Yamasa Shoyu Co., Ltd., Choshi, Japan); Kuninaka, A.; Yoshino, H.; Ui, M.



Partial separation of platelet and placental adenosine receptors from adenosine A2-like binding protein  

SciTech Connect

The ubiquitous adenosine A2-like binding protein obscures the binding properties of adenosine receptors assayed with 5'-N-({sup 3}H)ethylcarboxamidoadenosine (({sup 3}H)NECA). To solve this problem, we developed a rapid and simple method to separate adenosine receptors from the adenosine A2-like binding protein. Human platelet and placental membranes were solubilized with 1% 3-((3-cholamidopropyl)dimethylammonio)-1-propanesulfonate. The soluble platelet extract was precipitated with polyethylene glycol and the fraction enriched in adenosine receptors was isolated from the precipitate by differential centrifugation. The adenosine A2-like binding protein was removed from the soluble placental extract with hydroxylapatite and adenosine receptors were precipitated with polyethylene glycol. The specificity of the ({sup 3}H)NECA binding is typical of an adenosine A2 receptor for platelets and an adenosine A1 receptor for placenta. This method leads to enrichment of adenosine A2 receptors for platelets and adenosine A1 receptors for placenta. This provides a useful preparation technique for pharmacologic studies of adenosine receptors.

Zolnierowicz, S.; Work, C.; Hutchison, K.; Fox, I.H. (University Hospital, Ann Arbor, MI (USA))



21 CFR 864.7040 - Adenosine triphosphate release assay.  

Code of Federal Regulations, 2010 CFR

...2010-04-01 2010-04-01 false Adenosine triphosphate release assay. 864...Hematology Kits and Packages § 864.7040 Adenosine triphosphate release assay. (a) Identification. An adenosine triphosphate release assay is a...



21 CFR 864.7040 - Adenosine triphosphate release assay.  

Code of Federal Regulations, 2010 CFR

...2009-04-01 2009-04-01 false Adenosine triphosphate release assay. 864...Hematology Kits and Packages § 864.7040 Adenosine triphosphate release assay. (a) Identification. An adenosine triphosphate release assay is a...



Regulation of neutrophil function by adenosine  

PubMed Central

Adenosine is an endogenously released purine nucleoside that signals via four widely expressed G-protein coupled receptors: A1, A2A, A2B, and A3. In the setting of inflammation, the generation and release of adenosine is greatly enhanced. Neutrophils play an important role in host defense against invading pathogens and are the cellular hallmark of acute inflammation. Neutrophils both release adenosine and can respond to it via expression of all four adenosine receptor subtypes. At low concentrations, adenosine can act via the A1 and A3 adenosine receptor subtypes to promote neutrophil chemotaxis and phagocytosis. At higher concentrations, adenosine acts at the lower-affinity A2A and A2B receptors to inhibit neutrophil trafficking and effector functions such as oxidative burst, inflammatory mediator production, and granule release. Modulation of neutrophil function by adenosine is relevant in a broad array of disease models, including ischemia reperfusion injury, sepsis, and non-infectious acute lung injury. This review will summarize relevant research in order to provide a framework for understanding how adenosine directly regulates various elements of neutrophil function.

Barletta, Kathryn E.; Ley, Klaus; Mehrad, Borna



Regulation of neutrophil function by adenosine.  


Adenosine is an endogenously released purine nucleoside that signals via 4 widely expressed G protein-coupled receptors: A(1), A(2A), A(2B), and A(3). In the setting of inflammation, the generation and release of adenosine is greatly enhanced. Neutrophils play an important role in host defense against invading pathogens and are the cellular hallmark of acute inflammation. Neutrophils both release adenosine and can respond to it via expression of all 4 adenosine receptor subtypes. At low concentrations, adenosine can act via the A(1) and A(3) adenosine receptor subtypes to promote neutrophil chemotaxis and phagocytosis. At higher concentrations, adenosine acts at the lower-affinity A(2A) and A(2B) receptors to inhibit neutrophil trafficking and effector functions such as oxidative burst, inflammatory mediator production, and granule release. Modulation of neutrophil function by adenosine is relevant in a broad array of disease models, including ischemia reperfusion injury, sepsis, and noninfectious acute lung injury. This review will summarize relevant research in order to provide a framework for understanding how adenosine directly regulates various elements of neutrophil function. PMID:22423037

Barletta, Kathryn E; Ley, Klaus; Mehrad, Borna



Clinical application of adenosine and ATP for pain control  

Microsoft Academic Search

This review summarizes clinical application of adenosine and adenosine 5?-triphosphate (ATP) in pain conditions. Investigations have been performed in patients with acute perioperative pain or chronic neuropathic pain treated with intravenous adenosine or ATP, or intrathecal adenosine. Characteristic central adenosine A1 receptor-mediated pain-relieving effects have been observed after intravenous adenosine infusion in human inflammation\\/sensitization pain models and in patients with

Masakazu Hayashida; Ken-ichi Fukuda; Atsuo Fukunaga



Substrate inhibition of adenosine phosphorylation in adenosine deaminase deficiency and adenosine-mediated inhibition of PP-ribose-P dependent nucleotide synthesis in hypoxanthine phosphoribosyltransferase deficient erythrocytes  

Microsoft Academic Search

Summary The metabolism of adenosine and its effects on phosphoribosylpyrophosphate, PP-ribose-P, dependent nucleotide synthesis were studied using erythrocytes from patients with adenosine deaminase and hypoxanthine phosphoribosyltransferase deficiency as models. The phosphorylation of adenosine was progressively inhibited by concentrations of adenosine greater than 1 µmol L-1 for control and ADA deficient erythrocytes. There was essentially no initial rate of phosphorylation at

F. F. Snyder; C. Dyer; J. E. Seegmiller; R. M. Goldblum; G. C. Mills; F. C. Schmalstieg



Adenosine, energy metabolism and sleep homeostasis.  


Adenosine is directly linked to the energy metabolism of cells. In the central nervous system (CNS) an increase in neuronal activity enhances energy consumption as well as extracellular adenosine concentrations. In most brain areas high extracellular adenosine concentrations, through A1 adenosine receptors, decrease neuronal activity and thus the need for energy. Adenosine may be a final common pathway for various sleep factors. We have identified a relatively specific area, the basal forebrain (BF), which appears to be central in the regulation/execution of recovery sleep after sleep deprivation (SD), or prolonged wakefulness. Adenosine concentration increases in this area during SD, and this increase induces sleep while prevention of the increase during SD abolishes recovery sleep. The increase in adenosine is associated with local changes in energy metabolism as indicated by increases in levels of pyruvate and lactate and increased phosphorylation of AMP-activated protein kinase. The increases in adenosine and sleep are associated with intact cholinergic system since specific lesion of the BF cholinergic cells abolishes both. Whether adenosine during SD is produced by the cholinergic neurons or astrocytes associated with them remains to be explored. An interesting, but so far unexplored question regards the relationship between the local, cortical regulation of sleep homeostasis and the global regulation of the state of sleep as executed by lower brain mechanisms, including the BF. The increase in adenosine concentration during SD also in cortical areas suggests that adenosine may have a role in the local regulation of sleep homeostasis. The core of sleep need is probably related to primitive functions of life, like energy metabolism. It can be noted that this assumption in no way excludes the possibility that later in evolution additional functions may have developed, e.g., related to complex neuronal network functions like memory and learning. PMID:20970361

Porkka-Heiskanen, Tarja; Kalinchuk, Anna V



Regulation of Cardiovascular Development by Adenosine and Adenosine-Mediated Embryo Protection  

PubMed Central

Few signaling molecules have the potential to influence the developing mammal as the nucleoside adenosine. Adenosine levels increase rapidly with tissue hypoxia and inflammation. Adenosine antagonists include the methlyxanthines caffeine and theophylline. The receptors that transduce adenosine action are the A1, A2a, A2b, and A3 adenosine receptors (ARs). We examined how adenosine acts via A1ARs to influence embryo development. Transgenic mice were studied along with embryo cultures. Embryos lacking A1ARs were markedly growth retarded following intrauterine hypoxia exposure. Studies of mice selectively lacking A1AR in the heart identify the heart as a key site of adenosines embryo protective effects. Studies of isolated embryos showed that adenosine plays a key role in modulating embryo cardiac function, especially in the setting of hypoxia. When pregnant mice were treated during embryogenesis with the adenosine antagonist caffeine, adult mice had abnormal heart function. Adenosine acts via A1ARs to play an essential role in protecting the embryo against intra uterine stress, and adenosine antagonists, including caffeine, may be an unwelcome exposure for the embryo.

Rivkees, Scott A.; Wendler, Christopher C.



Endogenous adenosine and adenosine receptors localized to ganglion cells of the retina  

SciTech Connect

Using specific sensitive antisera against adenosine, we have immunocytochemically localized endogenous adenosine to specific layers of rat, guinea pig, monkey, and human retina. Highest adenosine immunoreactivity was observed in ganglion cells and their processes in the optic nerve fiber layer. Substantial staining was also found throughout the inner plexiform layer and in select cells in the inner nuclear layer. Adenosine A1 receptors, labeled with the agonists L-(/sup 3/H)phenylisopropyladenosine and /sup 125/I-labeled hydroxy-phenylisopropyladenosine, were autoradiographically localized. The highest levels of binding sites occurred in the nerve fiber, ganglion cell, and inner plexiform layers of the retina in all the species examined. The distribution of adenosine A1 receptor sites closely parallels that of retinal neurons and fibers containing immunoreactive adenosine. These results suggest a role for endogenous adenosine as a coneurotransmitter in ganglion cells and their fibers in the optic nerve.

Braas, K.M.; Zarbin, M.A.; Snyder, S.H.



Adenosine Neuromodulation and Traumatic Brain Injury  

PubMed Central

Adenosine is a ubiquitous signaling molecule, with widespread activity across all organ systems. There is evidence that adenosine regulation is a significant factor in traumatic brain injury (TBI) onset, recovery, and outcome, and a growing body of experimental work examining the therapeutic potential of adenosine neuromodulation in the treatment of TBI. In the central nervous system (CNS), adenosine (dys)regulation has been demonstrated following TBI, and correlated to several TBI pathologies, including impaired cerebral hemodynamics, anaerobic metabolism, and inflammation. In addition to acute pathologies, adenosine function has been implicated in TBI comorbidities, such as cognitive deficits, psychiatric function, and post-traumatic epilepsy. This review presents studies in TBI as well as adenosine-related mechanisms in co-morbidities of and unfavorable outcomes resulting from TBI. While the exact role of the adenosine system following TBI remains unclear, there is increasing evidence that a thorough understanding of adenosine signaling will be critical to the development of diagnostic and therapeutic tools for the treatment of TBI.

Lusardi, T.A



Quantitative analysis of the ion-dependent folding stability of DNA triplexes  

NASA Astrophysics Data System (ADS)

A DNA triplex is formed through binding of a third strand to the major groove of a duplex. Due to the high charge density of a DNA triplex, metal ions are critical for its stability. We recently developed the tightly bound ion (TBI) model for ion-nucleic acids interactions. The model accounts for the potential correlation and fluctuations of the ion distribution. We now apply the TBI model to analyze the ion dependence of the thermodynamic stability for DNA triplexes. We focus on two experimentally studied systems: a 24-base DNA triplex and a pair of interacting 14-base triplexes. Our theoretical calculations for the number of bound ions indicate that the TBI model provides improved predictions for the number of bound ions than the classical Poisson-Boltzmann (PB) equation. The improvement is more significant for a triplex, which has a higher charge density than a duplex. This is possibly due to the higher ion concentration around the triplex and hence a stronger ion correlation effect for a triplex. In addition, our analysis for the free energy landscape for a pair of 14-mer triplexes immersed in an ionic solution shows that divalent ions could induce an attractive force between the triplexes. Furthermore, we investigate how the protonated cytosines in the triplexes affect the stability of the triplex helices.

Chen, Gengsheng; Chen, Shi-Jie



Repeated administration of adenosine increases its cardiovascular effects in rats.  


Hypotensive and negative chronotropic responses to adenosine in anesthetized rats increased after previous administration of the nucleoside. Bradycardia after adenosine in the isolated perfused rat heart was also potentiated after repeated administration at short intervals. This self-potentiation could be due to extracellular accumulation of adenosine and persistent stimulation of receptors caused by saturation or inhibition of cellular uptake of adenosine. PMID:3556395

Vidrio, H; García-Márquez, F; Magos, G A



Adenosine receptors as drug targets--what are the challenges?  


Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors--either directly or indirectly--have now entered the clinic. However, only one adenosine receptor-specific agent--the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma)--has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges. PMID:23535933

Chen, Jiang-Fan; Eltzschig, Holger K; Fredholm, Bertil B



Mediation of tubuloglomerular feedback by adenosine: Evidence from mice lacking adenosine 1 receptors  

Microsoft Academic Search

Adenosine is a determinant of metabolic control of organ function increasing oxygen supply through the A2 class of adenosine receptors and reducing oxygen demand through A1 adenosine receptors (A1AR). In the kidney, activation of A1AR in afferent glomerular arterioles has been suggested to contribute to tubuloglomerular feedback (TGF), the vasoconstriction elicited by elevations in [NaCl] in the macula densa region

Daqing Sun; Linda C. Samuelson; Tianxin Yang; Yuning Huang; Alex Paliege; Thom Saunders; Josie Briggs; Jurgen Schnermann



Control of basal extracellular adenosine concentration in rat cerebellum  

PubMed Central

To re-examine how the basal extracellular concentration of adenosine is regulated in acutely isolated cerebellar slices we have combined electrophysiological and microelectrode biosensor measurements. In almost all cases, synaptic transmission was tonically inhibited by adenosine acting via A1 receptors. By contrast, in most slices, the biosensors did not measure an adenosine tone but did record a spatially non-uniform extracellular tone of the downstream metabolites (inosine and hypoxanthine). Most of the extracellular hypoxanthine arose from the metabolism of inosine by ecto-purine nucleoside phosphorylase (PNP). Adenosine kinase was the major determinant of adenosine levels, as its inhibition increased both adenosine concentration and A1 receptor-mediated synaptic inhibition. Breakdown of adenosine by adenosine deaminase was the major source of the inosine/hypoxanthine tone. However adenosine deaminase played a minor role in determining the level of adenosine at synapses, suggesting a distal location. Blockade of adenosine transport (by NBTI/dipyridamole) had inconsistent effects on basal levels of adenosine and synaptic transmission. Unexpectedly, application of NBTI/dipyridamole prevented the efflux of adenosine resulting from block of adenosine kinase at only a subset of synapses. We conclude that there is spatial variation in the functional expression of NBTI/dipyridamole-sensitive transporters. The increased spatial and temporal resolution of the purine biosensor measurements has revealed the complexity of the control of adenosine and purine tone in the cerebellum.

Wall, Mark J; Atterbury, Alison; Dale, Nicholas



Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons  

PubMed Central

Adenosine has been proposed as an endogenous homeostatic sleep factor that accumulates during waking and inhibits wake-active neurons to promote sleep. It has been specifically hypothesized that adenosine decreases wakefulness and promotes sleep recovery by directly inhibiting wake-active neurons of the basal forebrain (BF), particularly BF cholinergic neurons. We previously showed that adenosine directly inhibits BF cholinergic neurons. Here, we investigated 1) how adenosine modulates glutamatergic input to BF cholinergic neurons and 2) how adenosine uptake and adenosine metabolism are involved in regulating extracellular levels of adenosine. Our experiments were conducted using whole cell patch-clamp recordings in mouse brain slices. We found that in BF cholinergic neurons, adenosine reduced the amplitude of AMPA-mediated evoked glutamatergic excitatory postsynaptic currents (EPSCs) and decreased the frequency of spontaneous and miniature EPSCs through presynaptic A1 receptors. Thus we have demonstrated that in addition to directly inhibiting BF cholinergic neurons, adenosine depresses excitatory inputs to these neurons. It is therefore possible that both direct and indirect inhibition may synergistically contribute to the sleep-promoting effects of adenosine in the BF. We also found that blocking the influx of adenosine through the equilibrative nucleoside transporters or inhibiting adenosine kinase and adenosine deaminase increased endogenous adenosine inhibitory tone, suggesting a possible mechanism through which adenosine extracellular levels in the basal forebrain are regulated.

Hawryluk, J. M.; Ferrari, L. L.; Keating, S. A.



Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations.  


Adenosine, a signaling nucleoside, exhibits tissue-protective and tissue-destructive effects. Adenosine levels in tissues are controlled in part by the enzyme adenosine deaminase (ADA). ADA-deficient mice accumulate adenosine levels in multiple tissues, including the lung, where adenosine contributes to the development of pulmonary inflammation and chronic airway remodeling. The present study describes the development of pulmonary fibrosis in mice that have been genetically engineered to possess partial ADA enzyme activity and, thus, accumulate adenosine over a prolonged period of time. These partially ADA-deficient mice live for up to 5 mo and die from apparent respiratory distress. Detailed investigations of the lung histopathology of partially ADA-deficient mice revealed progressive pulmonary fibrosis marked by an increase in the number of pulmonary myofibroblasts and an increase in collagen deposition. In addition, in regions of the distal airways that did not exhibit fibrosis, an increase in the number of large foamy macrophages and a substantial enlargement of the alveolar air spaces suggest emphysemic changes. Furthermore, important proinflammatory and profibrotic signaling pathways, including IL-13 and transforming growth factor-beta1, were activated. Increases in tissue fibrosis were also seen in the liver and kidneys of these mice. These changes occurred in association with pronounced elevations of lung adenosine concentrations and alterations in lung adenosine receptor levels, supporting the hypothesis that elevation of endogenous adenosine is a proinflammatory and profibrotic signal in this model. PMID:16258000

Chunn, Janci L; Mohsenin, Amir; Young, Hays W J; Lee, Chun G; Elias, Jack A; Kellems, Rodney E; Blackburn, Michael R



Antinociception by adenosine analogs and an adenosine kinase inhibitor: dependence on formalin concentration  

Microsoft Academic Search

Spinal administration of adenosine analogs and an adenosine kinase inhibitor produces antinociception in thermal threshold tests. In the present study, we determined the effects of N6-cyclohexyladenosine (adenosine A1 receptor selective), 2-[p-(2-carboxyethyl)phenylethylamino]-5?-N-ethyl-carboxamidoadenosine (CGS-21680) (adenosine A2A receptor selective), and 5?-N-ethylcarboxamidoadenosine (NECA) (non-selective), on formalin induced nociceptive responses (flinching\\/lifting and licking\\/biting) using two concentrations of formalin (2% and 5%). We also examined the

Anthony Poon; Jana Sawynok



Brain Adenosine Triphosphate: Decreased Concentration Precedes Convulsions.  

National Technical Information Service (NTIS)

The concentration of adenosine triphosphate in the brain decreased before the onset of generalized convulsions in unanesthetized rats subjected to acute hypoxia or treated with hydroxylamine or pentylenetetrazole (Metrazol). As the convulsive episode cont...

A. P. Sanders R. S. Kramer B. Woodhall W. D. Currie



Hot Spot Mutations in Adenosine Deaminase Deficiency  

Microsoft Academic Search

We have previously characterized mutant adenosine deaminase (ADA; adenosine aminohydrolase, EC enzymes in seven children with partial ADA deficiency. Six children shared common origins, suggesting a common progenitor. However, we found evidence for multiple phenotypically different mutant enzymes. We hypothesized that many of the mutations would be at CpG dinucleotides, hot spots at which spontaneous deamination of 5-methylcytosine results

Rochelle Hirschhorn; Stephanie Tzall; Amy Ellenbogen



Role of adenosine receptors in caffeine tolerance  

SciTech Connect

Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity.

Holtzman, S.G.; Mante, S.; Minneman, K.P. (Emory Univ. School of Medicine, Atlanta, GA (USA))



Functional selectivity of adenosine receptor ligands  

Microsoft Academic Search

Adenosine receptors are plasma membrane proteins that transduce an extracellular signal into the interior of the cell. Basically\\u000a every mammalian cell expresses at least one of the four adenosine receptor subtypes. Recent insight in signal transduction\\u000a cascades teaches us that the current classification of receptor ligands into agonists, antagonists, and inverse agonists relies\\u000a very much on the experimental setup that

Dennis Verzijl; Ad P. IJzerman



Adenosine receptor activation ameliorates type 1 diabetes  

Microsoft Academic Search

Growing evidence indicates that adeno- sine receptors could be promising therapeutic targets in autoimmune diseases. Here we studied the role of adenosine receptors in controlling the course of type 1 diabetes. Diabetes in CD-1 mice was induced by multi- ple-low-dose-streptozotocin (MLDS) treatment and in nonobese diabetic (NOD) mice by cyclophosphamide injection. The nonselective adenosine receptor agonist 5-N-ethylcarboxamidoadenosine (NECA) prevented diabetes

Zoltan H. Nemeth; David Bleich; Balazs Csoka; Pal Pacher; Jon G. Mabley; Leonora Himer; E. Sylvester Vizi; Edwin A. Deitch; Csaba Szabo; Bruce N. Cronstein; Gyorgy Hasko



Adenosine Receptors, Cystic Fibrosis, and Airway Hydration  

Microsoft Academic Search

\\u000a Adenosine (Ado) regulates diverse cellular functions in the lung through its local production, release, metabolism, and subsequent\\u000a stimulation of G-protein-coupled P1 purinergic receptors. The A2B adenosine receptor (A2BAR) is the predominant P1 purinergic receptor isoform expressed in surface airway epithelia, and Ado is an important regulator\\u000a of airway surface liquid (ASL) volume through its activation of the cystic fibrosis transmembrane

J. P. Clancy


Mucosal adenosine stimulates chloride secretion in canine tracheal epithelium  

SciTech Connect

Adenosine is a local regulator of a variety of physiological functions in many tissues and has been observed to stimulate secretion in several Cl-secreting epithelia. In canine tracheal epithelium the authors found that adenosine stimulates Cl secretion from both the mucosal and submucosal surfaces. Addition of adenosine, or its analogue 2-chloroadenosine, to the mucosal surface potently stimulated Cl secretion with no effect on the rate of Na absorption. Stimulation resulted from an interaction of adenosine with adenosine receptors, because it was blocked by the adenosine receptor blocker, 8-phenyltheophylline. The adenosine receptor was a stimulatory receptor as judged by the rank-order potency of adenosine and its analogues and by the increase in cellular adenosine 3',5'-cyclic monophosphate levels produced by 2-chloroadenosine. Adenosine also stimulated Cl secretion when it was added to the submucosal surface, although the maximal increase in secretion was less and it was much less potent. The observation that mucosal 8-phenyletheophylline blocked the effect of submucosal 2-chloroadenosine, whereas submucosal 8-phenyltheophylline did not prevent a response to mucosal or submucosal 2-chloroadenosine, suggests that adenosine receptors are located on the mucosal surface. Thus submucosal adenosine may stimulate secretion by crossing the epithelium and interacting with receptors located on the mucosal surface. Because adenosine can be released from mast cells located in the airway lumen in response to inhaled material, and because adenosine stimulated secretion from the mucosal surface, it may be in a unique position to control the epithelium on a regional level.

Pratt, A.D.; Clancy, G.; Welsh, M.J.



Calcium and Magnesium Self-Diffusion in Natural Diopside Single Crystals  

NASA Astrophysics Data System (ADS)

Clinopyroxenes in slowly cooled igneous rocks in both planetary and terrestrial environments (e.g. lunar basalts, layered igneous intrusives) commonly show exsolution lamellae of augite and pigeonite (which may be inverted to orthopyroxene) normal to the c-axis. The Ca-Mg-Fe zoning and thickness of these lamellae depend on the cooling rate of the host rock. This can be retrieved if the self-diffusion data for these cations are available. We have, thus, been engaged in systematic experimental studies to determine self-diffusion coefficients of divalent cations and report recent results on Ca and Mg. Gem quality diopside single crystals were oriented in a four-circle X ray diffractometer and cut as thin slabs normal to the c, b and a* axial directions. The cut pieces were polished, then the polished slabs were pre- annealed for 1-2 days at or close to experimental temperature and oxygen fugacity conditions. The source materials for Mg and Ca diffusion, which were ^{26}MgO or 44CaO powders, respectively, were deposited on the polished surfaces by thermal evaporation in an evacuated chamber. The diffusion experiments were conducted at 1 bar pressure at 950-1100 °C in a vertical tube-furnace. The oxygen fugacity was imposed by a computer controlled flowing mixture of CO and CO2, with a mixing ratio corresponding to the f (O2) of the wustite-iron buffer. The induced diffusion profiles were measured by Secondary Ion Mass Spectrometry, and modeled by either thin film source or constant surface solutions for one-dimensional diffusion. The choice of the appropriate model was dictated by the criteria of better fit to the experimental data. Our results show that diffusion in diopside is anisotropic with the fastest diffusion parallel to c- and slowest diffusion parallel to a*-axis, with D(//c) ~ 2D(//a*). D(Mg) is slightly faster than D(Ca) but are ~ an order magnitude faster than the D(Ca) determined by Dimanov (1996). The activation energy for diffusion of Ca parallel to the c-axis is ~ 350 kJ/mol. These results will be updated with additional experimental data and applied to the modeling of exsolution processes in natural clinopyroxenes.

Zhang, X. Y.; Ganguly, J.; Ito, M.; Hervig, R. L.



Alterations in calcium and magnesium content of red cell membranes in patients with primary hypertension  

Microsoft Academic Search

A cellular calcium–magnesium antagonism seems to be involved in the pathogenesis of primary hypertension. Total plasma, intracellular, and membranous calcium (Ca) and magnesium (Mg) contents were determined in 39 untreated patients with essential hypertension (EH) and 40 normotensive healthy subjects (NT). Membranous and intracellular measurements were performed in erythrocytes. Ca and Mg contents were measured by atomic absorption spectroscopy and

Markus Kosch; Martin Hausberg; Gerald Westermann; Jens Köneke; Fritz Matzkies; Karl Heinz Rahn; Klaus Kisters



Treatment of cooling tower blowdown water containing silica, calcium and magnesium by electrocoagulation.  


This research investigated the effectiveness of electrocoagulation using iron and aluminium electrodes for treating cooling tower blowdown (CTB) waters containing dissolved silica (Si(OH)(4)), Ca(2 + ) and Mg(2 + ). The removal of each target species was measured as a function of the coagulant dose in simulated CTB waters with initial pH values of 5, 7, and 9. Experiments were also performed to investigate the effect of antiscaling compounds and coagulation aids on hardness ion removal. Both iron and aluminum electrodes were effective at removing dissolved silica. For coagulant doses < or =3 mM, silica removal was a linear function of the coagulant dose, with 0.4 to 0.5 moles of silica removed per mole of iron or aluminium. Iron electrodes were only 30% as effective at removing Ca(2 + ) and Mg(2 + ) as compared to silica. There was no measurable removal of hardness ions by aluminium electrodes in the absence of organic additives. Phosphonate based antiscaling compounds were uniformly effective at increasing the removal of Ca(2 + ) and Mg(2 + ) by both iron and aluminium electrodes. Cationic and amphoteric polymers used as coagulation aids were also effective at increasing hardness ion removal. PMID:19901466

Liao, Z; Gu, Z; Schulz, M C; Davis, J R; Baygents, J C; Farrell, J



Ca2+-activated K+ channels in murine endothelial cells: block by intracellular calcium and magnesium.  


The intermediate (IK(Ca)) and small (SK(Ca)) conductance Ca(2+)-sensitive K(+) channels in endothelial cells (ECs) modulate vascular diameter through regulation of EC membrane potential. However, contribution of IK(Ca) and SK(Ca) channels to membrane current and potential in native endothelial cells remains unclear. In freshly isolated endothelial cells from mouse aorta dialyzed with 3 microM free [Ca(2+)](i) and 1 mM free [Mg(2+)](i), membrane currents reversed at the potassium equilibrium potential and exhibited an inward rectification at positive membrane potentials. Blockers of large-conductance, Ca(2+)-sensitive potassium (BK(Ca)) and strong inward rectifier potassium (K(ir)) channels did not affect the membrane current. However, blockers of IK(Ca) channels, charybdotoxin (ChTX), and of SK(Ca) channels, apamin (Ap), significantly reduced the whole-cell current. Although IK(Ca) and SK(Ca) channels are intrinsically voltage independent, ChTX- and Ap-sensitive currents decreased steeply with membrane potential depolarization. Removal of intracellular Mg(2+) significantly increased these currents. Moreover, concomitant reduction of the [Ca(2+)](i) to 1 microM caused an additional increase in ChTX- and Ap-sensitive currents so that the currents exhibited theoretical outward rectification. Block of IK(Ca) and SK(Ca) channels caused a significant endothelial membrane potential depolarization (approximately 11 mV) and decrease in [Ca(2+)](i) in mesenteric arteries in the absence of an agonist. These results indicate that [Ca(2+)](i) can both activate and block IK(Ca) and SK(Ca) channels in endothelial cells, and that these channels regulate the resting membrane potential and intracellular calcium in native endothelium. PMID:18195387

Ledoux, Jonathan; Bonev, Adrian D; Nelson, Mark T



Why and how to implement sodium, potassium, calcium, and magnesium changes in food items and diets?  

Microsoft Academic Search

The present average sodium intakes, approximately 3000–4500 mg\\/day in various industrialised populations, are very high, that is, 2–3-fold in comparison with the current Dietary Reference Intake (DRI) of 1500 mg. The sodium intakes markedly exceed even the level of 2500 mg, which has been recently given as the maximum level of daily intake that is likely to pose no risk

H Karppanen; P Karppanen; E Mervaala



Experimental study of aluminum-, calcium-, and magnesium-acetate complexing at 80 degree C  

Microsoft Academic Search

The stabilities of Al-, Ca-, and Mg-acetate complexes were determined separately at 80°C by measuring the solubilities of gibbsite, portlandite, and brucite as functions of acetate concentrations. The experiments were conducted using geologically realistic acetate concentrations in order to observe the acetate complexes that are important in sedimentary basin fluids. The experimental measurements are used to calculate the stoichiometries and




Calcium and magnesium transport by in situ mitochondria: electron probe analysis of vascular smooth muscle  

SciTech Connect

The extent, time course, and reversibility of mitochondrial Ca/sup 2 +/ uptake secondary to cellular Ca/sup 2 +/ influx stimulated by massive Na+ efflux were evaluated by electron probe microanalysis of rabbit portal vein smooth muscle. Strips of portal vein were Na+ loaded for 3 hours at 37/sup 0/C in a K+-free 1 mM ouabain solution, after which rapid Na+ efflux was induced by washing with a Na+-free K+-Li+ solution (1 mM ouabain). Li+ washing Na+-loaded portal vein produced a large transient contraction accompanied by an increase (over 100-fold) in mitochondrial Ca/sup 2 +/ and also significant (p less than 0.05) increases in phosphorus and Mg/sup 2 +/. The Ca/sup 2 +/ loading of the mitochondria was reversed during prolonged Li+ wash, and by 2 hours, mitochondrial Ca/sup 2 +/, Mg/sup 2 +/, and phosphorus had returned to control levels. The maximal contractile response to stimulation remained normal, demonstrating that pathologic Ca/sup 2 +/ loading of mitochondria is reversible in situ and compatible with normal maximal force developed by the smooth muscle. Mitochondrial Ca/sup 2 +/ and phosphorus uptake were reduced but still significant when the Li+ wash contained 0.2 mM Ca/sup 2 +/ or when ouabain was omitted. The fact that mitochondrial Ca/sup 2 +/ loading accompanied submaximal contractions during 0.2 mM Ca/sup 2 +/-Li wash suggests supranormal affinity of mitochondria for Ca/sup 2 +/ and may be due, in part, to reverse operation of the mitochondrial Na+-Ca/sup 2 +/ exchanger. Mitochondrial Ca/sup 2 +/, Mg/sup 2 +/, and phosphorus uptake were eliminated when the Li+ wash was performed at 2/sup 0/C or when the wash contained no Ca/sup 2 +/.

Broderick, R.; Somlyo, A.P.



Effect of Mineral Water Containing Calcium and Magnesium on Calcium Oxalate Urolithiasis Risk Factors  

Microsoft Academic Search

Calcium oxalate kidney stone formers are invariably advised to increase their fluid intake. In addition, magnesium therapy is often administered. Recently, a prospective study showed that a high dietary intake of calcium reduces the risk of symptomatic kidney stones. The present study was performed to test whether simultaneous delivery of these factors – high fluid intake, magnesium ingestion and increased

Allen L. Rodgers




Technology Transfer Automated Retrieval System (TEKTRAN)

Nisin is a cationic peptide (lantibiotic) that inhibits bacteria by inserting into cell membranes to form pores that dissipate ion gradients. Nisin resistance has been correlated with alterations in the cell surface of previously sensitive bacteria. Nisin-resistant bacteria have more lipoteichoic ...


Spatial variability of plant analysis calcium and magnesium levels before and after liming  

Microsoft Academic Search

Plant samples were taken in an 82.5 ft grid at an early and late sampling date in both 1991 and 1992 from a forty acre field in Illinois. Calcium (Ca) and magnesium (Mg) were analyzed on each sample and maps were made showing the levels of each nutrient within the field. Soil pH measurements were also made from each of

David W. Franzen; Ted R. Peck



Optical Dating Properties of Calcium and Magnesium Sulfates: Important Components of Mars Surface Sediments  

Microsoft Academic Search

Because of their occurrence in martian surface sediments, the optical dating properties of various Ca- and Mg-sulfate minerals were examined as potential geochronometers for geomorphic features and processes on Mars.

V. O'Connor; K. Lepper



Effects of ion pairing with calcium and magnesium on selenate availability to higher plants  

SciTech Connect

The effects of solution speciation on the bioavailability of trace metals are well documented, but the role of speciation in the bioavailability of oxyanionic trace elements that may form significant ion pairs with Ca and Mg in saline media has not been investigated. The authors assessed the effects of such ion pairing on the availability of selenate to representative monocotyledonous and dicotyledonous higher plants. Formation constants for the CaSO{sub 4}{sup 0} formation was confirmed, but the value of 10{sup 2.7} for CaSeO{sub 4}{sup 0} was found to be in error; a value of 10{sup 2.0} is proposed here as the correct formation constant. Five solution culture experiments were conducted using alfalfa (Medicago sativa L.) or tall wheatgrass (Elytrigia pontica [Podp.] Holub) with treatments consisting of NaSeO{sub 4} levels in combination with various levels of MgCl{sub 2} or CaCl{sub 2}. Both shoot Se concentrations and whole-plant Se contents were highly correlated with the free SeO{sub 4}{sup 2{minus}} activity but were poorly correlated with the sum of the free ion plus Ca and Mg ion pair species. Thus, the authors have shown, for the first time, that the free ion model of trace metal bioavailability is also valid for oxyanions that form complexes with Ca and Mg in saline media but that this conclusion hinges critically on the accuracy of the pertinent formation constants.

Parker, D.R.; Tice, K.R.; Thomason, D.N. [Univ. of California, Riverside, CA (United States). Dept. of Soil and Environmental Sciences



Factors affecting ex-situ aqueous mineral carbonation using calcium and magnesium silicate minerals  

SciTech Connect

Carbonation of magnesium- and calcium-silicate minerals to form their respective carbonates is one method to sequester carbon dioxide. Process development studies have identified reactor design as a key component affecting both the capital and operating costs of ex-situ mineral sequestration. Results from mineral carbonation studies conducted in a batch autoclave were utilized to design and construct a unique continuous pipe reactor with 100% recycle (flow-loop reactor). Results from the flow-loop reactor are consistent with batch autoclave tests, and are being used to derive engineering data necessary to design a bench-scale continuous pipeline reactor.

Gerdemann, Stephen J.; Dahlin, David C.; O'Connor, William K.; Penner, Larry R.; Rush, G.E.



Phosphate, calcium and magnesium fluxes into the lumen of the rat proximal convoluted tubule  

Microsoft Academic Search

In order to study fluxes of phosphate (Pi), Ca and Mg into the rat proximal tubule, a modification of the split-droplet microinjection technique was used. Injected fluids were isotonic solutions containing no Pi, Ca or Mg. The initial NaCl concentration of the injectates was either (a) 115 mM\\/l (which resulted in net fluid entry into the lumen), (b) 125 mM\\/l

D. G. Shirley; P. Poujeol; C. Grimellec



Calcium and magnesium in plant cytokinesis and their antagonism with caffeine  

Microsoft Academic Search

Summary The efficiency of caffeine at different concentration on the induction of binucleate cells in onion root-tip was studied. The drug effect is strongly depressed in the Ca++ and\\/or Mg++ presence at half-rate of maximum efficiency (0.04%), about 2 mM). We therefore conclude that both cations must play a role in plant cytokinesis.

J. Becerra



The effect of oral administration of calcium and magnesium on intestinal oxalate absorption in humans  

Microsoft Academic Search

Calcium oxalate (CaOx) urolithiasis is the most common urinary stone disease (70–75 % of all stones consist of CaOx in countries with western diet). Oxalate is the most lithogenic substance in CaOx crystallisation in urine. Oxalate is either synthesized within the body or absorbed from food. As oxalate is not metabolized in the human body, it appears unchanged in urine. Conventional

Susanne Voss; Diana J. Zimmermann; Albrecht Hesse; Gerd E. Von Unruh



Effect of lactulose on calcium and magnesium absorption: a study using stable isotopes in adult men.  


To evaluate the effect of lactulose on calcium (Ca) and magnesium (Mg) absorption, we performed a clinical trial with a double-blind, randomized, crossover design in 24 healthy adult male volunteers. The absorptions of Ca and Mg were evaluated by a single-labeling method using stable isotopes. The test foods, containing lactulose at a dose of 0 g (placebo), 2 g (low-dose), or 4 g (high-dose) together with 300 mg of Ca containing 20 mg of 44Ca, and 150 mg of Mg containing 28 mg of 25Mg, were administered orally. Urine samples were collected for 8 h after the ingestion of the test food. The ratios of stable isotopes in urine (44Ca/40Ca and 25Mg/24Mg) were measured by ICP-MS (inductively coupled plasma-mass spectrometry). The urinary stable-isotopes ratios (44Ca/40Ca and 25Mg/24Mg) increased with lactulose dosage. Significant differences were observed in the Ca ratio between placebo and high-dose lactulose (p<0.01), and in the Mg ratio between placebo and low-dose lactulose and between placebo and high-dose lactulose (p<0.01). Lactulose ingestion did not change the levels of bone-resorption markers (type I collagen cross-linked N-telopeptide and deoxypyridinoline) in urine. The test foods did not cause any side effects. This study demonstrates that lactulose enhances the absorptions of Ca and Mg in adult men. PMID:17484373

Seki, Nobuo; Hamano, Hirokazu; Iiyama, Yuriko; Asano, Yuzo; Kokubo, Sadayuki; Yamauchi, Koji; Tamura, Yoshitaka; Uenishi, Kazuhiro; Kudou, Hideki



The effect of oral administration of calcium and magnesium on intestinal oxalate absorption in humans.  


Calcium oxalate (CaOx) urolithiasis is the most common urinary stone disease (70-75 % of all stones consist of CaOx in countries with western diet). Oxalate is the most lithogenic substance in CaOx crystallisation in urine. Oxalate is either synthesized within the body or absorbed from food. As oxalate is not metabolized in the human body, it appears unchanged in urine. Conventional analysis methods cannot distinguish between endogenous and exogenous oxalate. Our [13C2]oxalate absorption test enabled measurement of intestinal oxalate absorption and quantification of the influence of Ca- and Mg-supplementation on it. The effects of the oral administration of these supplements were compared in order to obtain valid data for recommendations for CaOx urolithiasis patients. A 10 mmol supplement of both ions decreased the oxalate absorption significantly, calcium being more than twice as effective. PMID:15370283

Voss, Susanne; Zimmermann, Diana J; Hesse, Albrecht; von Unruh, Gerd E



CaSR-mediated interactions between calcium and magnesium homeostasis in mice.  


Calcium (Ca) and magnesium (Mg) homeostasis are interrelated and share common regulatory hormones, including parathyroid hormone (PTH) and vitamin D. However, the role of the calcium-sensing receptor (CaSR) in Mg homeostasis in vivo is not well understood. We sought to investigate the interactions between Mg and Ca homeostasis using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR) (double knockout, DKO). Serum Mg is lower in PTH KO and DKO mice than in WT mice on standard chow, whereas supplemental dietary Ca leads to equivalent Mg levels for all three genotypes. Mg loading increases serum Mg in all genotypes; however, the increase in serum Mg is most pronounced in the DKO mice. Serum Ca is increased with Mg loading in the PTH KO and DKO mice but not in the WT mice. Here, too, the hypercalcemia is much greater in the DKO mice. Serum and especially urinary phosphate are reduced during Mg loading, which is likely due to intestinal chelation of phosphate by Mg. Mg loading decreases serum PTH in WT mice and increases serum calcitonin in both WT and PTH KO mice but not DKO mice. Furthermore, Mg loading elevates serum 1,25-dihydroxyvitamin D in all genotypes, with greater effects in PTH KO and DKO mice, possibly due to reduced levels of serum phosphorus and FGF23. These hormonal responses to Mg loading and the CaSR's role in regulating renal function may help to explain changes in serum Mg and Ca found during Mg loading. PMID:23360827

Quinn, Stephen J; Thomsen, Alex R B; Egbuna, Ogo; Pang, Jian; Baxi, Khanjan; Goltzman, David; Pollak, Martin; Brown, Edward M



Calcium and magnesium contents and volume of the terminal cisternae in caffeine-treated skeletal muscle  

PubMed Central

(a) The effects of caffeine on the composition and volume of the terminal cisternae (TC) of the sarcoplasmic reticulum (SR) in frog skeletal muscle were determined with rapid freezing, electron microscopy, and electron probe analysis. (b) Caffeine (5 mM) released approximately 65% of the Ca content of the TC in 1 min and 84% after 3 min. The release of Ca from the TC was associated with a highly significant increase in its Mg content. This increase in Mg was not reduced by valinomycin. There was also a small increase in the K content of the TC at 1 min, although not after 3 min of caffeine contracture. (c) On the basis of the increase in Mg content during caffeine contracture and during tetanus (Somlyo, A. V., H. Gonzalez- Serratos, H. Shuman, G. McClellan, and A. P. Somlyo, 1981, J. Cell Biol., 90:577-594), we suggest that both mechanisms of Ca release are associated with an increase in the Ca and Mg permeability of the SR membranes, the two ions possibly moving through a common channel. (d) There was a significant increase in the P content of the TC during caffeine contracture, while in tetanized muscle (see reference above) there was no increase in the P content of the TC. (e) Mitochondrial Ca content was significantly increased (at 1 and at 3 min) during caffeine contracture. Valinomycin (5 microM) blocked this mitochondrial Ca uptake. (f) The sustained Ca release caused by caffeine in situ contrasts with the transient Ca release observed in studies of fragmented SR preparations, and could be explained by mediation of the caffeine-induced Ca release by a second messenger produced more readily in intact muscle than in isolated SR. (g) The TC were not swollen in rapidly frozen, caffeine-treated muscles, in contrast to the swelling of the TC observed in conventionally fixed, caffeine-treated preparation, the latter finding being in agreement with previous studies. (h) The fractional volume of the TC in rapidly frozen control (resting) frog semitendinosus muscles (approximately 2.1%) was less than the volume (approximately 2.5%) after glutaraldehyde-osmium fixation.



Calcium and magnesium fluxes across the plasma membrane of the toad rod outer segment.  

PubMed Central

1. Membrane current was recorded from an isolated, dark-adapted toad rod by sucking either its inner segment or outer segment into a tight-fitting glass pipette containing Ringer solution. The remainder of the cell was exposed to bath solution which could be changed rapidly. 2. In normal Ringer solution the current response of a cell to a saturating flash or step of light showed a small secondary rise at its initial peak. The profile of this secondary rise (i.e. amplitude and time course) was independent of both the intensity and the duration of illumination once the light response had reached a plateau level. 3. This secondary rise disappeared when external Na+ around the outer segment was replaced by Li+ or guanidinium, suggesting that it represented an electrogenic Na+-dependent Ca2+ efflux which was declining after the onset of light. 4. This Na+-Ca2+ exchange activity showed a roughly exponential decline, with a time constant of about 0.5 s. Exponential extrapolation of the exchange current to the time at half-height of the light response gave an initial amplitude of about 2 pA. Using La3+ as a blocker, we did not detect any steady exchange current after the initial exponential decline. 5. An intense flash superposed on a just-saturating steady background light failed to produce any incremental exchange current transient. 6. Our interpretation of the above results is that in darkness there are counterbalancing levels of Ca2+ influx (through the light-sensitive conductance) and efflux (through the Na+-Ca2+ exchange) across the plasma membrane of the rod outer segment. The exchange current transient at the onset of light merely represents the unidirectional Ca2+ efflux which becomes revealed as a result of the stoppage of the Ca2+ influx, rather than a de novo Ca2+ efflux triggered by light. 7. Consistent with this interpretation, a test light delivered soon after a saturating, conditioning light elicited little exchange current, which then gradually recovered to control value with a time course parallel to the restoration of the dark current. Conversely, when the dark current was increased above its physiological level by IBMX (isobutylmethylxanthine) the exchange current transient became larger than control.(ABSTRACT TRUNCATED AT 400 WORDS) Images Fig. 8

Nakatani, K; Yau, K W



Relief of Casein Inhibition of Bacillus stearothermophilus by Iron, Calcium, and Magnesium1  

PubMed Central

Growth of Bacillus stearothermophilus strain NCA 1518 Smooth in Dextrose Tryptone Agar (DTA) was inhibited by sodium caseinate. Binding studies indicated that sodium caseinate, when present in DTA, had the capacity to effect an iron deficiency which could cause inhibition of growth. Additions of essential cations, iron (1 mM), calcium (5 mM), magnesium (10 mM), or hydrogen ion (pH 5.7), relieved inhibition. Responses to and interactions among these relief factors were analyzed statistically. Equations were fitted to the data and were used to estimate responses to all treatment combinations within the ranges tested. Results from these studies indicated that calcium, magnesium, and hydrogen ion acted by decreasing the binding capacity of the protein for iron, rendering this metal available for metabolic needs. Evidence was obtained that ferrous rather than ferric iron was the limiting factor in DTA containing sodium caseinate.

Ashton, D. H.; Busta, F. F.; Warren, J. A.



Effects of boron supplements on bones from rats fed calcium and magnesium deficient diets  

Microsoft Academic Search

Sixty female, weanling rats were fed, for 6 wks, diets providing: casein, 20; CHO, 40; fat, 40. Vitamins and minerals, except Ca and Mg, were fed according to AIN'76 recommendations. Gp A (control) was fed 100% AIN Ca, Mg and P with no boron (B) added. Gps CD and CD+B were fed 30% AIN Ca and 100% AIN Mg and

H. McCoy; A. Irwin; M. A. Kenney; L. Williams



Decadal changes in potassium, calcium, and magnesium in a deciduous forest soil  

SciTech Connect

Decadal changes in soil exchangeable K{sup +}, Ca{sup 2+}, and Mg{sup 2+} concentrations and contents from 1972 to 2004 in eight intensively monitored plots on Walker Branch Watershed were compared with estimates of increments or decrements in vegetation and detritus. The results from these eight plots compared favorably with those from a more extensive set from 24 soil sampling plots sampled in 1972 and 2004. Increases in exchangeable K{sup +} were noted between 1972 and 1982, but few changes were noted between 1982 and 2004 despite significant increments in vegetation and detritus and significant potential losses by leaching. Total K contents of soils in the 0- to 60-cm sampling depth were very large and a slight amount of weathering could have replenished the K{sup +} lost from exchanges sites. With one notable exception, exchangeable Ca{sup 2+} and Mg{sup 2+} concentrations and contents decreased continuously during the sampling period. Decreases in exchangeable Ca{sup 2+} could be attributed mostly to increments in biomass and detritus, whereas decreases in exchangeable Mg{sup 2+} could not and were attributed to leaching. The major exception to these patterns was in the case of exchangeable Ca{sup 2+}, where significant increases were noted in one plot and attributed to Ca release from the decomposition of Ca-rich coarse woody debris from oak (Quercus spp.) mortality. With minor exceptions, soils and changes in soils among the eight intensively sampled core plots were similar to those in a more extensive set of plots distributed across the watershed. This study shows that averaging among plots can mask significant and important spatial patterns in soil change that must be taken into account in assessing long-term trends.

Mulholland, Patrick J [ORNL; Johnson, Dale W. [University of Nevada, Reno; Todd Jr, Donald E [ORNL; Trettin, Carl [USDA Forest Service



Sodium, Calcium, and Magnesium in Tissues of the Gerbil, Meriones Unguiculatus Exercised to Exhaustion.  

National Technical Information Service (NTIS)

Calcium is decreased in the heart and kidneys of exercise-exhausted gerbils. Magnesium is decreased in liver, kidney, heart and lungs but increased in muscle of these animals. Sodium is markedly decreased in the kidneys of the exhausted gerbils. (Author)

C. G. Wilber



Incubation of silver catfish, Rhamdia quelen (Pimelodidae), eggs at different calcium and magnesium concentrations  

Microsoft Academic Search

Ca2+ and Mg2+ are important for ionic regulation of freshwater fish because both ions influence the permeability of biological membranes, preventing diffusive flow and high ionic loss to water. The objective of this study was to analyze the hatchery rate and post-hatch survival of silver catfish (Rhamdia quelen) eggs at different Ca2+ and Mg2+ concentrations. Eggs were incubated in continuously

L. V. F Silva; J. I Golombieski; B Baldisserotto



Blood Copper, Zinc, Calcium, and Magnesium Levels During Different Duration of Pregnancy in Chinese  

Microsoft Academic Search

Concentrations of various trace elements are altered during pregnancy with changes in the mother’s physiology and the requirements\\u000a of growing fetus. The aim of the present longitudinal study was to learn the changes of trace element copper (Cu), zinc (Zn),\\u000a calcium (Ca), and magnesium (Mg) of normal pregnant woman during different durations of pregnancy and establish the reference\\u000a values of

Jinhao Liu; Hui Yang; Hua Shi; Chuan Shen; Wenjie Zhou; Qingkai Dai; Yongmei Jiang



Improvement of strawberry nutrition in sandy soils by addition of manure, calcium and magnesium  

Microsoft Academic Search

The addition of manure, gypsum, and dolomite as improvers of the organic matter, calcium (Ca), and magnesium (Mg) levels in the soils has been tested in a greenhouse experiment in order to enhance results obtained from strawberry cultivation in the southwest of Spain. The manure addition resulted in a significant increase in the Ca content in plants and decreased potassium

J. M. Peńalosa; C. Cadahia; M. J. Sarro; A. Masaguer



Effects of calcium and magnesium hardness on acute copper toxicity to juvenile channel catfish, Ictalurus punctatus  

Microsoft Academic Search

Two experiments were conducted to evaluate the effects of calcium or magnesium hardness on the acute toxicity of copper sulfate to juvenile channel catfish (Ictalurus punctatus) in low alkalinity environments. A preliminary bioassay determined the 48-h LC50 of copper sulfate to be 1.25 mg l?1 for juvenile catfish placed in water with calcium hardness and total alkalinity set at 20

Peter W. Perschbacher; William A. Wurts



Calcium and magnesium binding in native and structurally perturbed purple membrane  

SciTech Connect

The number and identity of the metal cations bound to wild-type bacteriorhodopsin (bR) are determined by using inductively coupled plasma mass spectrometry (ICP-MS) and ICP emission techniques. The results indicate that there at = 2 total Ca{sup 2+} and Mg{sup 2+} per bR molecule with a ratio of = 3:1 Ca{sup 2+} to Mg{sup 2+}. This observed ratio is found to agree with the calculated ratio using previously determined binding constants for the two high affinity sites of Ca{sup 2+} to deionized bR. This suggests that the high-affinity binding sites in deionized bR are similar to those in native bR. Structural perturbation of the native membrane by cleavage of the C-terminus decreases the number of ions per bR to 1.4. The observed ratio of total ions in this sample to total ions in bR is found to agree with that calculated using known binding constants for each. The results on the number of metal cations/bR and their ratio in bacteriorhodopsin agree with the calculated number using previously observed binding constants in deionized bO only if one assumes that the second high-affinity site (not the first) is removed by retinal removal. Removal of 75% of the lipids from the purple membrane is found to greatly reduce the number of metal cations from 2 to 0.16. This suggest that if metal cations are in the two high-affinity sites (which are the only type of binding sites evident in our native bR sample), the removal of lipids, known to change the protein tertiary structure, changes also the metal ion binding sites. 37 refs., 1 fig., 2 tabs.

Griffiths, J.A.; King, J.; Yang, D.; Browner, R.; El-Sayed, M.A. [Georgia Inst. of Technology, Atlanta, GA (United States)



Gypsum Amendment and Exchangeable Calcium and Magnesium Affecting Phosphorus and Nitrogen in Runoff  

Microsoft Academic Search

Loss of N and P from soil to water is not only an agronomic but also an environmental and human health problem. The main objective of this study was to evaluate the effect of gypsum amendment and soil- exchangeable Ca and Mg on the concentration and loss of nutrients in runoff, sediment, and soil. The experiment was performed in the

N. Favaretto; L. D. Norton; B. C. Joern; S. M. Brouder



Transcapillary adenosine transport and interstitial adenosine concentration in guinea pig hearts  

PubMed Central

We used the multiple-indicator-dilution technique to observe the capillary transport of adenosine in isolated Krebs-Henseleit-perfused guinea pig hearts. Tracer concentrations of radiolabeled albumin, sucrose, and adenosine were injected into the coronary inflow; outflow samples were collected for 10-25 s and analyzed by high-performance liquid chromatography (HPLC) and by ?- and ?-counting. The albumin data define the intravascular transport characteristics; the sucrose data define permeation through interendothelial clefts and dilution in interstitial fluid (ISF). Parameters calculated from adenosine data include permeability-surface area products for endothelial cell uptake at the luminal and abluminal membranes and intraendothelial metabolism. We found that in situ endothelial cells avidly take up and metabolize adenosine. Tracer adenosine in the capillary lumen is twice as likely to enter an endothelial cell as it is to permeate the clefts. There was no adenosine in the arterial perfusate. Under control conditions, the steady-state venous adenosine concentration was 3.6 ± 0.8 nM, which from the flow and the parameters estimated from the tracer data gave a calculated ISF concentration of 6.8 ± 1.5 nM. During dipyridamole infusion (10 ?M) at constant pressure, the cell permeabilities went essentially to zero, whereas the venous adenosine concentration increased to 44.0 ± 12.6 nM, giving an estimated ISF concentration of 191 ± 53 nM. With constant flow perfusion, venous concentration during dipyridamole infusion was 30.9 ± 6.3 nM, and estimated ISF concentration was 88 ± 20 mM. We conclude that in this preparation, at rest, the ISF adenosine concentration is about twice the venous concentration and the ISF adenosine concentration increases with dipyridamole administration.




Modulation and metamodulation of synapses by adenosine.  


The presence of adenosine in all nervous system cells (neurones and glia) together with its intensive release following insults makes adenosine as a sort of 'regulator' of synaptic communication, leading to the homeostatic coordination of brain function. Besides the direct actions of adenosine on the neurosecretory mechanisms, to tune neurotransmitter release, adenosine receptors interact with other receptors as well as with transporters as part of its attempt to fine-tune synaptic transmission. This review will focus on examples of the different ways adenosine can use to modulate or metamodulate synapses, in other words, to trigger or brake the action of some neurotransmitters and neuromodulators, to cross-talk with other G protein-coupled receptors, with ionotropic receptors and with receptor kinases as well as with transporters. Most of these interactions occur through A2A receptors, which in spite of their low density in some brain areas, such as the hippocampus, may function as amplifiers of the signalling of other mediators at synapses. PMID:20345418

Ribeiro, J A; Sebastiăo, A M



CD73-generated adenosine promotes osteoblast differentiation  

PubMed Central

CD73 is a GPI-anchored cell surface protein with ecto-5?-nucleotidase enzyme activity that plays a crucial role in adenosine production. While the roles of adenosine receptors (AR) on osteoblasts and osteoclasts have been unveiled to some extent, the roles of CD73 and CD73-generated adenosine in bone tissue are largely unknown. To address this issue, we first analyzed the bone phenotype of CD73-deficient (cd73?/?) mice. The mutant male mice showed osteopenia, with significant decreases of osteoblastic markers. Levels of osteoclastic markers were, however, comparable to those of wild type mice. A series of in vitro studies revealed that CD73 deficiency resulted in impairment in osteoblast differentiation but not in the number of osteoblast progenitors. In addition, over expression of CD73 on MC3T3-E1 cells resulted in enhanced osteoblastic differentiation. Moreover, MC3T3-E1 cells expressed adenosine A2A receptors (A2AAR) and A2B receptors (A2BAR) and expression of these receptors increased with osteoblastic differentiation. Enhanced expression of osteocalcin (OC) and bone sialoprotein (BSP) observed in MC3T3-E1 cells over expressing CD73 were suppressed by treatment with an A2BAR antagonist but not with an A2AAR antagonist. Collectively, our results indicate that CD73 generated adenosine positively regulates osteoblast differentiation via A2BAR signaling.

Takedachi, Masahide; Oohara, Hiroyuki; Smith, Brenda J.; Iyama, Mitsuyoshi; Kobashi, Mariko; Maeda, Kenichiro; Long, Courtney L.; Humphrey, Mary B.; Stoecker, Barbara J.; Toyosawa, Satoru; Thompson, Linda F.; Murakami, Shinya



Adenosine Signalling and Function in Glial Cells  

PubMed Central

Despite major advances in a variety of neuroscientific research fields, the majority of neurodegenerative and neurological diseases are poorly controlled by currently available drugs, which are largely based on a neurocentric drug design. Research from the past five years has established a central role of glia to determine how neurons function and – consequently – glial dysfunction is implicated in almost every neurodegenerative and neurological disease. Glial cells are key regulators of the brain’s endogenous neuroprotectant and anticonvulsant adenosine. This review will summarize how glial cells contribute to adenosine homeostasis and how glial adenosine receptors affect glial function. We will then move on to discuss how glial cells interact with neurons and the vasculature and outline new methods to study glial function. We will discuss how glial control of adenosine-function affects neuronal cell death and its implications for epilepsy, traumatic brain injury, ischemia, and Parkinson’s disease. Eventually, glial adenosine-modulating drug targets might be an attractive alternative for the treatment of neurodegenerative diseases. There are, however, several major open questions that remain to be tackled.

Boison, Detlev; Chen, Jiang-Fan; Fredholm, Bertil B.



Adenosiland: walking through adenosine receptors landscape.  


Adenosine receptors (ARs) belong to the family of G protein-coupled receptors. Four distinct subtypes are known, termed adenosine A(1), A(2A), A(2B) and A(3). receptors and they are regulated by adenosine which is one of the most ancient and widespread chemical messengers in the animal and plant kingdoms. Moreover, ARs are widely distributed in human body and they are expressed with different density in diverse tissues. It is not surprising that they are involved in the regulation of several physiopathological processes. Adenosiland represents the first tentative of an integrated bioinformatics and chemoinformatics web-resource dedicated to adenosine receptors. This informatics platform provides a wide-ranging of structure based and ligand based query functions to facilitate the exploration of adenosine receptor structures from primary sequences to three-dimensional architectures. Here, we present an overview of Adenosiland platform describing the most valuable searching tools and their functionalities. Adenosiland can be freely accessed at PMID:23127988

Floris, Matteo; Sabbadin, Davide; Medda, Ricardo; Bulfone, Alessandro; Moro, Stefano



A new class of adenosine receptors in brain: Characterization by 2-chloro( sup 3 H)adenosine binding  

SciTech Connect

Considerable evidence has accumulated in recent years to support a role for adenosine as an important physiological modulator in many mammalian tissues. In brain, adenosine is a potent depressant of neuronal firing and synaptic transmission. The exact mechanisms by which adenosine analogs depress nerve cell activity in the brain are not clear. Despite considerable investigation, neither the A1 nor the A2 adenosine receptors associated with adenylate cyclase have been able to account adequately for the actions of adenosine in brain. It has been proposed that additional adenosine receptors, possibly linked to calcium channels, are present in the central nervous system and are responsible for the physiological actions of adenosine. In this thesis, evidence is provided for the existence of a novel class of adenosine receptors in rat brain. The methods used to identify this new class of receptors involved radioligand binding techniques which have been successfully employed to characterize the properties of many neurotransmitter and drug receptors. 2-Chloro({sup 3}H)adenosine (Cl({sup 3}H)Ado) was selected as the ligand for these experiments since is a water-soluble, metabolically-stable analog of adenosine and a potent depressant of synaptic transmission in brain. The results demonstrate the presence of a distinct class of 2-chloro({sup 3}H)adenosine binding sites in rat forebrain membranes with an apparent K{sub D} of about 10 {mu}M and a B{sub max} of about 60 pmol per mg of protein. Specific 2-chloro ({sup 3}H)adenosine binding is highly specific for adenosine agonists and antagonists. Inhibition of binding by adenosine agonists exhibits an order of potency 2-chloroadenosine > 5{prime}-N-ethylcarboxamide adenosine > ({minus})-N{sup 6}-(R-phenylisopropyl)adenosine, which differs from that of both A1 and A2 adenosine receptors.

Chin, Jerome Hsicheng.



Renal Deoxyadenosine Transport and Immunodeficiency Associated with Adenosine Deaminase Deficiency  

Microsoft Academic Search

Accumulation of deoxyadenosine (or possibly adenosine) is thought to mediate the immune defect associated with adenosine deaminase deficiency. It is postulated that deoxyadenosine is particularly immunosuppressive in the neonate due to an undeveloped renal secretory mechanism.

J. Arly Nelson



Novel adenosine receptors in rat hippocampus identification and characterization  

SciTech Connect

2-chloro(/sup 3/H)adenosine, a stable analog of adenosine, was used to investigate the presence of adenosine receptors in rat hippocampal membranes that may mediate the depressant effects of adenosine on synaptic transmission in this tissue. Equilibrium binding studies reveal the presence of a previously undescribed class of receptors with a K/sub D/ of 4.7 and a Bmax of 130 pmol/mg of protein. Binding is sensitive to alkylxanthines and to a number of adenosine-related compounds. The pharmacological properties of this binding site are distinct from those of the A1 and A2 adenosine receptors associated with adenylate cyclase. The results suggest that this adenosine binding site is a novel central purinergic receptor through which adenosine may regulate hippocampal excitability. 50 references, 2 figures, 1 table.

Chin, J.H.; Mashman, W.E.; DeLorenzo, R.J.



The catalytic site structural gate of adenosine deaminase allosterically modulates ligand binding to adenosine receptors.  


The enzyme adenosine deaminase (ADA) is a multifunctional protein that can both degrade adenosine and bind extracellularly to adenosine receptors, acting as an allosteric modulator regulating the hormonal effects of adenosine. The molecular regions of ADA responsible for the latter are unknown. In this work, alanine scanning mutagenesis of various ADA amino acid stretches, selected through in silico docking experiments, allowed us to identify regions of the enzyme responsible for modulating both its catalytic activity and its ability to modulate agonist binding to A and A adenosine receptors (AR and AR). The combination of computational and in vitro experiments show that the structural gate to the catalytic site; i.e., the ?-1 helix containing residues L58-I72 and the loop containing residues A184-I188 of ADA, were important to maintain both the catalytic efficiency of the enzyme and its action as an allosteric modulator of the adenosine receptors. These data are consistent with a predicted supramolecular assembly, in which ADA bridges AR and CD26 and are in line with the notion that the interaction of ADA with adenosine receptors has an important role in the immunosynapse. We propose that it is the ADA open form, but not the closed one, that is responsible for the functional interaction with A?R and A?AR. PMID:23193172

Gracia, Eduard; Farré, Daniel; Cortés, Antoni; Ferrer-Costa, Carles; Orozco, Modesto; Mallol, Josefa; Lluís, Carme; Canela, Enric I; McCormick, Peter J; Franco, Rafael; Fanelli, Francesca; Casadó, Vicent



Depression of evoked potentials in brain slices by adenosine compounds.  

PubMed Central

1 A study has been made of the action of adenosine on surface slices of guinea-pig olfactory cortex in vitro. 2 With extracellular recordings from the pial surface and stimulation of the presynaptic input, the lateral olfactory tract (LOT) generated a monosynaptic negative wave representing dendritic excitatory potentials. This negative wave was depressed by bath application of 1 micron adenosine with increasing effect up to 1 mM. Adenosine 5'--triphosphate (ATP), adenosine 5'-monophosphate (AMP) and cyclic adenosine 3',5'-monophosphate (cyclic AMP) had similar depressant actions. Adenine and guanosine were very weak depressants. 3 Theophylline concentrations in the range 10 micron to 3 mM progressively antagonized the action of adenosine. 4 Dibuyryl cyclic AMP (100 micron) and agents which increase intracellular cyclic AMP were not depressants, suggesting that the action of adenosine was not cyclic AMP-mediated. 5 Intracellular recordings confirmed the depressant effect of adenosine on excitatory potentials generated by LOT stimulation and also showed that postsynatpic action potentials and the membrane of the soma were unaffected by adenosine. 6 Since presynaptic action potentials were also unaffected by adenosine, these experiments suggest that adenosine reduces excitatory transmission at LOT synapses and fortifies the idea that adenosine has a 'neurohumoral' action.

Scholfield, C N



Regulation of adenosine transport by acute and chronic ethanol exposure  

SciTech Connect

Chronic exposure to ethanol results in a desensitization of adenosine receptor-stimulated cAMP production. Since adenosine is released by cells and is known to desensitize its own as well as other receptors, it may be involved in ethanol-induced desensitization of adenosine receptor function. Therefore, we have examine the acute and chronic effects of ethanol on the transport of adenosine via the nucleoside transport. Acute exposure to ethanol caused an inhibition of adenosine uptake in S49 lymphoma cells. This decrease in uptake resulted in accumulation of extracellular adenosine after ethanol exposure. The effect of ethanol was specific to nucleoside transport. Uptake of uridine, also transported by the nucleoside transporter, was inhibited by ethanol to the same degree as adenosine uptake, while neither isoleucine nor deoxyglucose uptake was altered by ethanol treatment. Inhibition of adenosine uptake by ethanol was non-competitive and dependent on the concentration of ethanol. After chronic exposure to ethanol, cells became tolerant to the acute effects of ethanol. There was no longer an acute inhibition of adenosine uptake, nor was these accumulation of extracellular adenosine. Chronic ethanol exposure also resulted in a decrease in the absolute rate of adenosine uptake. Binding studies using a high affinity lignad for the nucleoside transporter, nitrobenzylthioinosine (NBMPR), indicate that this decreased uptake was due to a decrease in the maximal number of binding sites. These ethanol-induced changes in adenosine transport may be important for the acute and chronic effects of ethanol.

Nagy, L.E.; Casso, D.; Diamond, I.; Gordon, A.S. (Univ. of California, San Francisco (USA))



Two Distinct Adenosine-Sensitive Sites on Adenylate Cyclase  

Microsoft Academic Search

The effects of adenosine and adenosine analogs on adenylate cyclases from several tissues have been examined. Two adenosine-reactive sites have been identified: (i) the ``R'' site, occupancy of which usually leads to activation of cyclase and which requires integrity of the ribose ring for activity, and (ii) the ``P'' site, which mediates inhibition and requires integrity of the purine ring

Constantine Londos; J. Wolff



A Role for Adenosine Deaminase in Drosophila Larval Development  

Microsoft Academic Search

Adenosine deaminase (ADA) is an enzyme present in all organisms that catalyzes the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine. Both adenosine and deoxyadenosine are biologically active purines that can have a deep impact on cellular physiology; notably, ADA deficiency in humans causes severe combined immunodeficiency. We have established a Drosophila model to study the effects of

Tomas Dolezal; Eva Dolezelova; Michal Zurovec; Peter J. Bryant



Interactions between cyclosporine A and adenosine in kidney transplant recipients  

Microsoft Academic Search

Interactions between cyclosporine A and adenosine in kidney transplant recipients. Adenosine is involved in a large number of physiological processes including immune response and vasomotor function. But its precise involvement in renal physiology is poorly understood. We have investigated the putative relationships between cyclosporine A (CsA) and adenosine (ADO) metabolism in kidney transplant recipients (KTR). We first compared ADO plasma

Regis Guieu; Bertrand Dussol; Christiane Devaux; Jerome Sampol; Phillppe Brunet; Hervé Rochat; Guy Bechis; Yvon François Berland



Structure and function studies of mammalian adenosine kinase  

Microsoft Academic Search

Adenosine kinase (AK) is a purine salvage enzyme which catalyses the phosphorylation of the 5?-hydroxyl of adenosine via ATP. AK is a key enzyme which controls the intra and extracellular concentration of adenosine (Ado). Agents which inhibit the activity of AK have been found to attenuate cellular damage, demonstrating therapeutic utility in a variety of disease processes. In order to

Mary Christine Maj




Microsoft Academic Search

Adenosine kinase (AK) is a purine salvage enzyme which catalyzes the phosphorylation of the 5'-hydroxyl of adenosine via ATP. AK is a key enzyme which controls the intra and extracellular concentration of adenosine (Ado). Agents which inhibit the activity of AK have been found to attentuate cellular damage, demonstrating therapeutic utility in a variety of disease processes. In order to




Mechanisms of adenosine-induced renal vasodilatation in hypertensive patients  

Microsoft Academic Search

BACKGROUND: Adenosine is an endogenous nucleoside with potent vasodilatory capacities, released under ischaemic conditions in particular. Its mechanisms of action, however, remain elusive. OBJECTIVE: To evaluate the role of adenosine, using a non-selective purinergic receptor antagonist, and the possible involvement of nitric oxide in this mechanism. In addition, the production of renin and catecholamines was studied during infusion of adenosine,

Thomas KA Wierema; Alphons JHM Houben; Abraham A Kroon; Cornelis T Postma; Derk Koster; Jos MA van Engelshoven; Paul Smits; Peter W de Leeuw



Interactions of Esmolol and Adenosine in Atrioventricular Nodal-Dependent Supraventricular Tachycardia: Implication for the Cellular Mechanisms of Adenosine  

Microsoft Academic Search

Introduction: Cellular mechanisms of adenosine include a direct effect on the activation of the adenosine-sensitive potassium current (IK,Ado) and an indirect effect on antagonism of catecholamine-stimulated adenylate cyclase activity. However, previous studies evaluating the influence of catecholamine activity on the electrophysiologic effects of adenosine have yielded conflicting results. We tested the hypotheses that if adenosine exerts its atrioventricular (AV) nodal

Kuan-Cheng Chang; Yu-Chin Lin; Jan-Yow Chen; Hsiang-Tai Chou; Jui-Sung Hung



A selective adenosine A1 receptor antagonist attenuates renal dysfunction during controlled hypotension with adenosine in rats.  


Adenosine infusion produces sustained, reversible, controlled hypotension in humans, but markedly compromises renal function. Since adenosine inhibits renal perfusion and filtration via stimulation of intrarenal A1 receptors, we hypothesized that antagonism of A1-subtype receptors with the selective adenosine A1-receptor antagonist (+-)N6-endonorbornan-2-yl-9-methyladenine (N-0861) would attenuate adenosine-induced renal dysfunction while still allowing induction and maintenance of hypotension. Systemic and renal hemodynamic and excretory responses were measured in clearance studies conducted in six groups of anesthetized rats treated with: vehicle+saline, vehicle+adenosine, N-0861 (10 or 30 mumol/kg intravenously [i.v.])+saline, or N-0861 (10 or 30 mumol/kg i.v.),+adenosine. The A1-receptor antagonist had little effect on the magnitude, maintenance, or reversibility of controlled hypotension produced by adenosine infusion. Oliguria, hypofiltration, and electrolyte retention induced by adenosine infusion were attenuated in rats pretreated with N-0861. Adenosine A1-receptor antagonism also reduced the rebound hyperfiltration and hyperperfusion associated with cessation of adenosine infusion. N-0861 alone had only a modest effect on renal or systemic hemodynamics, but produced significant dose-related diuresis/natriuresis. These results suggest that coadministration of, or pretreatment with, a selective adenosine A1-receptor antagonist may attenuate the undesirable renal effects of adenosine while allowing maintenance of controlled hypotension. PMID:8067549

Barrett, R J; Wright, K F



Shaping of monocyte and macrophage function by adenosine receptors  

PubMed Central

Adenosine is an endogenous purine nucleoside that, following its release into the extracellular space, binds to specific adenosine receptors expressed on the cell surface. Adenosine appears in the extracellular space under metabolically stressful conditions, which are associated with ischemia, inflammation, and cell damage. There are 4 types of adenosine receptors (A1, A2A, A2B and A3) and all adenosine receptors are members of the G protein-coupled family of receptors. Adenosine receptors are expressed on monocytes and macrophages and through these receptors adenosine modulates monocyte and macrophage function. Since monocytes and macrophages are activated by the same danger signals that cause accumulation of extracellular adenosine, adenosine receptors expressed on macrophages represent a sensor system that provide monocytes and macrophages with information about the stressful environment. Adenosine receptors, thus, allow monocytes and macrophages to fine-tune their responses to stressful stimuli. Here, we review the consequences of adenosine receptor activation on monocyte/macrophage function. We will detail the effect of stimulating the various adenosine receptor subtypes on macrophage differentiation/proliferation, phagocytosis, and tissue factor (TF) expression. We will also summarize our knowledge of how adenosine impacts the production of extracellular mediators secreted by monocytes and macrophages in response to toll-like receptor (TLR) ligands and other inflammatory stimuli. Specifically, we will delineate how adenosine affects the production of superoxide, nitric oxide (NO), tumor necrosis factor-?, interleukin (IL)-12, IL-10, and vascular endothelial growth factor (VEGF). A deeper insight into the regulation of monocyte and macrophage function by adenosine receptors should assist in developing new therapies for inflammatory diseases.

Hasko, Gyorgy; Pacher, Pal; Deitch, Edwin A.; Vizi, E. Sylvester



Expression of Human Adenosine Deaminase after Fusion of Adenosine Deaminase-Deficient Cells with Mouse Fibroblasts  

Microsoft Academic Search

Two human choriocarcinoma cell lines were shown to be deficient in adenosine deaminase (ADA; adenosine aminohydrolase, EC such that they did not produce bands on starch gels after electrophoresis and histochemical staining. Radiometric assay indicated that their ADA specific activity was approximately 2% that of HeLa (human) cell controls. Subclone analysis of one of the lines indicated that this

Michael J. Siciliano; Mary R. Bordelon; Peter O. Kohler



Origin of Cyclic Adenosine Monophosphate in Saliva  

Microsoft Academic Search

The level of cyclic adenosine monophosphate (AMP) in duct saliva from the dog submandibular gland was increased after cyclic AMP was administered intravenously in vivo. Isoproterenol increased the level of cyclic AMP in plasma and saliva in vivo and in salivary gland slices in vitro, but increased the level only slightly in saliva in a perfused dog submaxillary gland.

Takao Kanamori; Toshiharu Nagatsu; Shosei Matsumoto



Prenatal diagnosis for adenosine deaminase deficiency  

Microsoft Academic Search

Amniocentesis was performed in two successive pregnancies of the mother of a child with adenosine deaminase (ADA) deficient severe combined immunodeficiency. Assay of ADA in amniotic fluid fibroblasts showed the pregnancies to be normal and homozygous deficient, respectively. These findings were confirmed by the demonstration of a normal level of erythrocyte ADA in the cord blood of the healthy male

J B Ziegler; M B Van der Weyden; C H Lee; A Daniel



Adenosine deaminase deficiency with mosaicism for a \\  

Microsoft Academic Search

Four patients from 3 Saudi Arabian fami- lies had delayed onset of immune defi- ciency due to homozygosity for a novel intronic mutation, g.31701T>A, in the last splice acceptor site of the adenosine deaminase (ADA) gene. Aberrant splicing mutated the last 4 ADA amino acids and added a 43-residue \\

Francisco X. Arredondo-Vega; Ines Santisteban; Eva Richard; Pawan Bali; Majed Koleilat; Michael Loubser; Abdulaziz Al-Ghonaium; Mariam Al-Helali; Michael S. Hershfield



Dipeptidyl peptidase IV and adenosine deaminase activity  

Microsoft Academic Search

Dipeptidyl peptidase IV (DPPIV) and adenosine deaminase (ADA), two T cell associated enzymes, are known to have a possible interaction and play essential roles in immune system functioning. On the other hand, depression has been shown to be accompanied with some immune-inflammatory alterations. In this regard, in order to make a contribution to the understanding of the ongoing immune disturbances

Serenay Elgün; Aytaç Keskinege; Hakan Kumbasar



Adenosine: an endogenous regulator of innate immunity  

Microsoft Academic Search

Although inflammatory and immunological reactions protect the host from invasion by microorganisms and eliminate debris at sites of tissue injury, they can also be responsible for significant tissue damage. Thus, regulatory mechanisms that limit damage from an overly exuberant immune response have evolved. It is increasingly apparent that adenosine, a purine nucleoside that is elaborated at injured and inflamed sites,

György Haskó; Bruce N. Cronstein



Upregulation of adenosine kinase in rasmussen encephalitis.  


Rasmussen encephalitis (RE) is a rare neurologic disorder of childhood characterized by unihemispheric inflammation, progressive neurologic deficits, and intractable focal epilepsy. The pathogenesis of RE is still enigmatic. Adenosine is a key endogenous signaling molecule with anticonvulsive and anti-inflammatory effects, and our previous work demonstrated that dysfunction of the adenosine kinase (ADK)-adenosine system and astrogliosis are the hallmarks of epilepsy. We hypothesized that the epileptogenic mechanisms underlying RE are related to changes in ADK expression and that those changes might be associated with the development of epilepsy in RE patients. Immunohistochemistry was used to examine the expression of ADK and glial fibrillary acidic protein in surgically resected human epileptic cortical specimens from RE patients (n = 12) and compared with control cortical tissues (n = 6). Adenosine kinase expression using Western blot and enzymatic activity for ADK were assessed in RE versus control samples. Focal astrogliosis and marked expression of ADK were observed in the lesions of RE. Significantly greater ADK expression in RE versus controls was demonstrated by Western blot, and greater enzymatic activity for ADK was demonstrated using an enzyme-coupled bioluminescent assay. These results suggest that upregulation of ADK is a common pathologic hallmark of RE and that ADK might be a target in the treatment of epilepsy associated with RE. PMID:24128682

Luan, Guoming; Gao, Qing; Guan, Yuguang; Zhai, Feng; Zhou, Jian; Liu, Changqing; Chen, Yin; Yao, Kun; Qi, Xueling; Li, Tianfu



Cardiovascular adenosine receptors: Expression, actions and interactions.  


Intra- and extracellular adenosine levels rise in response to physiological stimuli and with metabolic/energetic perturbations, inflammatory challenge and tissue injury. Extracellular adenosine engages members of the G-protein coupled adenosine receptor (AR) family to mediate generally beneficial acute and adaptive responses within all constituent cells of the heart. In this way the four AR sub-types-A1, A2A, A2B, and A3Rs-regulate myocardial contraction, heart rate and conduction, adrenergic control, coronary vascular tone, cardiac and vascular growth, inflammatory-vascular cell interactions, and cellular stress-resistance, injury and death. The AR sub-types exert both distinct and overlapping effects, and may interact in mediating these cardiovascular responses. The roles of the ARs in beneficial modulation of cardiac and vascular function, growth and stress-resistance render them attractive therapeutic targets. However, interactions between ARs and with other receptors, and their ubiquitous distribution throughout the body, can pose a challenge to the implementation of site- and target-specific AR based pharmacotherapy. This review outlines cardiovascular control by adenosine and the AR family in health and disease, including interactions between AR sub-types within the heart and vessels. PMID:23764371

Headrick, John P; Ashton, Kevin J; Rose'meyer, Roselyn B; Peart, Jason N



Fluorescence sensing of adenosine deaminase based on adenosine induced self-assembly of aptamer structures.  


A new approach is proposed for simple detection of adenosine deaminase (ADA) based on adenosine induced self-assembly of two pieces of single-stranded DNA (ssDNA). These ssDNA are two fragments of the aptamer that has a strong affinity for adenosine and are labeled with carboxyfluorescein and black hole quencher-1, respectively. The complementarities of the bases in the two pieces of ssDNA are insufficient to form a stable structure. In the presence of adenosine, however, the ssDNA can be assembled into the intact aptamer tertiary structure, which results in fluorescence quenching of the carboxyfluorescein-labeled aptamer fragment. As a result, the adenosine-ssDNA complex shows a low background signal, which is rather desired for achieving sensitive detection. Reaction of the complex with ADA causes a great fluorescence enhancement by converting adenosine into inosine that has no affinity for the aptamer. This behaviour leads to the development of a simple and sensitive fluorescent method for assaying ADA activity, with a detection limit of 0.05 U mL(-1), which is more sensitive than most of the existing approaches. Furthermore, the applicability of the method has been demonstrated by detecting ADA in mouse serum samples. PMID:23462984

Feng, Tingting; Ma, Huimin



Effects of adenosine infusion into renal interstitium on renal hemodynamics  

SciTech Connect

This study was designed to investigate the hemodynamic effects of exogenous adenosine in the interstitium of the rat kidney. Adenosine or its analogues were infused into the renal interstitium by means of chronically implanted capsules. In fusion of adenosine decreased glomerular filtration rate (GFR) from 0.81 +/- 0.06 to 0.37 +/- 0.06 ml/min while having no effect on renal blood flow (RBF). The metabolically stable analogue, 2-chloradenosine (2-ClAdo), decreased GFR from 0.73 +/- 0.07 to 021 +/- 0.06 ml/min. Interstitial infusion of theophylline, an adenosine receptor antagonist, completely abolished the effects of adenosine and 2-ClAdo on GFR. The distribution of adenosine, when infused into the renal interstitium, was determined using radiolabeled 5'-(N-ethyl)-carboxamidoadenosine (NECA), a metabolically stable adenosine agonist. After continuous infusion, (/sup 3/H)NECA was distributed throughout the kidney. The effects of NECA to reduce GFR were similar to those of adenosine and 2-ClAdo. They conclude that increased levels of adenosine in the renal interstitium markedly decrease GFR without affecting RBF in steady-state conditions. The marked effects of adenosine agonists during their infusion into the renal interstitium and the complete blockade of these effects by theophylline suggest an extracellular action of adenosine.

Pawlowska, D.; Granger, J.P.; Knox, F.G.



Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia  

PubMed Central

An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the “adenosine hypothesis” of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia.

Shen, Hai-Ying; Singer, Philipp; Lytle, Nikki; Wei, Catherine J.; Lan, Jing-Quan; Williams-Karnesky, Rebecca L.; Chen, Jiang-Fan; Yee, Benjamin K.; Boison, Detlev



Targeting adenosine receptors in the development of cardiovascular therapeutics.  


Adenosine receptor stimulation has negative inotropic and dromotropic actions, reduces cardiac ischemia-reperfusion injury and remodeling, and prevents cardiac arrhythmias. In the vasculature, adenosine modulates vascular tone, reduces infiltration of inflammatory cells and generation of foam cells, and may prevent the development of atherosclerosis as a result. Modulation of insulin sensitivity may further add to the anti-atherosclerotic properties of adenosine signaling. In the kidney, adenosine plays an important role in tubuloglomerular feedback and modulates tubular sodium reabsorption. The challenge is to take advantage of the beneficial actions of adenosine signaling while preventing its potential adverse effects, such as salt retention and sympathoexcitation. Drugs that interfere with adenosine formation and elimination or drugs that allosterically enhance specific adenosine receptors seem to be most promising to meet this challenge. PMID:22390562

Riksen, Niels P; Rongen, Gerard A



[3H]Adenosine Triphosphate: Release during Stimulation of Enteric Nerves  

Microsoft Academic Search

The isolated taenia coli of the guinea pig takes up tritiated adenosine, adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate, in preference to tritiated inosine and adenine. After uptake, [3H]adenosine is converted and retained primarily as [3H]adenosine triphosphate. Tritium is released from taenia coli treated with [3H]adenosine upon activation of the nonadrenergic inhibitory nerves. These results are consistent with the previous

Che Su; John A. Bevan; Geoffrey Burnstock



Adenosine receptor activation ameliorates type 1 diabetes  

PubMed Central

Growing evidence indicates that adenosine receptors could be promising therapeutic targets in autoimmune diseases. Here we studied the role of adenosine receptors in controlling the course of type 1 diabetes. Diabetes in CD-1 mice was induced by multiple-low-dose-streptozotocin (MLDS) treatment and in nonobese diabetic (NOD) mice by cyclophosphamide injection. The nonselective adenosine receptor agonist 5?-N-ethylcarboxamidoadenosine (NECA) prevented diabetes development in both MLDS-challenged mice and in cyclophosphamide-treated NOD mice. The effect of NECA was reversed by the selective A2B receptor antagonist N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS 1754). The selective A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and A3 receptor agonist N6-(3-iodobenzyl)-adenosine-5?-N-methyluronamide (IB-MECA) were less efficacious in ameliorating the course of diabetes. NECA inhibited diabetes in A2A receptor KO mice and the selective A2A receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5?-N-ethyl-carboxamidoadenosine (CGS21680) had no effect in normal mice, indicating a lack of role of A2A receptors. NECA failed to prevent cytokine-induced ?-cell death in vitro, but NECA strongly suppressed expression of the proinflammatory cytokines TNF-?, MIP-1?, IL-12, and IFN-? in pancreata, endotoxin, or anti-CD3-stimulated splenic cells, and T helper 1 lymphocytes, indicating that the beneficial effect of NECA was due to immunomodulation. These results demonstrate that adenosine receptor ligands are potential candidates for the treatment of type 1 diabetes.

Nemeth, Zoltan H.; Bleich, David; Csoka, Balazs; Pacher, Pal; Mabley, Jon G.; Himer, Leonora; Vizi, E. Sylvester; Deitch, Edwin A.; Szabo, Csaba; Cronstein, Bruce N.; Hasko, Gyorgy



Adenosine A(2) receptors modulate tubuloglomerular feedback.  


Adenosine can mediate the tubuloglomerular (TGF) response via activation of A(1) receptors on the afferent arteriole, but both adenosine A(1) and A(2) receptors can regulate preglomerular resistance. We tested the hypothesis that adenosine A(2) receptors offset the effect of A(1) receptors and modulate the TGF. Maximal TGF responses were measured in male Sprague-Dawley rats as changes in proximal stop-flow pressure (DeltaP(SF)) in response to increased perfusion of the loop of Henle (0 to 40 nl/min) with artificial tubular fluid (ATF). The maximal TGF response was studied after 5 min of intratubular perfusion (10 nl/min) with ATF alone, or with ATF plus the A(2A) receptor antagonist (ZM-241385; 10(-7) or 10(-5) mol/l), A(1) receptor antagonist (PSB-36; 10(-8) mol/l), or with a combination of A(1) (PSB-36; 10(-8) mol/l) and A(2A) (ZM-241385; 10(-7) mol/l) antagonists. The maximal TGF response (DeltaP(SF)) with ATF alone was 11.7 +/- 1.0 mmHg. Specific A(2) inhibition (low dose) enhanced the maximal TGF response (15.7 +/- 0.8 mmHg; P < 0.01), whereas a high dose (unspecific inhibition) attenuated the response (5.0 +/- 0.4 mmHg; P < 0.001). A(1) inhibition alone led to a paradoxical TGF response, with an increase in P(SF) of 3.1 +/- 0.5 mmHg (P < 0.05). Simultaneous application of A(1) and A(2) antagonists abolished the TGF response (DeltaP(SF): 0.4 +/- 0.3 mmHg). In conclusion, adenosine A(2) receptors modulate the TGF response by counteracting the effects of adenosine A(1) receptors. PMID:20519378

Carlström, Mattias; Wilcox, Christopher S; Welch, William J



Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury.  


Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A2B adenosine receptor (A2BAR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these observations are lacking. Adenosine deaminase-deficient (ADA-deficient) mice develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels. To investigate the role of the A2BAR in vivo, ADA-deficient mice were treated with the selective A2BAR antagonist CVT-6883, and pulmonary inflammation, fibrosis, and airspace integrity were assessed. Untreated and vehicle-treated ADA-deficient mice developed pulmonary inflammation, fibrosis, and enlargement of alveolar airspaces; conversely, CVT-6883-treated ADA-deficient mice showed less pulmonary inflammation, fibrosis, and alveolar airspace enlargement. A2BAR antagonism significantly reduced elevations in proinflammatory cytokines and chemokines as well as mediators of fibrosis and airway destruction. In addition, treatment with CVT-6883 attenuated pulmonary inflammation and fibrosis in wild-type mice subjected to bleomycin-induced lung injury. These findings suggest that A2BAR signaling influences pathways critical for pulmonary inflammation and injury in vivo. Thus in chronic lung diseases associated with increased adenosine, antagonism of A2BAR-mediated responses may prove to be a beneficial therapy. PMID:16841096

Sun, Chun-Xiao; Zhong, Hongyan; Mohsenin, Amir; Morschl, Eva; Chunn, Janci L; Molina, Jose G; Belardinelli, Luiz; Zeng, Dewan; Blackburn, Michael R



A protective role for the A1 adenosine receptor in adenosine-dependent pulmonary injury.  


Adenosine is a signaling nucleoside that has been implicated in the regulation of asthma and chronic obstructive pulmonary disease. Adenosine signaling can serve both pro- and anti-inflammatory functions in tissues and cells. In this study we examined the contribution of A(1) adenosine receptor (A(1)AR) signaling to the pulmonary inflammation and injury seen in adenosine deaminase-deficient (ADA-deficient) mice, which exhibit elevated adenosine levels. Experiments revealed that transcript levels for the A(1)AR were elevated in the lungs of ADA-deficient mice, in which expression was localized predominantly to alveolar macrophages. Genetic removal of the A(1)AR from ADA-deficient mice resulted in enhanced pulmonary inflammation along with increased mucus metaplasia and alveolar destruction. These changes were associated with the exaggerated expression of the Th2 cytokines IL-4 and IL-13 in the lungs, together with increased expression of chemokines and matrix metalloproteinases. These findings demonstrate that the A(1)AR plays an anti-inflammatory and/or protective role in the pulmonary phenotype seen in ADA-deficient mice, which suggests that A(1)AR signaling may serve to regulate the severity of pulmonary inflammation and remodeling seen in chronic lung diseases by controlling the levels of important mediators of pulmonary inflammation and damage. PMID:15630442

Sun, Chun-Xiao; Young, Hays W; Molina, Jose G; Volmer, Jonathan B; Schnermann, Jurgen; Blackburn, Michael R



Adenosine thallium 201 myocardial perfusion scintigraphy  

SciTech Connect

Pharmacologic coronary vasodilation as an adjunct to myocardial perfusion imaging has become increasingly important in the evaluation of patients with coronary artery disease, in view of the large number of patients who cannot perform an adequate exercise test or in whom contraindications render exercise inappropriate. Adenosine is a very potent coronary vasodilator and when combined with thallium 201 scintigraphy produces images of high quality, with the added advantages of a very short half-life (less than 10 seconds) and the ability to adjust the dose during the infusion, which may enhance safety and curtail the duration of side effects. The reported sensitivity and specificity of adenosine thallium 201 scintigraphy for the detection of coronary artery disease are high and at least comparable with imaging after exercise or dipyridamole administration. 23 refs.

Verani, M.S. (Baylor College of Medicine and Nuclear Cardiology, The Methodist Hospital, Houston, TX (USA))



[Adenosine deaminase in severe combined immunodeficiency syndrome].  


Adenosine deaminase is an enzyme of the purine metabolism whose function is to convert adenosine to inosine and deoxyadenosine to deoxyinosine. The ecto-ADA1 binding to the cell surface through CD26 contributes to the regulation of cytokines and stimulates the proliferation of T cells by activating CD45. The deficiency of this enzyme generates the severe combined immunodeficiency syndrome, characterized by the accumulation of deoxyadenosine and adenine metabolites, which have toxic effects on lymphocytes, affecting DNA synthesis and consequently, clonal expansion. Early diagnosis of this immunodeficiency is essential, as it significantly reduces morbidity and mortality associated with recurrent infections. Recent advances in molecular biology and genetics have led to the identification of genetic defects of many primary immunodeficiencies and the development of promising diagnostic tools and treatment. PMID:23248974

Pérez-Aguilar, Mary Carmen; Goncalves, Loredana; Bonfante-Cabarcas, Rafael



Adenosine-to-inosine RNA editing  

PubMed Central

Ribonucleic acid (RNA) editing is a mechanism that generates RNA and protein diversity, which is not directly encoded in the genome. The most common type of RNA editing in vertebrates is the conversion of adenosine to inosine in double-stranded RNA which occurs in the higher eukaryotes. This editing is carried out by the family of adenosine deaminase acting on RNA (ADAR) proteins. The most-studied substrates of ADAR proteins undergo editing which is very consistent, highly conserved, and functionally important. However, editing causes changes in protein-coding regions only at a small proportion of all editing sites. The vast majority of editing sites are in noncoding sequences. This includes microRNAs, as well as the introns and 3? untranslated regions of messenger RNAs, which play important roles in the RNA-mediated regulation of gene expression.

Zinshteyn, Boris; Nishikura, Kazuko



Effect of adenosine and adenosine analogs on ( sup 14 C)aminopyrine accumulation by rabbit parietal cells  

SciTech Connect

Adenosine receptors that modulate adenylate cyclase activity have been identified recently in a number of tissues. Adenosine A2 receptor is stimulatory to adenylate cyclase, whereas adenosine A1 receptor is inhibitory to adenylate cyclase. We investigated the effect of adenosine and its analogs on (14C)aminopyrine accumulation by rabbit parietal cells. Rabbit gastric mucosal cells were isolated by enzyme digestion. Parietal cells were enriched by nonlinear percoll gradients. (14C)Aminopyrine accumulation was used as an indicator of acid secretion. The effect of 2-chloroadenosine on histamine-stimulated (14C)aminopyrine accumulation was studied. The effects of N-ethylcarboxamideadenosine, 2-chloroadenosine, stable analogs of adenosine, and adenosine on (14C)aminopyrine accumulation were assessed. Cyclic AMP content of parietal cells was determined by radioimmunoassay. Histamine and carbachol, known secretagogues, stimulated (14C)aminopyrine accumulation. 2-Chloroadenosine did not suppress histamine-stimulated (14C)aminopyrine accumulation. 2-Chloroadenosine, N-ethylcarboxamideadenosine, and adenosine dose dependently increased (14C)aminopyrine accumulation. The order of potency was N-ethylcarboxamideadenosine greater than 2-chloroadenosine greater than adenosine. 8-Phenyltheophylline and theophylline, adenosine-receptor antagonists, or cimetidine did not have significant effects on the increase of AP uptake induced by 2-chloroadenosine. Coadministration of dipyridamole, and adenosine uptake inhibitor, augmented the effect of adenosine on (14C)aminopyrine accumulation. 2-Chloroadenosine, N-ethylcarboxamideadenosine, and adenosine each induced a significant increase in cellular cyclic AMP. We conclude that there may be adenosine A2 receptors on rabbit parietal cells which modulate gastric acid secretion.

Ota, S.; Hiraishi, H.; Terano, A.; Mutoh, H.; Kurachi, Y.; Shimada, T.; Ivey, K.J.; Sugimoto, T. (Univ. of Tokyo (Japan))



Adenosine-induced worsening of supraventricular tachycardia.  


An approximately 20-year-old to 30-year-old patient presented with a haemodynamically stable supraventricular tachycardia . The patient was managed with intravenous adenosine primarily, with two bolus doses of 6 and 12 mg. This, however, caused a rare paradoxical surge of tachycardia with mild haemodynamic compromise. The patient further required a combination of Metoprolol and Verapamil administration to slow down and reverse the arrhythmia. Following this the patient remained stable with no further episodes till discharge. PMID:23230260

Kunnumpuram, Georgey Koshy; Patel, Ashfaq



Use of adenosine echocardiography for diagnosis of coronary artery disease  

SciTech Connect

Two-dimensional echocardiography combined with exercise is sensitive and specific in the detection of coronary artery disease (CAD) by demonstrating transient abnormalities in wall motion. Frequently, however, patients cannot achieve maximal exercise because of various factors. Pharmacologic stress testing with intravenous adenosine was evaluated as a means of detecting CAD in a noninvasive manner. Patients with suspected CAD underwent echocardiographic imaging and simultaneous thallium 201 single-photon emission computed tomography during the intravenous administration of 140 micrograms/kg/min of adenosine. An increase in heart rate, decrease in blood pressure, and increase in double product were observed during adenosine administration. Initial observations revealed that wall motion abnormalities were induced by adenosine in areas of perfusion defects. The adenosine infusion was well tolerated, and symptoms disappeared within 1 to 2 minutes after termination of the infusion. Therefore preliminary observations suggest that adenosine echocardiography appears to be useful in the assessment of CAD.

Zoghbi, W.A. (Section of Cardiology Baylor College of Medicine, Methodist Hospital, Houston, TX (USA))



Adenosine signaling promotes regeneration of pancreatic ?-cells in vivo  

PubMed Central

Diabetes can be controlled with insulin injections, but a curative approach that restores the number of insulin-producing ?-cells is still needed. Using a zebrafish model of diabetes, we screened ~7000 small molecules to identify enhancers of ?-cell regeneration. The compounds we identified converge on the adenosine signaling pathway and include exogenous agonists and compounds that inhibit degradation of endogenously produced adenosine. The most potent enhancer of ?-cell regeneration was the adenosine agonist 5?-N-Ethylcarboxamidoadenosine (NECA), which acting through the adenosine receptor A2aa increased ?-cell proliferation and accelerated restoration of normoglycemia in zebrafish. Despite markedly stimulating ?-cell proliferation during regeneration, NECA had only a modest effect during development. The proliferative and glucose-lowering effect of NECA was confirmed in diabetic mice, suggesting an evolutionarily conserved role for adenosine in ?-cell regeneration. With this whole-organism screen, we identified components of the adenosine pathway that could be therapeutically targeted for the treatment of diabetes.

Andersson, Olov; Adams, Bruce A.; Yoo, Daniel; Ellis, Gregory C.; Gut, Philipp; Anderson, Ryan M.; German, Michael S.; Stainier, Didier Y. R.



Adenosine deaminase activity in fertile and infertile men.  


Adenosine deaminase (ADA; E.C. catalyses the deamination of adenosine to inosine. In the human reproductive system, the importance of enzymes that affect metabolism of adenosine, particularly adenosine deaminase, has been noticed. The purpose of this study was to determine the plasma activities of total adenosine deaminase (ADAT), and its isoenzymes, ADA1 and ADA2, in fertile and infertile men. Plasma activities of ADA and its isoenzymes were measured in 55 fertile men and 70 infertile men. There was a significant difference in the ADA1 and ADA2 activities between fertile and infertile individuals (P < 0.01). The activity of ADAT, ADA2 and ADA1 in infertile men was higher than that in fertile individuals. This alteration in ADA activity can lead to reduced adenosine levels, which may be involved in disturbing the fertility process. PMID:21919946

Rostampour, F; Biglari, M; Vaisi-Raygani, A; Salimi, S; Tavilani, H



Adenosine receptors as potential targets in melanoma.  


Melanoma is one of the most aggressive types of cancer, that is difficult to manage clinically. A major feature of melanoma cells is their ability to escape immune surveillance. Adenosine receptors play a pivotal role in host immune-surveillance. A2a (A2aR) and, partially, A2bR receptors mediate the adenosine-induced immune-suppression, which markedly facilitates tumor development/progression. On the contrary, A3R stimulation enhances the anti-tumor immune response and thus limits tumor growth. A3R also inhibits the proliferation of many cancer cells. Given that A2aR and A3R have profound effects on tumor growth and metastasis, they are attractive targets for novel therapeutic anti-cancer agents. Here, we review the role played by A2aR and A3R in regulating cancer pathogenesis, with a focus on melanoma, and the therapeutic potential of adenosine receptors pharmacological modulation. PMID:23856527

Montinaro, Antonella; Iannone, Raffaella; Pinto, Aldo; Morello, Silvana



ATP- and adenosine-mediated signaling in the central nervous system: adenosine stimulates glutamate release from astrocytes via A2a adenosine receptors.  


Adenosine enhanced intracellular Ca(2+) concentrations in astrocytes via A(2a) adenosine receptors involving protein kinase A (PKA) activation. The Ca(2+) rise is inhibited by brefeldin A, an inhibitor of vesicular transport; but not by neomycin and U73122, phospholipase C inhibitors; xestospongin, an IP(3)-receptor inhibitor; ryanodine, a ryanodine-receptor inhibitor; TMB-8, an endoplasmic reticulum calcium-release blocker; octanol, a gap-junction inhibitor; or cadmium, a non-selective, calcium-channel blocker. Adenosine stimulates astrocytic glutamate release via an A(2a) adenosine receptors/PKA pathway, and the release is inhibited by the vesicular transport inhibitors brefeldin A and bafilomycin A1. A(2a) adenosine receptors and the ensuing PKA events, thus, are endowed with vesicular Ca(2+) release from an unknown intracellular calcium store and vesicular glutamate release from astrocytes. PMID:14978344

Nishizaki, Tomoyuki



Turnover of adenosine in plasma of human and dog blood  

SciTech Connect

To determine half-life and turnover of plasma adenosine, heparinized blood from healthy volunteers was incubated with radiolabeled adenosine in the physiological concentration range of 0.1-1 microM. Plasma levels of adenosine in vitro were 82 +/- 14 nM and were similar to those determined immediately after blood collection with a ''stopping solution.'' Dipyridamole (83 microM) and erythro-9(2-hydroxynon-3yl)-adenine (EHNA) (8 microM) did not measurably alter basal adenosine levels but completely blocked the uptake of added adenosine. Inhibition of ecto-5'-nucleotidase with 100 microM alpha, beta-methyleneadenosine 5'-diphosphate (AOPCP) reduced plasma adenosine to 22 +/- 6 nM. For the determination of adenosine turnover, the decrease in specific radioactivity of added (/sup 3/H)adenosine was measured using a dipyridamole-containing stopping solution. Without altering basal adenosine levels, the half-life was estimated to be 0.6 s. Similar experiments were carried out with washed erythrocytes or in the presence of AOPCP, yielding half-lives of 0.7 and 0.9 s, respectively. When the initial adenosine concentration was 1 microM, its specific activity decreased by only 11% within 5 s, whereas total plasma adenosine exponentially decreased with a half-life of 1.5 s. Venous plasma concentrations were measured after relief of a 3-min forearm ischemia. Changes in plasma adenosine did not correlate well with changes in blood flow but were augmented in the presence of dipyridamole.

Moeser, G.H.S.; Schrader, J.; Deussen, A.



Stimulation of Wound Revascularization by Adenosine Receptor Activation  

Microsoft Academic Search

\\u000a Adenosine is an endogenous mediator implicated in wound healing. The exact mechanisms and receptors involved are still under\\u000a evaluation. We have observed that topical application of a selective adenosine A2A receptor agonist promotes wound healing in experimental animals, both healthy and with impaired healing. Histological analysis\\u000a revealed that adenosine promoted granulation tissue formation, with increased cellularity, matrix deposition, and vessel

M. Carmen Montesinos; María D. Valls


Adenosine Receptors in Wound Healing, Fibrosis and Angiogenesis  

Microsoft Academic Search

\\u000a Wound healing and tissue repair are critical processes, and adenosine, released from injured or ischemic tissues, plays an\\u000a important role in promoting wound healing and tissue repair. Recent studies in genetically manipulated mice demonstrate that\\u000a adenosine receptors are required for appropriate granulation tissue formation and in adequate wound healing. A2A and A2B adenosine receptors stimulate both of the critical functions

Igor Feoktistov; Italo Biaggioni; Bruce N. Cronstein


Adenosine receptors: therapeutic aspects for inflammatory and immune diseases  

Microsoft Academic Search

Adenosine is a key endogenous molecule that regulates tissue function by activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. Cells of the immune system express these receptors and are responsive to the modulatory effects of adenosine in an inflammatory environment. Animal models of asthma, ischaemia, arthritis, sepsis, inflammatory bowel disease and wound healing have helped to elucidate the

Joel Linden; Bruce Cronstein; Pál Pacher; György Haskó



A 1 Adenosine Receptor: Role in Diabetes and Obesity  

Microsoft Academic Search

\\u000a Adenosine mediates its diverse effects via four subtypes (A1, A2A, A2B and A3) of G-protein-coupled receptors. The A1 adenosine receptor (A1AR) subtype is the most extensively studied and is well characterized in various organ systems. The A1ARs are highly expressed in adipose tissue, and endogenous adenosine has been shown to tonically activate adipose tissue A1ARs. Activation of the A1ARs in

Arvinder K. Dhalla; Jeffrey W. Chisholm; Gerald M. Reaven; Luiz Belardinelli


Adenosine, an endogenous distress signal, modulates tissue damage and repair  

Microsoft Academic Search

Adenosine is formed inside cells or on their surface, mostly by breakdown of adenine nucleotides. The formation of adenosine increases in different conditions of stress and distress. Adenosine acts on four G-protein coupled receptors: two of them, A1 and A3, are primarily coupled to Gi family G proteins; and two of them, A2A and A2B, are mostly coupled to Gs

B B Fredholm



A 1 adenosine receptor of human and mouse adipose tissues  

Microsoft Academic Search

The aberrant functioning of the A1 adenosine receptor of adipose tissue has been implicated as a factor in obesity. To begin to address questions concerning this relationship, the possibility of a unique A1 adenosine receptor in adipose tissue must be investigated. Therefore, cDNAs encoding the A1 adenosine receptors of adipose tissues of a mouse and an obese human were isolated,

Irene Tatsis-Kotsidis; Bernard F Erlanger



Measurement of plasma adenosine concentration: methodological and physiological considerations  

SciTech Connect

This study tested the hypothesis that measurements of plasma adenosine concentration made on samples of blood obtained in dipyridamole and EHNA (i.e., stopping solution) may be falsely elevated as a result of ongoing in vitro production and accumulation of adenosine during sample processing. Studies were performed with samples of anticoagulated blood obtained from anesthesized domestic swine. Adenosine concentration of ultra filtrated plasma was determined by HPLC. The following parameters were evaluated: (i) rate of clearance of (/sup 3/H)adenosine added to plasma, (ii) endogenous adenosine concentration of matched blood samples obtained in stopping solution alone, stopping solution plus EDTA, and perchloric acid (PCA), (iii) plasma and erythrocyte endogenous adenosine concentration in nonhemolyzed samples, and (iv) plasma adenosine concentration of samples hemolyzed in the presence of stopping solution alone or stopping solution plus EDTA. We observed that (i) greater than or equal to 95% of (/sup 3/H)adenosine added to plasma is removed from it by formed elements of the blood in less than 20 s, (ii) plasma adenosine concentration of samples obtained in stopping solution alone is generally 10-fold greater than that of matched samples obtained in stopping solution plus EDTA, (iii) deliberate mechanical hemolysis of blood samples obtained in stopping solution alone resulted in substantial augmentation of plasma adenosine levels in comparison with matched nonhemolyzed specimens--addition of EDTA to stopping solution prevented this, and (iv) adenosine content of blood samples obtained in PCA agreed closely with the sum of plasma and erythrocyte adenosine content of samples obtained in stopping solution plus EDTA.

Gewirtz, H.; Brown, P.; Most, A.S.



Adenosine receptors in the nervous system: pathophysiological implications  

Microsoft Academic Search

Adenosine is a ubiquitous homeostatic substance released from most cells, including neurones and glia. Once in the extracellular space, adenosine modifies cell functioning by operating G-protein-coupled receptors (GPCR; A1, A2A, A2B, A3) that can inhibit (A1) or enhance (A2) neuronal communication. Interactions between adenosine receptors and other G-protein-coupled receptors, ionotropic receptors and receptors for neurotrophins also occur, and this might

J. A. Ribeiro; A. M. Sebastiăo; A. de Mendonça



Coronary spasm after completion of adenosine pharmacologic stress test  

Microsoft Academic Search

Adenosine is a frequently used pharmacologic stress agent in myocardial perfusion imaging. Its safety profile is well established,\\u000a and most of its side effects are mild and transient. Coronary vasospasm occurs occasionally during or after adenosine stress\\u000a test in rare cases, which may lead to seriously adverse outcomes. This study reported 3 such cases after completion of adenosine\\u000a pharmacologic stress

Ping-Ping Han; Yue-Qin Tian; Hong-Xing Wei; Qi Wang; Zuo-Xiang He


A 1-adenosine receptor gene expression in fetal rat brain  

Microsoft Academic Search

Adenosine influences neurotransmitter release, neuronal excitability, and firing rate, through A1-adenosine receptors (A1-R). Caffeine and related methylxanthines are adenosine receptor antagonists. Exposure of developing rodents to caffeine is associated with subtle, long-term changes in neurochemistry and behavior. The developmental appearance of A1-R gene expression was examined in rats by in situ hybridization. On gestational day (GD) 10, A1-R mRNA was



Characterization of adenosine receptors involved in adenosine-induced bronchoconstriction in allergic rabbits.  

PubMed Central

1. Recent work has suggested that adenosine may be involved in asthma via the activation of A1 receptors. However, the role of the recently cloned A3 receptor in airways is largely unknown. In the present study, we have investigated the role of the A3 receptor in adenosine-induced bronchoconstriction in allergic rabbits. 2. Aerosol challenge of antigen (Ag) immunized rabbits with the adenosine precursor, adenosine 5'-monophosphate (AMP), resulted in a dose-dependent fall in dynamic compliance (Cdyn). The maximum fall in Cdyn in these rabbits was significantly greater than that in litter matched, sham immunized animals (P < 0.05). However, there was no significant difference in the maximum increase in airways resistance (Rt) between Ag and sham immunized rabbits (P > 0.05). 3. Aerosol challenge of Ag immunized rabbits with cyclopentyl-adenosine (CPA) (A1-receptor agonist) elicited a dose-dependent fall in Cdyn in Ag immunized rabbits and the maximum fall in Cdyn in these rabbits was significantly greater than that observed in sham immunized rabbits (P < 0.05). Similarly, CPA induced dose-dependent increases in R1 in Ag immunized rabbits whereas sham immunized rabbits failed to respond to CPA within the same dose range. The maximum increase in RL in Ag immunized rabbits was significantly greater than that of sham immunized rabbits (P < 0.05). 4. Aerosol challenge of either Ag or sham immunized rabbits with the A3 agonist aminophenylethyladenosine (APNEA) did not elicit dose-dependent changes in either RL or Cdyn. Moreover, there was no significant difference in the maximum response, measured by either parameter, between the two animal groups (P > 0.05). 5. These data provide further evidence for a role of the A1 receptor in the airways, but do not support a role for the A3 receptor in adenosine-induced bronchoconstriction in the allergic rabbit.

el-Hashim, A.; D'Agostino, B.; Matera, M. G.; Page, C.



Fluorometric Determination of Adenosine Nucleotide Derivatives as Measures of the Microfouling, Detrital, and Sedimentary Microbial Biomass and Physiological Status.  

National Technical Information Service (NTIS)

Adenosine, adenine, cyclic adenosine monophosphate (AMP), AMP, nicotinamide adenine dinucleotide, adenosine diphosphate, and adenosine triphosphate (ATP) were recovered quantitatively from aqueous portions of lipid extracts of microfouling, detrital, and ...

W. M. Davis D. C. White



Adenosine is present in rat brain synaptic vesicles.  


Evidences in the central nervous system are in favor that adenosine under basal conditions is released by a direct excitation-secretion modality. However, till now, there is no direct evidence that adenosine is contained in synaptic vesicles. Eight synaptic vesicle fractions were recovered on a discontinuous sucrose gradient after ultracentrifugation of the crude synaptosomal fraction (pellet P2) of rat brain. The adenosine content in each fraction was measured by high-performance liquid chromatography coupled to a fluorescence detector (minimum sensitivity 10 femtomoles). The immunoblot analysis, to detect synaptophysin, a molecular marker for the vesicle membrane, showed that fractions from 3 to 8 were rich in synaptophysin. The sum of adenosine found in fractions 3-8 was (mean±SEM, n=4) 3325.6±94.6 pmol/mg of tissue protein. We proved that adenosine measured in synaptic vesicle fractions was not contaminated by cytosolic adenosine, as adenosine exogenously added to the P2 preferentially distributed in fractions 1 and 2 that are synaptophysin-free and did not contaminate the vesicle pellet P3. Data provide direct demonstration that adenosine is present in rat brain synaptic vesicle fractions. This information is consistent with the notion that adenosine is stored in synaptic vesicles and is released under normoxic physiological conditions by an excitation-secretion mechanism typical of neuronal cells. PMID:24051680

Corti, Francesca; Cellai, Lucrezia; Melani, Alessia; Donati, Chiara; Bruni, Paola; Pedata, Felicita



Primary adenosine monophosphate (AMP) deaminase deficiency in a hypotonic infant.  


The spectrum of the adenosine monophosphate (AMP) deaminase deficiency ranges from asymptomatic carriers to patients who manifest exercise-induced muscle pain, occasionally rhabdomyolysis, and idiopathic hyperCKemia. However, previous to the introduction of molecular techniques, rare cases with congenital weakness and hypotonia have also been reported. We report a 6-month-old girl with the association of congenital muscle weakness and hypotonia, muscle deficiency of adenosine monophosphate deaminase, and the homozygous C to T mutation at nucleotide 34 of the adenosine monophosphate deaminase-1 gene. This observation indicates the possible existence of a primary adenosine monophosphate deaminase deficiency manifested by congenital muscle weakness and hypotonia. PMID:21343608

Castro-Gago, Manuel; Gómez-Lado, Carmen; Pérez-Gay, Laura; Eirís-Puńal, Jesús; Martínez, Elena Pintos; García-Consuegra, Inés; Martín, Miguel Angel



Adenosine receptor ligands: differences with acute versus chronic treatment  

PubMed Central

Adenosine receptors have been the target of intense research with respect to potential use of selective ligands in a variety of therapeutic areas. Caffeine and theophylline are adenosine receptor antagonists, and over the past three decades a wide range of selective agonists and antagonists for adenosine receptor subtypes have been developed. A complication to the therapeutic use of adenosine receptor ligands is the observation that the effects of acute administration of a particular ligand can be diametrically opposite to the chronic effects of the same ligand. This ‘effect inversion’ is discussed here by Ken Jecobson and colleagues, and has been observed for effects on cognitive processes, seizures and ischaemic damage.

Jacobson, Kenneth A.; von Lubitz, Dag K. J. E.; Daly, John W.; Fredholm, Bertil B.



Adenosine analogs inhibit fighting in isolated male mice  

SciTech Connect

The potent adenosine analogs N-ethylcarboxamide adenosine (NECA) and phenylisopropyladenosine (PIA) inhibit fighting and associated agonistic behaviors in isolated male mice. These effects are reversed by methylxanthines; moderate doses of NECA which inhibit fighting have minimal effects on spontaneous locomotor activity. At very low doses, both NECA and PIA increase fighting in parallel with previously reported increases of motor activity. Brain levels of (/sup 3/H)-NECA and (/sup 3/H)-PIA achieved at behaviorally effective doses suggest an involvement of adenosine receptors. The biochemical mechanism of adenosine receptor action with respect to fighting is unknown, but may include neuromodulatory effects on the release of other, more classical neurotransmitters.

Palmour, R.M.; Lipowski, C.J.; Simon, C.K.; Ervin, F.R.



Effects of adenosine uptake blockers and adenosine on evoked potentials of guinea-pig olfactory cortex  

Microsoft Academic Search

1.The olfactory cortex slice preparation from guinea-pig has been used to test compounds which inhibit the cellular uptake of adenosine.2.The uptake inhibitors dipyridamole (0.1–10 µmol\\/l), dilazep (1–10 µmol\\/l) nitrobenzylthioguanosine (1–10 µmol\\/l), nitrobenzylthioinosine (0.1–5 µmol\\/l), and hexobendine (1–100 µmol\\/l) increased the potency of adenosine (0.1–30 µmol\\/l) by up to 5-fold but did not potentiate cyclohexyladenosine (0.01–10 µmol\\/l).3.The benzodiazepine, diazepam (1µmol\\/l) slightly

G. Sanderson; C. N. Scholfield



Selective Deletion of the A1 Adenosine Receptor Abolishes Heart-Rate Slowing Effects of Intravascular Adenosine In Vivo  

Microsoft Academic Search

ObjectiveIntravenous adenosine induces temporary bradycardia. This is due to the activation of extracellular adenosine receptors (ARs). While adenosine can signal through any of four ARs (A1AR, A2AAR, A2BAR, A3AR), previous ex vivo studies implicated the A1AR in the heart-rate slowing effects. Here, we used comparative genetic in vivo studies to address the contribution of individual ARs to the heart-rate slowing

Michael Koeppen; Tobias Eckle; Holger K. Eltzschig; Arnold Schwartz



Adenosine-receptor subtypes: their relevance to adenosine-mediated responses in asthma and chronic obstructive pulmonary disease  

Microsoft Academic Search

Adenosine administration by inhalation elicits concentration-related bronchoconstriction in subjects with asthma and chronic obstructive pulmonary disease (COPD). The mechanisms of adenosine-induced bronchoconstriction appear to involve a selective interaction with activated mast cells with subsequent release of preformed and newly-formed mediators. Further evidence linking adenosine signalling to asthma and COPD comes from the finding that many cell types that play important

R. Polosa



Ion-dependent conformational switching by a DNA aptamer that induces remyelination in a mouse model of multiple sclerosis.  


We recently reported that a guanosine-rich 40-mer DNA aptamer (LJM-3064) mediates remyelination in the Theiler's murine encephalomyelitis virus mouse model of multiple sclerosis. Here, we characterize the G-quadruplex forms of this aptamer in vitro, and demonstrate using circular dichroism spectroscopy that LJM-3064 undergoes a monovalent ion-dependent conformational switch. In the presence of sodium ions and no potassium ions, LJM-3064 adopts an antiparallel-stranded G-quadruplex structure. When presented with low concentrations of potassium ions in a buffer that mimics the composition of interstitial fluid and blood plasma, LJM-3064 rapidly switches to a parallel-stranded G-quadruplex conformation, which is presumably the physiologically active folded form. We characterize these conformational states using dimethyl sulfate reactivity studies and Bal 31 nuclease probing. Our analysis indicates that only the 5'-terminal 26 nucleotides are involved in G-quadruplex formation. Thermodynamic characterization of LJM-3064 at physiologically relevant ion concentrations reveals the G-quadruplex to be metastable at human body temperature. These data provide important structural and thermodynamic insights that may be valuable in optimizing LJM-3064 as a therapeutic remyelinating agent. PMID:23175609

Smestad, John; Maher, L James



Ion-dependent conformational switching by a DNA aptamer that induces remyelination in a mouse model of multiple sclerosis  

PubMed Central

We recently reported that a guanosine-rich 40-mer DNA aptamer (LJM-3064) mediates remyelination in the Theiler’s murine encephalomyelitis virus mouse model of multiple sclerosis. Here, we characterize the G-quadruplex forms of this aptamer in vitro, and demonstrate using circular dichroism spectroscopy that LJM-3064 undergoes a monovalent ion-dependent conformational switch. In the presence of sodium ions and no potassium ions, LJM-3064 adopts an antiparallel-stranded G-quadruplex structure. When presented with low concentrations of potassium ions in a buffer that mimics the composition of interstitial fluid and blood plasma, LJM-3064 rapidly switches to a parallel-stranded G-quadruplex conformation, which is presumably the physiologically active folded form. We characterize these conformational states using dimethyl sulfate reactivity studies and Bal 31 nuclease probing. Our analysis indicates that only the 5?-terminal 26 nucleotides are involved in G-quadruplex formation. Thermodynamic characterization of LJM-3064 at physiologically relevant ion concentrations reveals the G-quadruplex to be metastable at human body temperature. These data provide important structural and thermodynamic insights that may be valuable in optimizing LJM-3064 as a therapeutic remyelinating agent.

Smestad, John; Maher, L. James



[The comparative characteristics and receptor mechanism of the effect of adenosine-receptor agonists in total cerebral ischemia].  


The duration of gasping has no normal distribution, so nonparametric statistic criteria should be used. Three adenosine receptor agonists have a highly cerebro-protective effect which decreases in the order: N-ethylcarboxamide adenosine > > cyclohexyl adenosine > adenosine. Theophylline completely blocks these effects. Thus, they act through adenosine receptors. Adenosine receptor agonist are likely to protect themselves neurons. PMID:8111286

Kulinski?, V I; Usov, L A; Sufianova, G Z; Lidak, M Iu; Iurkevich, A M


Characterization of the Residual Adenosine Deaminating Activity in the Spleen of a Patient with Combined Immunodeficiency Disease and Adenosine Deaminase Deficiency  

Microsoft Academic Search

A number of infants with an autosomal recessive form of combined immunodeficiency disease also lack adenosine deaminase (adenosine aminohydrolase; EC activity in their erythrocytes. Other tissues from these infants contain only a few percent of the adenosine-deaminating activity present in corresponding normal tissue. The residual adenosine-deaminating activity in extracts from the spleen of a combined immunodeficient, adenosine deaminase-deficient patient

William P. Schrader; Bernard Pollara; Hilaire J. Meuwissen



Adenosine signaling in normal and sickle erythrocytes and beyond.  


Sickle cell disease (SCD) is a debilitating hemolytic genetic disorder with high morbidity and mortality affecting millions of individuals worldwide. Although SCD was discovered more than a century ago, no effective mechanism-based prevention and treatment are available due to poorly understood molecular basis of sickling, the fundamental pathogenic process of the disease. SCD patients constantly face hypoxia. One of the best-known signaling molecules to be induced under hypoxic conditions is adenosine. Recent studies demonstrate that hypoxia-mediated elevated adenosine signaling plays an important role in normal erythrocyte physiology. In contrast, elevated adenosine signaling contributes to sickling and multiple life threatening complications including tissue damage, pulmonary dysfunction and priapism. Here, we summarize recent research on the role of adenosine signaling in normal and sickle erythrocytes, progression of the disease and therapeutic implications. In normal erythrocytes, both genetic and pharmacological studies demonstrate that adenosine can enhance 2,3-bisphosphoglycerate (2,3-BPG) production via A(2B) receptor (ADORA2B) activation, suggesting that elevated adenosine has an unrecognized role in normal erythrocytes to promote O(2) release and prevent acute ischemic tissue injury. However, in sickle erythrocytes, the beneficial role of excessive adenosine-mediated 2,3-BPG induction becomes detrimental by promoting deoxygenation, polymerization of sickle hemoglobin and subsequent sickling. Additionally, adenosine signaling via the A(2A) receptor (ADORA2A) on invariant natural killer T (iNKT) cells inhibits iNKT cell activation and attenuates pulmonary dysfunction in SCD mice. Finally, elevated adenosine coupled with ADORA2BR activation is responsible for priapism, a dangerous complication seen in SCD. Overall, the research reviewed here reveals a differential role of elevated adenosine in normal erythrocytes, sickle erythrocytes, iNK cells and progression of disease. Thus, adenosine signaling represents a potentially important therapeutic target for the treatment and prevention of disease. PMID:22634345

Zhang, Yujin; Xia, Yang



Characterization of adenosine binding proteins in human placental membranes  

SciTech Connect

We have characterized two adenosine binding proteins in human placenta. In membranes, one site is detected with ({sup 3}H) -N-ethylcarboxamidoadenosine (({sup 3}H)NECA). This site is similar to the adenosine A{sub 2} receptor. We call this site the adenosine A{sub 2}-like binding site. In detergent extracts, the second site is detected and has the characteristics of an adenosine A{sub 1} receptor. The soluble adenosine A{sub 2}-like binding site cannot be detected without a rapid assay. Binding to the adenosine A{sub 1} receptor with ({sup 3}H)-2-chloroadenosine and ({sup 3}H)NECA is time dependent, saturable, and reversible. Equilibrium displacement analysis with adenosine agonists reveals an A{sub 1} specificity: 2-chloroadenosine > R-phenylisopropyladenosine > 5{prime}-N-ethylcarboxamidoadenosine. The antagonist potency order is 1,3-diethyl-8-phenylxanthine > isobutylmethylxanthine > theophylline. Competition analysis of membranes with the A,-selective ligands ({sup 3}H)-cyclohexyladenosine ({sup 3}H) cylopentylxanthine revealed adenosine A{sub 1} agonist and antagonist potency orders. We have purified the adenosine A{sub 2}-like binding site. The adenosine A{sub 2}-like binding site is an ubiquitous major cellular protein. It is glycosylated, highly asymmetric, and acidic. The native protein is an homodimer with a subunit molecular mass of 98 kDa. The sedimentation coefficient and partial specific volume of the binding complex are 6.9 s and 0.698 ml/g, respectively. The Stokes' radius is 70 {Angstrom}. The native molecular mass of the detergent-protein complex is 230 kDa. The adenosine A{sub 2}-like binding site has an agonist potency order of 5'-N-ethylcarboxamidoadenosine > 2-chloroadenosine >> R-phenylisopropyladenosine and an antagonist potency order of isobutylmethylxanthine > theophylline >> 1,3-diethyl-8-phenylxanthine.

Hutchison, K.A.



Too much of a good thing: adenosine overload in adenosine-deaminase-deficient mice  

Microsoft Academic Search

Chronic lung diseases are associated with persistent lung inflammation and damage. The mechanisms that govern the chronic nature of these disorders are not known. Adenosine is a signaling nucleoside that is generated in hypoxic environments such as that found in the inflamed lung, which suggests that it might serve a regulatory role in chronic lung diseases. Support for this hypothesis

Michael R Blackburn



Further evidence that propentofylline (HWA 285) influences both adenosine receptors and adenosine transport.  


We have examined the actions of a novel xanthine derivative, propentofylline (HWA 285), that has been shown to protect against ischemic brain damage in rats and gerbils, on adenosine receptors (A1 and A2), and on adenosine transporters using several techniques, cells and tissues. Propentofylline and its hydroxylated metabolite A 72 0287 were about 20 times less potent than theophylline in displacing A1-agonist binding to membranes from rat cortex, and A1-antagonist binding to whole DDT, MF-2 smooth muscle cells. A1-agonist binding to adenosine A1-receptors in several brain structures was inhibited in a concentration-dependent manner by A 72 0287 and propentofylline as judged by quantitative autoradiography (IC50-values 300-600 microM in eg striatum and in cortex layer IV). In two functional assays, A1-receptor mediated effects were blocked by propentofylline. A1-receptor-mediated inhibition of cyclic AMP accumulation was virtually abolished by 100 microM propentofylline. The A1-receptor-mediated inhibition of evoked acetylcholine release was also reduced by propentofylline, but in this case the effect is not due exclusively to adenosine receptor antagonism but also to another action since the presynaptic inhibitory effect of carbachol was also inhibited. Adenosine A2-receptors were also antagonized by propentofylline as judged by a concentration-dependent antagonism of A2-agonist-induced cAMP accumulation in human T-leukemia cells (possessing putative A2b-receptors; pA2-value 180 microM compared to 0.26 microM for 8-cpt), and in PC-12 cells (possessing putative A2a-receptors, Ki-value 365 microM). Finally, adenosine transporters were affected by propentofylline and A 72 0287. Thus, [3H]-nitrobenzylthioinosine-binding to guinea-pig cardiac membranes was blocked by propentofylline or A 72 0287 (Ki 270 microM). The present results show that propentofylline and its hydroxylated metabolite can influence adenosine mechanisms in a multitude of ways. How these different actions may contribute to the ability of propentofylline to reduce the magnitude of ischemic damage is discussed. PMID:1628877

Fredholm, B B; Fastbom, J; Kvanta, A; Gerwins, P; Parkinson, F



Characterization of adenosine receptors in human erythroleukemia cells and platelets: further evidence for heterogeneity of adenosine A2 receptor subtypes.  


Adenosine receptors are present in platelets, and their activation results in accumulation of cAMP and inhibition of aggregation. The study of platelet adenosine receptors, however, is limited by the impossibility of maintaining these cells in vitro. Human erythroleukemia (HEL) cells express megakaryocytic/platelet markers and have been used as a model to study platelet receptors. Therefore, we sought to determine whether adenosine receptors were present in HEL cells. Adenosine agonists produced an accumulation of cAMP in HEL cells, implying the presence of A2 receptors. Xanthine and nonxanthine adenosine receptor antagonists blocked this effect in a simple competitive manner (Schild analysis). Therefore, both platelets and HEL cells possess A2 adenosine receptors. There were, however, significant differences between them. Adenosine agonists were, in general, less potent in HEL cells, compared with platelets. In particular, the adenosine analog CGS 21680, one of the most potent agonists in platelets, was virtually inactive in HEL cells. The orders of potencies for agonists (and their EC50 values for cAMP production) were 5'-N-ethylcarboxamidoadenosine (0.19 microM) = CGS 21680 (0.18 microM) > (R)-(-)-N6-(2-phenylisopropyl)adenosine (0.5 microM) in platelets and 5'-N-ethylcarboxamidoadenosine (2.4 microM) > (R)-(-)-N6-(2-phenylisopropyl)adenosine (160 microM) > CGS 21680 (1600 microM) in HEL cells. In contrast to the decreased potency of agonists in HEL cells, the antagonist 1,3-dipropyl-8-p-sulfophenylxanthine was more potent in HEL cells, compared with platelets. Based on the striking differences in the rank orders of potencies of agonists and antagonists, we propose that HEL cells and platelets have different subtypes of adenosine A2 receptors. We found CGS 21680 particularly helpful in distinguishing between these receptor subtypes. PMID:8391117

Feoktistov, I; Biaggioni, I



Norepinephrines effect on adenosine transport in the proximal straight tubule  

SciTech Connect

The effect of norepinephrine on C/sup 14/-adenosine transport in the rabbit proximal tubule (S/sub 2/) was studied. The transepithelial transport of adenosine (0.02 mM0 from lumin to bathing solution was measured by its rate of appearance (J/sub A/) in the bathing solution and by its disappearances (J/sub D/) from the luminal fluid. Norepinephrine (0.24 was added to the bathing solution after a control flux period. After three samples from the experiment period the tubules were quickly harvested and the cellular concentration of C/sup 14/-adenosine was determined. The high cellular adenosine concentration and th marked difference in adenosine appearance rate in the bathing solution compared to the luminal disappearance rate indicates the absorbed adenosine is trapped in the cells. This trapping may be due to adenosine metabolism or difficulty of crossing the basolateral membrane. Whichever is the case, norepinephrine appears to stimulate movement of adenosine or its metabolites into the bathing solution across the basolateral membrane.

Barfuss, D.W.; McCann, W.P.; Katholi, R.E.



Adenosine receptor signaling in the brain immune system  

Microsoft Academic Search

The brain immune system, which consists mainly of astrocytes, microglia and infiltrating immune cells, is quiescent normally, but it is activated in response to pathophysiological events such as ischemia, trauma, inflammation and infection. Adenosine is an endo- genous purine nucleoside that is generated at sites that are subjected to these 'stressful' conditions. Adenosine interacts with specific G-protein-coupled receptors on astrocytes,

György Haskó; Pál Pacher; E. Sylvester Vizi; Peter Illes



Adenosine receptors in regulation of dendritic cell differentiation and function  

Microsoft Academic Search

Differentiation of functional dendritic cells (DCs) critically depends on the microenvi- ronment. DCs differentiate in hypoxic tu- mor sites and inflamed or damaged tis- sue. Because local concentrations of adenosine reach high physiologically rel- evant levels in these conditions, we as- sessed the expression of adenosine re- ceptors and the effect of their activation on differentiation of human monocytes and

Sergey V. Novitskiy; Sergey Ryzhov; Rinat Zaynagetdinov; Anna E. Goldstein; Yuhui Huang; Oleg Y. Tikhomirov; Michael R. Blackburn; Italo Biaggioni; David P. Carbone; Igor Feoktistov; Mikhail M. Dikov



Adenosine A1 receptor antagonists in clinical research and development  

Microsoft Academic Search

Selective adenosine A1 receptor antagonists targeting renal microcirculation are novel pharmacologic agents that are currently under development for the treatment of acute heart failure as well as for chronic heart failure. Despite several studies showing improvement of renal function and\\/or increased diuresis with adenosine A1 antagonists, particularly in chronic heart failure, these findings were not confirmed in a large phase

Berthold Hocher



Adenosine and its receptors as therapeutic targets: An overview  

PubMed Central

The main goal of the authors is to present an overview of adenosine and its receptors, which are G-protein coupled receptors. The four known adenosine receptor subtypes are discussed along with the therapeutic potential indicating that these receptors can serve as targets for various dreadful diseases.

Sachdeva, Sakshi; Gupta, Monika



Silk Fibroin Encapsulated Powder Reservoirs for Sustained Release of Adenosine  

PubMed Central

Due to its unique properties, silk fibroin was studied as a biodegradable polymer vehicle for sustained, local delivery of the anticonvulsant adenosine from encapsulated reservoirs. Silk is a biologically derived protein polymer that is biocompatible, mechanically strong and degrades to non-toxic products in vivo. To achieve local, sustained, controlled adenosine release from fully degradable implants, solid adenosine powder reservoirs were coated with silk fibroin. Material properties of the silk coating including thickness, crystallinity and morphology were investigated to assess the relationships between silk coating biomaterial features and adenosine release from silk encapsulated reservoirs. Reservoir coating thickness was varied through manipulation of the silk coating solution concentration and number of coatings applied. Release studies were also performed in proteinase type XIV to model the effects of degradation. Increasing the barrier to diffusion, either by increasing coating thickness or crystallinity was found to delay adenosine burst, decrease average daily release rate, and increase duration of release. In the case of encapsulated reservoirs coated with eight layers of 8% (w/v) silk, a linear release profile was observed and adenosine release was sustained for 14 days. The ability to achieve nearly constant release for two weeks for adenosine via control of the silk coating suggests these encapsulated reservoirs represent a novel system for delivering adenosine. We anticipate that this approach could also be extended to other implant needs and small molecule drugs to treat a range of clinical needs.

Pritchard, Eleanor M.; Szybala, Cory; Boison, Detlev; Kaplan, David L.



Isolation, characterization and immunological properties of bovine liver adenosine kinase  

SciTech Connect

Adenosine kinase catalyzes the transfer of phosphate from nucleoside triphosphates to adenosine. It also is important in the phosphorylation of adenosine analogs active as anti-cancer and anti-viral drugs. Adenosine kinase from bovine liver was purified by sequential chromatography on DEAE-Sephacel, hydroxylapatite, Ultrogel AcA54, octyl Sepharose, and heptylamine-Sepharose. It exhibited one major band (approx.40 kDa) by sodium dodecylsulfate-polyacrylamide gel electrophoresis and a single peak of similar size by gel permeation chromatography. (/sup 35/S) GTP..gamma..S binding was stimulated in the presence of Mg/sup 2 +/ and adenosine. The K/sub m/ for adenosine was 2.6 Antibodies raised in rabbits to adenosine kinase, after purification on Protein A-and adenosine kinase-Sepharose, were used to screen several bovine tissues. A 40 kDa immunoreactive protein was most abundant in liver, but was also detected in heart; it was found predominantly in soluble fractions. Antibodies did not significantly cross-react with other guanyl nucleotide-binding proteins.

Noda, M.; Kunz, B.C.; Tsai, S.C.; Adamik, R.; Murtagh, J.J.; Chen, H.C.; Moss, J.; Vaughan, M.



Release and actions of adenosine in the central nervous system  

Microsoft Academic Search

Adenosine is released from active neurons into the extracellular fluid at a concentration of about 1µmol\\/l. Neither the precise cellular origin nor the biochemical form of release has been firmly established, though the nucleotide is probably released partly directly, as a result of raised intracellular levels, and partly as nucleotides, which are subsequently hydrolysed. Once in the extracellular medium, adenosine

M. J. Higgins; H. Hosseinzadeh; D. G. MacGregor; H. Ogilvy; T. W. Stone



Reproducibility of heart rate changes following adenosine infusion in man  

Microsoft Academic Search

The change in heart rate following infusion of adenosine in healthy human subjects was studied on two occasions. Adenosine produced a significant, dose-related increase in heart rate. Tachyphylaxis to this effect of the naturally occurring nucleoside did not occur. There was a tendency for prolonged infusion to cause a greater increase in heart rate, but this did not reach significance.

B. Clarke; T.-B. Conradson; C. M. S. Dixon; P. J. Barnes



[Protective effect of adenosine in total brain ischemia].  


Adenosine has prominent cerebro-protective effect at total brain ischemia. Other nucleotides and nucleosides are less active or have no effect at all. It suggests participation of A-receptors. Adenosine is more effective than 8 other drugs that have protective effect in different models of brain ischemia (nimodipine, gamma-hydroxybutyrate etc). PMID:8054577

Kulinski?, V I; Usov, L A; Sufianova, G Z



Variation in One Residue Associated with the Metal Ion-Dependent Adhesion Site Regulates ?IIb?3 Integrin Ligand Binding Affinity  

PubMed Central

The Asp of the RGD motif of the ligand coordinates with the ? I domain metal ion dependent adhesion site (MIDAS) divalent cation, emphasizing the importance of the MIDAS in ligand binding. There appears to be two distinct groups of integrins that differ in their ligand binding affinity and adhesion ability. These differences may be due to a specific residue associated with the MIDAS, particularly the ?3 residue Ala252 and corresponding Ala in the ?1 integrin compared to the analogous Asp residue in the ?2 and ?7 integrins. Interestingly, mutations in the adjacent to MIDAS (ADMIDAS) of integrins ?4?7 and ?L?2 increased the binding and adhesion abilities compared to the wild-type, while the same mutations in the ?2?1, ?5?1, ?V?3, and ?IIb?3 integrins demonstrated decreased ligand binding and adhesion. We introduced a mutation in the ?IIb?3 to convert this MIDAS associated Ala252 to Asp. By combination of this mutant with mutations of one or two ADMIDAS residues, we studied the effects of this residue on ligand binding and adhesion. Then, we performed molecular dynamics simulations on the wild-type and mutant ?IIb?3 integrin ? I domains, and investigated the dynamics of metal ion binding sites in different integrin-RGD complexes. We found that the tendency of calculated binding free energies was in excellent agreement with the experimental results, suggesting that the variation in this MIDAS associated residue accounts for the differences in ligand binding and adhesion among different integrins, and it accounts for the conflicting results of ADMIDAS mutations within different integrins. This study sheds more light on the role of the MIDAS associated residue pertaining to ligand binding and adhesion and suggests that this residue may play a pivotal role in integrin-mediated cell rolling and firm adhesion.

Wu, Xue; Xiu, Zhilong; Li, Guohui; Luo, Bing-Hao



Variation in One Residue Associated with the Metal Ion-Dependent Adhesion Site Regulates ?IIb?3 Integrin Ligand Binding Affinity.  


The Asp of the RGD motif of the ligand coordinates with the ? I domain metal ion dependent adhesion site (MIDAS) divalent cation, emphasizing the importance of the MIDAS in ligand binding. There appears to be two distinct groups of integrins that differ in their ligand binding affinity and adhesion ability. These differences may be due to a specific residue associated with the MIDAS, particularly the ?3 residue Ala(252) and corresponding Ala in the ?1 integrin compared to the analogous Asp residue in the ?2 and ?7 integrins. Interestingly, mutations in the adjacent to MIDAS (ADMIDAS) of integrins ?4?7 and ?L?2 increased the binding and adhesion abilities compared to the wild-type, while the same mutations in the ?2?1, ?5?1, ?V?3, and ?IIb?3 integrins demonstrated decreased ligand binding and adhesion. We introduced a mutation in the ?IIb?3 to convert this MIDAS associated Ala(252) to Asp. By combination of this mutant with mutations of one or two ADMIDAS residues, we studied the effects of this residue on ligand binding and adhesion. Then, we performed molecular dynamics simulations on the wild-type and mutant ?IIb?3 integrin ? I domains, and investigated the dynamics of metal ion binding sites in different integrin-RGD complexes. We found that the tendency of calculated binding free energies was in excellent agreement with the experimental results, suggesting that the variation in this MIDAS associated residue accounts for the differences in ligand binding and adhesion among different integrins, and it accounts for the conflicting results of ADMIDAS mutations within different integrins. This study sheds more light on the role of the MIDAS associated residue pertaining to ligand binding and adhesion and suggests that this residue may play a pivotal role in integrin-mediated cell rolling and firm adhesion. PMID:24116162

Raborn, Joel; Fu, Ting; Wu, Xue; Xiu, Zhilong; Li, Guohui; Luo, Bing-Hao



Adenosine A3 receptor stimulation and cerebral ischemia  

PubMed Central

Chronic treatment with the selective adenosine A3 receptor agonist N6-(3-iodobenzyl)adenosine-5’-N-methylcarboxamide (IB-MECA) administered prior to either 10 or 20 min forebrain ischemia in gerbils resulted in improved postischemic cerebral blood circulation, survival, and neuronal preservation. Opposite effects, i.e., impaired postischemic blood flow, enhanced mortality, and extensive neuronal destruction in the hippocampus were seen when IB-MECA was given acutely. Neither adenosine A1 nor A2 receptors are involved in these actions. The data indicate that stimulation of adenosine A3 receptors may play an important role in the development of ischemic damage, and that adenosine A3 receptors may offer a new target for therapeutic interventions.

Von Lubitz, Dag K.J.E.; Lin, Rick C.-S.; Popik, Piotr; Carter, Margaret F.; Jacobson, Kenneth A.



ADA2 isoform of adenosine deaminase from pleural fluid.  


Adenosine deaminase isoenzyme 2 (ADA2) was isolated from human pleural fluid for the first time. Molecular and kinetic properties were characterized. It was shown that the inhibitors of adenosine deaminase isoenzyme 1 (ADA1), adenosine, and erithro-9-(2-hydroxy-3-nonyl)adenine (EHNA) derivatives are poor inhibitors of ADA2. Comparison of the interaction of ADA2 and ADA1 with adenosine and its derivative, 1-deazaadenosine, indicates that the isoenzymes have similar active centers. The absence of ADA2 inhibition by EHNA is evidence of a difference of these active centers in a close environment. The possible role of Zn2+ ions and the participation of acidic amino acids Glu and Asp in adenosine deamination catalyzed by ADA2 were shown. PMID:15670822

Andreasyan, Nune A; Hairapetyan, Hripsime L; Sargisova, Yelizaveta G; Mardanyan, Sona S



A High Affinity Adenosine Kinase from Anopheles gambiae  

PubMed Central

Genome analysis revealed a mosquito orthologue of adenosine kinase in Anopheles gambiae (AgAK; the most important vector for the transmission of Plasmodium falciparum in Africa). P. falciparum are purine auxotrophs and do not express an adenosine kinase but rely on their hosts for purines. AgAK was kinetically characterized and found to have the highest affinity for adenosine (Km 8.1 nM) of any known adenosine kinase. AgAK is specific for adenosine at the nucleoside site but several nucleotide triphosphate phosphoryl donors are tolerated. The AgAK crystal structure with a bound bisubstrate analogue Ap4A (2.0 Ĺ resolution) reveals interactions for adenosine, ATP and the geometry for phosphoryl transfer. The polyphosphate charge is partly neutralized by a bound Mg2+ ion and an ion pair to a catalytic site Arg. The AgAK structure consists of a large catalytic core in a three-layered ?/?/? sandwich, and a small cap domain in contact with adenosine. The specificity and tight-binding for adenosine arises from hydrogen bond interactions of Asn14, Leu16, Leu40, Leu133, Leu168, Phe168 and Thr171 and the backbone of Ile39 and Phe168 with the adenine ring as well as through hydrogen bond interactions between Asp18, Gly64 and Asn68 and the ribosyl 2?- and 3?-hydroxyl groups. The structure is more similar to human adenosine kinase (48% identity) than to AK from Toxoplasma gondii (31% identity). With this extraordinary affinity for AgAK, adenosine is efficiently captured and converted to AMP at near the diffusion limit, suggesting an important role of this enzyme to maintain the adenine nucleotide pool. mRNA analysis verifies that AgAK transcripts are produced in the adult insects.

Cassera, Maria B.; Ho, Meng-Chiao; Merino, Emilio F.; Burgos, Emmanuel S.; Rinaldo-Matthis, Agnes; Almo, Steven C.; Schramm, Vern L.



A High-Affinity Adenosine Kinase from Anopheles Gambiae  

SciTech Connect

Genome analysis revealed a mosquito orthologue of adenosine kinase in Anopheles gambiae (AgAK; the most important vector for the transmission of Plasmodium falciparum in Africa). P. falciparum are purine auxotrophs and do not express an adenosine kinase but rely on their hosts for purines. AgAK was kinetically characterized and found to have the highest affinity for adenosine (K{sub m} = 8.1 nM) of any known adenosine kinase. AgAK is specific for adenosine at the nucleoside site, but several nucleotide triphosphate phosphoryl donors are tolerated. The AgAK crystal structure with a bound bisubstrate analogue Ap{sub 4}A (2.0 {angstrom} resolution) reveals interactions for adenosine and ATP and the geometry for phosphoryl transfer. The polyphosphate charge is partly neutralized by a bound Mg{sup 2+} ion and an ion pair to a catalytic site Arg. The AgAK structure consists of a large catalytic core in a three-layer {alpha}/{beta}/{alpha} sandwich, and a small cap domain in contact with adenosine. The specificity and tight binding for adenosine arise from hydrogen bond interactions of Asn14, Leu16, Leu40, Leu133, Leu168, Phe168, and Thr171 and the backbone of Ile39 and Phe168 with the adenine ring as well as through hydrogen bond interactions between Asp18, Gly64, and Asn68 and the ribosyl 2'- and 3'-hydroxyl groups. The structure is more similar to that of human adenosine kinase (48% identical) than to that of AK from Toxoplasma gondii (31% identical). With this extraordinary affinity for AgAK, adenosine is efficiently captured and converted to AMP at near the diffusion limit, suggesting an important role for this enzyme in the maintenance of the adenine nucleotide pool. mRNA analysis verifies that AgAK transcripts are produced in the adult insects.

M Cassera; M Ho; E Merino; E Burgos; A Rinaldo-Matthis; S Almo; V Schramm



Maintenance of renal autoregulation during infusion of aminophylline or adenosine.  


Adenosine has been postulated to link control of glomerular filtration rate (GFR) and renal blood flow (RBF) with changes in renal metabolism. In the present study, we examined the role of adenosine in renal autoregulation by comparing the responses of normal anesthetized dogs to step decreases in renal artery pressure (RAP) to the response obtained after receptor blockade of adenosine with aminophylline or by flooding the kidney with exogenous adenosine. In six dogs at normal RAP, intrarenal infusion of aminophylline (10 mumol/min) did not alter renal hemodynamics. GFR and RBF were well autoregulated (greater than 90% of control) at RAP values equal to or greater than 85 mmHg before and after aminophylline. At RAP equal to 75 mmHg, GFR and RBF decreased by 27 +/- 10 and 20 +/- 8%, respectively, before aminophylline and by 25 +/- 7 and 13 +/- 6% after aminophylline. In a different group of six dogs, intrarenal infusion of adenosine (6 mumol/min) significantly increased RBF (32 +/- 9%) and decreased GFR (38 +/- 10%) at normal RAP. However, GFR and RBF were both well autoregulated (greater than 90% of control) at RAP values equal to or greater than 85 mmHg before and after adenosine. At RAP equal to 75 mmHg, GFR and RBF decreased by 10 +/- 5 and 7 +/- 3%, respectively, before adenosine and by 12 +/- 6 and 17 +/- 5% after adenosine. Neither aminophylline nor adenosine attenuated the elevations in plasma renin activity associated with reductions in RAP. These data fail to provide evidence that adenosine is an important factor in autoregulation of GFR and RBF during acute reductions in RAP within the autoregulatory range. PMID:2983569

Premen, A J; Hall, J E; Mizelle, H L; Cornell, J E



Adenosine receptors and asthma in humans.  


According to an executive summary of the GINA dissemination committee report, it is now estimated that approximately 300 million people (5% of the global population or 1 in 20 persons) have asthma. Despite the scientific progress made over the past several decades toward improving our understanding of the pathophysiology of asthma, there is still a great need for improved therapies, particularly oral therapies that enhance patient compliance and that target new mechanisms of action. Adenosine is an important signalling molecule in human asthma. By acting on extracellular G-protein-coupled ARs on a number of different cell types important in the pathophysiology of human asthma, adenosine affects bronchial reactivity, inflammation and airway remodelling. Four AR subtypes (A(1), A(2a), A(2b) and A(3)) have been cloned in humans, are expressed in the lung, and are all targets for drug development for human asthma. This review summarizes what is known about these AR subtypes and their function in human asthma as well as the pros and cons of therapeutic approaches to these AR targets. A number of molecules with high affinity and high selectivity for the human AR subtypes have entered clinical trials or are poised to enter clinical trials as anti-asthma treatments. With the availability of these molecules for testing in humans, the function of ARs in human asthma, as well as the safety and efficacy of approaches to the different AR targets, can now be determined. PMID:18852693

Wilson, C N



Adenosine augments IL-10 production by microglial cells through an A2B adenosine receptor-mediated process.  


Microglia are activated by pathogen-associated molecular patterns and produce proinflammatory cytokines, such as TNF-?, IL-6, and IL-12, and the anti-inflammatory cytokine IL-10. Adenosine is an endogenous purine nucleoside and a ligand of four G protein-coupled adenosine receptors (ARs), which are the A(1)AR, A(2A)AR, A(2B)AR, and A(3)AR. ARs have been shown to suppress TNF-? production by microglia, but their role in regulating IL-10 production has not been studied. In this study, we demonstrate that adenosine augments IL-10 production by activated murine microglia while suppressing the production of proinflammatory cytokines. Because the order of potency of selective AR agonists in inducing IL-10 production was NECA > IB-MECA > CCPA ? CGS21680, and the A(2B)AR antagonist MRS1754 prevented the effect of NECA, we conclude that the stimulatory effect of adenosine on IL-10 production is mediated by the A(2B)AR. Mechanistically, adenosine augmented IL-10 mRNA accumulation by a transcriptional process. Using mutant IL-10 promoter constructs we showed that a CREB-binding region in the promoter mediated the augmenting effect of adenosine on IL-10 transcription. Chromatin immunoprecipitation analysis demonstrated that adenosine induced CREB phosphorylation at the IL-10 promoter. Silencing CREB using lentivirally delivered short hairpin RNA blocked the enhancing effect of adenosine on IL-10 production, confirming a role for CREB in mediating the stimulatory effect of adenosine on IL-10 production. In addition, adenosine augmented IL-10 production by stimulating p38 MAPK. Collectively, our results establish that A(2B)ARs augment IL-10 production by activated murine microglia. PMID:22116830

Koscsó, Balázs; Csóka, Balázs; Selmeczy, Zsolt; Himer, Leonóra; Pacher, Pál; Virág, László; Haskó, György



Adenosine deaminase in disorders of purine metabolism and in immune deficiency  

SciTech Connect

This book consists of five parts and a section of poster papers. Some of the selection titles are: Adenosine Deaminase Impairment and Ribonucleotide Reductase in Human Cells; Adenosine Deaminase and Malignant Cells; Inhibition of Adenosine Deaminase to Increase the Antitumor Activity of Adenine Nucleoside Analogues; and Molecular Biology of the Adenosine Deaminase Gene and Messenger RNA.

Tritsch, G.L.



HIF-dependent induction of adenosine A2B receptor in hypoxia  

Microsoft Academic Search

Adenosine has been widely associated with hypoxia of many origins, including those associ- ated with inflammation and tumorogenesis. A number of recent studies have implicated metabolic control of adenosine generation at sites of tissue hypoxia. Here, we examine adenosine receptor control and amplifica- tion of signaling through transcriptional regulation of endothelial and epithelial adenosine receptors. Initial studies confirmed previous findings

Tianqing Kong; Karen A. Westerman; Marion Faigle; Holger K. Eltzschig; Sean P. Colgan



Elevated expression of adenosine A1 receptor in bronchial biopsy specimens from asthmatic subjects  

Microsoft Academic Search

Asthmatics, unlike healthy subjects, experience bronchoconstriction in response to inhaled adenosine, and extracellular adenosine concentrations are elevated in the bronchoalveolar lavage fluid and exhaled breath condensate of asthmatic subjects. However, little is known about the location and expression of adenosine receptors in asthmatic airways. The aim of the present study was to investigate the distribution of adenosine A1 receptors in

R. A. Brown; G. W. Clarke; C. L. Ledbetter; M. J. Hurle; J. C. Denyer; D. E. Simcock; J. E. Coote; T. J. Savage; R. D. Murdoch; C. P. Page; D. Spina; B. J. O'Connor



Recent Caffeine Ingestion Reduces Adenosine Efficacy in the Treatment of Paroxysmal Supraventricular Tachycardia  

Microsoft Academic Search

Objectives: Caffeine, an adenosine receptor blocker, should theoretically reduce adenosine efficacy in the treatment of paroxysmal supraventricular tachycardia (SVT). We aimed to determine the effect of recent caffeine ingestion on the likelihood of reversion of SVT with adenosine. Methods: This was a multicenter, case-control study of adult patients with SVT treated with adenosine between September 2007 and July 2008. The

Miguel S. Cabalag; David McDonald Taylor; Jonathan C. Knott; Paul Buntine; DeVilliers Smit; Alastair Meyer



Adenosine–dopamine receptor–receptor interactions as an integrative mechanism in the basal ganglia  

Microsoft Academic Search

Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the motor depressant effects of adenosine receptor agonists and the motor stimulant effects of adenosine receptor antagonists, such as caffeine. The GABAergic striatopallidal neurons are regulated by interacting adenosine A2A and dopamine D2 receptors. On the other hand, the

Sergi Ferré; Kjell Fuxe; Bertil B. Fredholm; Micaela Morelli; Patrizia Popoli




Microsoft Academic Search

? Abstract Adenosine is a modulator that has a pervasive and generally inhibitory effect on neuronal activity. Tonic activation of adenosine receptors by adenosine that is normally present in the extracellular space in brain tissue leads to inhibitory effects that appear to be mediated by both adenosine A1 and A2A receptors. Relief from this tonic inhibition by receptor antagonists such

Thomas V. Dunwiddie; Susan A. Masino



Identification of possible adenosine receptors in vascular smooth muscle  

SciTech Connect

Adenosine is a vasodilator and has been implicated in increased blood flow in tissues that undergo energy deficiency. During conditions such as hypoxia and ischemia, adenosine is produced and is said to increase blood flow by relaxing the vascular smooth muscle (VSM) lining the resistance vessels. The goal of this research was to identify receptors that might be responsible for adenosine-mediated VSM relaxation. When an insoluble fraction from calf aortic VSM was incubated with /sup 32/P-ATP, two components were phosphorylated. One was identified as myosin light chain by MW, pl, and immunoprecipitation. The other product was identified as phosphatidylinositol-4-phosphate (DPI) by tic. Both phosphorylations were inhibited by adenosine and by 5'-chloro-5'-deoxyadenosine (Cl-Ado). DPI production was much more sensitive to the nucleosides than was myosin phosphorylation. Neither inhibition involved change in cAMP production. Phosphatidylinositol (Pl) kinase in the VSM membranes required magnesium, was activated and solubilized by Triton X-100, and phosphorylated both endogenous and exogenous Pl. Cl-Ado inhibited Pl kinase in a manner competitive with respect to ATP and noncompetitive with respect to Pl. Adenosine and adenosine analogs modified in the ribose ring were inhibitors with potencies comparable to that of Cl-Ado. Adenine nucleotides and purine-modified adenosine analogs were weaker inhibitors than Cl-Ado.

Doctrow, S.R.



Adenosine-mediated cardiovascular toxicity in amitriptyline-poisoned rats.  


We investigated the contribution of endogenous adenosine to amitriptyline-induced cardiovascular toxicity in rats. A control group of rats was pretreated with intraperitoneal (i.p.) 5% dextrose and received intravenous 0.94 mg/kg/min of amitriptyline for 60 minutes. The second and third groups of rats pretreated with i.p. 10 mg/kg of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, and i.p. 1 mg/kg of S-(4-nitrobenzyl)-6-thioinosine (NBTI), a facilitated adenosine transport inhibitor, received 5% dextrose and amitriptyline infusion, respectively. Outcome parameters were mean arterial pressure (MAP), heart rate (HR), QT and QRS durations, and plasma adenosine concentrations. Plasma adenosine concentrations were increased in all groups. In the control group, amitriptyline decreased MAP and HR and prolonged QT and QRS durations after 10 minutes of infusion. In EHNA/NBTI-pretreated rats, amitriptyline prolonged QRS duration at 10 and 20 minutes. In EHNA/NBTI pretreated rats, amitriptyline-induced MAP, HR reductions, and QRS prolongations were more significant than that of dextrose-infusion-induced changes. Our results indicate that amitriptyline augmented the cardiovascular effects of endogen adenosine by increasing plasma levels of adenosine in rats. PMID:22168308

Kalkan, Sule; Hocaoglu, Nil; Oransay, Kubilay; Buyukdeligoz, Mujgan; Tuncok, Yesim



Metformin prevents myocardial reperfusion injury by activating the adenosine receptor.  


Metformin improves cardiovascular outcomes in patients with type 2 diabetes compared with other glucose-lowering drugs. Experimental studies have shown that metformin can increase the intracellular concentration of adenosine monophosphate, which is a major determinant of the intracellular formation of adenosine. We hypothesize that metformin, given at reperfusion, can limit myocardial infarct size due to increased adenosine receptor stimulation. Isolated perfused hearts from Sprague-Dawley rats were subjected to 35 minutes of regional ischemia and 120 minutes of reperfusion. Perfusion with metformin (50 microM) for the first 15 minutes of reperfusion reduced infarct size (percent area at risk) from 42% +/- 2% to 19% +/- 4% (n >or= 6; P < 0.01), which was blocked by a concomitant perfusion with the adenosine receptor antagonist 8-p-sulfophenyltheophylline (100 microM; 43% +/- 3%) or nitrobenzylthioinosine (a blocker of transmembranous adenosine transport; 1 microM; 45% +/- 5%). In addition, intravenous administration of metformin (5 mg/kg) reduced infarct size in a rat in situ model of myocardial infarction (34% +/- 6% vs. 62% +/- 5%; P < 0.01), which was completely abolished by 8-p-sulfophenyltheophylline (61% +/- 3%). We conclude that metformin, given at reperfusion, reduces infarct size in a rat model of myocardial infarction, which is critically dependent on adenosine receptor stimulation, probably via increased intracellular formation of adenosine. PMID:19295441

Paiva, Marta; Riksen, Niels P; Davidson, Sean M; Hausenloy, Derek J; Monteiro, Pedro; Gonçalves, Lino; Providęncia, Luís; Rongen, Gerard A; Smits, Paul; Mocanu, Mihaela M; Yellon, Derek M



The pulmonary effects of intravenous adenosine in asthmatic subjects  

PubMed Central

Background We have shown that intravenous adenosine in normal subjects does not cause bronchospasm, but causes dyspnea, most likely by an effect on vagal C fibers in the lungs [Burki et al. J Appl Physiol 2005; 98:180-5]. Since airways inflammation and bronchial hyperreactivity are features of asthma, it is possible that intravenous adenosine may be associated with an increased intensity of dyspnea, and may cause bronchospasm, as noted anecdotally in previous reports. Methods We compared the effects of placebo and 10 mg intravenous adenosine, in 6 normal and 6 asthmatic subjects. Results Placebo injection had no significant (p > 0.05) effect on the forced expiratory spirogram, heart rate, minute ventilation (Ve), or respiratory sensation. Similarly, adenosine injection caused no significant changes (p > 0.05) in the forced expiratory spirogram; however, there was a rapid development of dyspnea as signified visually on a modified Borg scale, and a significant (p < 0.05) tachycardia in each subject (Asthmatics +18%, Normals + 34%), and a significant (p < 0.05) increase in Ve (Asthmatics +93%, Normals +130%). The intensity of dyspnea was significantly greater (p < 0.05) in the asthmatic subjects. Conclusion These data indicate that intravenous adenosine does not cause bronchospasm in asthmatic subjects, and supports the concept that adenosine-induced dyspnea is most likely secondary to stimulation of vagal C fibers in the lungs. The increased intensity of adenosine-induced dyspnea in the asthmatic subjects suggests that airways inflammation may have sensitized the vagal C fibers.

Burki, Nausherwan K; Alam, Mahmud; Lee, Lu-Yuan



Temporal variations of adenosine metabolism in human blood.  


Eight diurnally active (06:00-23:00 h) subjects were adapted for 2 days to the room conditions where the experiments were performed. Blood sampling for adenosine metabolites and metabolizing enzymes was done hourly during the activity span and every 30 min during sleep. The results showed that adenosine and its catabolites (inosine, hypoxanthine, and uric acid), adenosine synthesizing (S-adenosylhomocysteine hydrolase and 5'-nucleotidase), degrading (adenosine deaminase) and nucleotide-forming (adenosine kinase) enzymes as well as adenine nucleotides (AMP, ADP, and ATP) undergo statistically significant fluctuations (ANOVA) during the 24 h. However, energy charge was invariable. Glucose and lactate chronograms were determined as metabolic indicators. The same data analyzed by the chi-square periodogram and Fourier series indicated ultradian oscillatory periods for all the metabolites and enzymatic activities determined, and 24-h oscillatory components for inosine, hypoxanthine, adenine nucleotides, glucose, and the activities of SAH-hydrolase, 5'-nucleotidase, and adenosine kinase. The single cosinor method showed significant oscillatory components exclusively for lactate. As a whole, these results suggest that adenosine metabolism may play a role as a biological oscillator coordinating and/or modulating the energy homeostasis and physiological status of erythrocytes in vivo and could be an important factor in the distribution of purine rings for the rest of the organism. PMID:8874980

Chagoya de Sánchez, V; Hernández-Muńoz, R; Suárez, J; Vidrio, S; Yáńez, L; Aguilar-Roblero, R; Oksenberg, A; Vega-González, A; Villalobos, L; Rosenthal, L; Fernández-Cancino, F; Drucker-Colín, R; Díaz-Muńoz, M



Behavioral effects of adenosine analogs in squirrel monkeys: relation to adenosine A 2 receptors  

Microsoft Academic Search

The behavioral effects of seven metabolically stable analogs of adenosine were studied in squirrel monkeys responding under a fixed-interval (FI) schedule of stimulus-shock termination. All drugs produced dose-related decreases in response rate, but differed in potency by up to three orders of magnitude. The 5'-carboxamine and 2-chlorine substituted analogs were more potent than the N6-substituted analogs. The potencies of the

R. D. Spealman; V. L. Coffin



Mediation of tubuloglomerular feedback by adenosine: Evidence from mice lacking adenosine 1 receptors  

PubMed Central

Adenosine is a determinant of metabolic control of organ function increasing oxygen supply through the A2 class of adenosine receptors and reducing oxygen demand through A1 adenosine receptors (A1AR). In the kidney, activation of A1AR in afferent glomerular arterioles has been suggested to contribute to tubuloglomerular feedback (TGF), the vasoconstriction elicited by elevations in [NaCl] in the macula densa region of the nephron. To further elucidate the role of A1AR in TGF, we have generated mice in which the entire A1AR coding sequence was deleted by homologous recombination. Homozygous A1AR mutants that do not express A1AR mRNA transcripts and do not respond to A1AR agonists are viable and without gross anatomical abnormalities. Plasma and urinary electrolytes were not different between genotypes. Likewise, arterial blood pressure, heart rates, and glomerular filtration rates were indistinguishable between A1AR+/+, A1AR+/?, and A1AR?/? mice. TGF responses to an increase in loop of Henle flow rate from 0 to 30 nl/min, whether determined as change of stop flow pressure or early proximal flow rate, were completely abolished in A1AR?/? mice (stop flow pressure response, ?6.8 ± 0.55 mmHg and ?0.4 ± 0.2 in A1AR+/+ and A1AR?/? mice; early proximal flow rate response, ?3.4 ± 0.4 nl/min and +0.02 ± 0.3 nl/min in A1AR+/+ and A1AR?/? mice). Absence of TGF responses in A1AR-deficient mice suggests that adenosine is a required constituent of the juxtaglomerular signaling pathway. A1AR null mutant mice are a promising tool to study the functional role of A1AR in different target tissues.

Sun, Daqing; Samuelson, Linda C.; Yang, Tianxin; Huang, Yuning; Paliege, Alex; Saunders, Thom; Briggs, Josie; Schnermann, Jurgen



Adenosine A2A receptors in Parkinson's disease treatment  

PubMed Central

Latest results on the action of adenosine A2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia possess high levels of adenosine A2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus, and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects. In combination therapy, the adenosine A2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration of adenosine A2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It was demonstrated in various animal models that inhibition of adenosine A2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor of adenosine A2A receptors, as an anti-Parkinson drug.

Cieslak, Marek; Wojtczak, Andrzej



9-?-L(+) Adenosine: A new naturally occurring plant growth substance elicited by triacontanol in rice  

Microsoft Academic Search

The naturally occurring plant growth substance elicited by triacontanol was found to be 9-ß-L(+) adenosine by physical and spectral methods. At picomolar concentrations, 9-ß-L(+) adenosine stimulated growth as determined by dry weight measurements of several plant species. Reaction of adenosine deaminase with adenosine from rice showed that small quantities of 9-ß-L(+) adenosine exist in plants. We believe this is the

Stanley Ries; Violet Wert; N. F. D. O'Leary; Muraleedharan Nair



Potentiation of adenosine triphosphate-induced contractile responses of the guinea-pig isolated vas deferens by adenosine monophosphate and adenosine 5'-monophosphorothioate.  

PubMed Central

The effects of incubating the guinea-pig isolated vas deferens in the presence of adenine nucleotides (adenosine triphosphate, ATP; adenosine diphosphate, ADP; and adenosine monophosphate, AMP), or in the presence of their phosphorothioate analogues (adenosine 5'-O-(3-thiotriphosphate), ATP gamma S; adenosine 5'-O-(2-thiodiphosphate), ADP beta S; and adenosine 5'-monophosphorothioate, AMP alpha S), on contractile responses to ATP were compared. After challenge with a low (1 microM) or high (300 microM) concentration of ATP to obtain control responses, one vas deferens of a pair was incubated for 5 min with one of the adenine nucleotides, while the contralateral preparation was incubated with the corresponding phosphorothioate analogue. At the conclusion of the incubation the preparations were challenged again with ATP. Incubation with AMP or AMP alpha S resulted in a transient potentiation of responses to 1 microM and 300 microM ATP. The potentiation following incubation with AMP alpha S was larger than that produced by AMP. After incubation with ADP, ADP beta S, ATP and ATP gamma S, responses to 1 microM ATP were decreased, while those to 300 microM ATP were unaffected. Thus, incubation with AMP and AMP alpha S results in potentiation, rather than inhibition, of ATP-induced responses. On the other hand, 5'-diphosphate, 5'-triphosphate, 5'-O-(2-thiodiphosphate) and 5'-O-(3-thiotriphosphate) moieties on adenosine have no effect or cause autoinhibition. These results indicate that AMP exerts a potentiating effect on reactivity to exogenous ATP. AMP arising from the enzymatic degradation of ATP might modulate the level of response to ATP released endogenously as a cotransmitter.

Fedan, J. S.



Possible mechanism of adenosine protection in carbon tetrachloride acute hepatotoxicity. Role of adenosine by-products and glutathione peroxidase.  


Adenosine proved to be an effective hepatoprotector increasing the survival rate of rats receiving lethal doses of CCl4. Searching for the mechanism of action, we found that adenosine transiently prevents the necrotic liver damage associated to an acute CCl4 treatment. The antilipoperoxidative action of the nucleoside was evidenced by a decrease of TBA-reactive products and the diene conjugates elicited by the hepatotoxin. Adenosine's protective effect was demonstrated by reverting the decrease of cytochrome P-450 while preserved intact the activity of the microsomal enzyme glucose-6-phosphatase. CCl4 promoted an increase in the oxidant stress through an enhancement in oxidized glutathione levels. This action was also completely counteracted by the nucleoside. Adenosine was unable to prevent CCl4 activation and, even, increased .CCl3 formation in the presence of PBN in vivo. However, in the presence of the nucleoside, irreversible binding of 14CCl4 to the microsomal lipid fraction of the treated animals was decreased. These results suggest that adenosine protective action might be exerted at the level of the propagation reaction following CCl4 activation. Two possible mechanisms were associated to the nucleoside protection: (1) the peroxide-metabolyzed enzymes, GSH-per, showed a marked increase after 30 minutes of adenosine treatment, which was potentiated by the hepatotoxin, suggesting an important role of this enzyme in the nucleoside's action; (2) the adenosine catabolism induced an increase in uric acid level, and allopurinol, a purine metabolism inhibitor, prevented such elevation as well as the antilipoperoxidative action of adenosine and the increase of GSH-per associated with the nucleoside treatment. These facts strongly suggest that the protective effect elicited by adenosine is not a direct one, but rather is related to its catabolic products, such as uric acid, which has been recognized as a free radical scavenger. PMID:7595931

Chagoya de Sánchez, V; Hernández-Muńoz, R; Yáńez, L; Vidrio, S; Díaz-Muńoz, M



Enhanced activity or resistance of adenosine derivatives towards adenosine deaminase-catalyzed deamination: Influence of ribose modifications.  


The effect of the presence of the 1'-C-methyl group and 2',3'-O-substitution in the adenosine structure on ADA activity has been investigated by modeling studies. Results show that the 2'- and 3'-O- substituents are harbored in a quite large cavity of intermediate polarity, whereas the 1'-C-substituent clashes against Ala180 distorting the architecture of the catalytic centre. Globally, the study emphasizes the ability of ADA to transform a large set of 2',3'-O-substituted adenosine analogues as well as the opportunity to design 1'-C-substituted adenosine derivatives resistant to ADA-catalyzed deamination. PMID:19361992

Vistoli, Giulio; Pedretti, Alessandro; Alessandrini, Laura; Casati, Silvana; Ciuffreda, Pierangela; Meroni, Giuseppe; Santaniello, Enzo



Alpha-Adrenergic Receptor Modulation of beta-Adrenergic, Adenosine and Prostaglandin E sub 1 Increased Adenosine 3':5'-Cyclic Monophosphate Levels in Primary Cultures of Glia.  

National Technical Information Service (NTIS)

Beta-adrenergic agonists, adenosine and prostaglandin E sub 1 increased the level of adenosine 3' : 5'-monophosphate (cAMP) in glial cultures prepared from rat cerebral cortical tissue. In addition to these physiological effectors, cholera toxin also incr...

K. D. McCarthy J. de Vellis



A label-free fluorescent molecular beacon based on DNA-templated silver nanoclusters for detection of adenosine and adenosine deaminase.  


A simple and reliable fluorescent molecular beacon is developed utilizing DNA-templated silver nanoclusters as a signal indicator and adenosine triphosphate (ATP) and adenosine deaminase as mechanical activators. PMID:22543727

Zhang, Min; Guo, Su-Miao; Li, Ying-Ru; Zuo, Peng; Ye, Bang-Ce



Adenosine-induced enhanced recovery of evoked responses after anoxia.  


Transverse slices of rat hippocampus were used to test the effect of adenosine on recovery of synaptically-evoked potentials after anoxia. To produce conditions better resembling ischaemia, glucose was omitted during the period of anoxia. Anoxia abolished all electrical activity within 5 min. The responses recovered completely after short periods of anoxia (3 min), but the amount of recovery was progressively reduced with longer exposures. The recovery was enhanced by the presence of 100 microM adenosine: the exposure time giving a 50% recovery of the response was 17.6 +/- 1.8 min in normal solution and 29.0 +/- 4.1 min with adenosine. These results are consistent with the idea that adenosine offers some protection from anoxia. PMID:1966602

Donaghy, K; Scholfield, C N



Adenosine triphosphate (ATP) in the marine environment: a bibliography  

Microsoft Academic Search

This bibliography lists published works on adenosine triphosphate (ATP) detected in the marine environment. Over 100 citations are listed in four categories: field measurements; macroscopic organisms; benthic populations; and papers on analytical methods.

A. T. Jones; E. O. Hartwig; M. S. Quinby-Hunt



21 CFR 864.7040 - Adenosine triphosphate release assay.  

Code of Federal Regulations, 2013 CFR

...a device that measures the release of adenosine triphosphate (ATP) from platelets following aggregation. This measurement...extract. Simultaneous measurements of platelet aggregation and ATP release are used to evaluate platelet function disorders....



Adenosine triphosphate (ATP) in the marine environment: a bibliography  

SciTech Connect

This bibliography lists published works on adenosine triphosphate (ATP) detected in the marine environment. Over 100 citations are listed in four categories: field measurements; macroscopic organisms; benthic populations; and papers on analytical methods.

Jones, A.T.; Hartwig, E.O.; Quinby-Hunt, M.S.



Relaxation of the mouse isolated aorta and carotid artery in response to adenosine analogues in genetically-modified mice lacking the adenosine A 2A receptor  

Microsoft Academic Search

The aim of this study was to characterise the receptor(s) mediating responses to adenosine and\\/or adenosine analogues in mouse isolated aorta and carotid artery. In addition, since mice lacking the A2A adenosine receptor are reported to be hypertensive, the possibility that this gene deletion or the altered phenotype results in alteration of responses mediated via adenosine analogues was investigated. This

D. J. Prentice; M. D. W. Kelly; C. Ledent; S. M. O. Hourani



Adenosine deaminase 1 and concentrative nucleoside transporters 2 and 3 regulate adenosine on the apical surface of human airway epithelia: implications for inflammatory lung diseases.  


Adenosine is a multifaceted signaling molecule mediating key aspects of innate and immune lung defenses. However, abnormally high airway adenosine levels exacerbate inflammatory lung diseases. This study identifies the mechanisms regulating adenosine elimination from the apical surface of human airway epithelia. Experiments conducted on polarized primary cultures of nasal and bronchial epithelial cells showed that extracellular adenosine is eliminated by surface metabolism and cellular uptake. The conversion of adenosine to inosine was completely inhibited by the adenosine deaminase 1 (ADA1) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). The reaction exhibited Km and Vmax values of 24 microM and 0.14 nmol x min(-1) x cm(-2). ADA1 (not ADA2) mRNA was detected in human airway epithelia. The adenosine/mannitol permeability coefficient ratio (18/1) indicated a minor contribution of paracellular absorption. Adenosine uptake was Na+-dependent and was inhibited by the concentrative nucleoside transporter (CNT) blocker phloridzin but not by the equilibrative nucleoside transporter (ENT) blocker dipyridamole. Apparent Km and Vmax values were 17 microM and 7.2 nmol x min(-1) x cm(-2), and transport selectivity was adenosine = inosine = uridine > guanosine = cytidine > thymidine. CNT3 mRNA was detected throughout the airways, while CNT2 was restricted to nasal epithelia. Inhibition of adenosine elimination by EHNA or phloridzin raised apical adenosine levels by >3-fold and stimulated IL-13 and MCP-1 secretion by 6-fold. These responses were reproduced by the adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA) and blocked by the adenosine receptor antagonist, 8-(p-sulfophenyl) theophylline (8-SPT). This study shows that adenosine elimination on human airway epithelia is mediated by ADA1, CNT2, and CNT3, which constitute important regulators of adenosine-mediated inflammation. PMID:17696452

Hirsh, Andrew J; Stonebraker, Jaclyn R; van Heusden, Catja A; Lazarowski, Eduardo R; Boucher, Richard C; Picher, Maryse



Chronic carbamazepine down-regulates adenosine A 2 receptors: studies with the putative selective adenosine antagonists PD115,199 and PD116,948  

Microsoft Academic Search

Carbamazepine (CBZ), an anticonvulsant with psychotropic and anti-pain properties, has been reported to displace ligands at adenosine binding sites. This paper describes biochemical and behavioural studies in rodents comparing CBZ to the adenosine agonistsl-phenylisopropyl-adenosine (l-PIA) and N-ethylcarboxamido-adenosine (NECA), the new antagonists PD116,948 and PD115,199 which are also relatively A1 and A2 specific respectively, and the mixed antagonists theophylline and caffeine,

M. Elphick; Z. Taghavi; T. Powell; P. P. Godfrey



Pharmacological characterization of adenosine receptors on isolated human bronchi.  


Adenosine induces airways obstruction in subjects with asthma, but the receptor subtype responsible remains unknown. The objectives of this study were to determine the pharmacological profile of adenosine receptor subtypes mediating contraction and to investigate the mechanism in normal and passively sensitized human airway tissues. Contraction of bronchial rings isolated from resected lung tissue of patients with lung carcinoma was measured in response to nonselective adenosine receptor agonists, 5-AMP and 5'-(N-Ethylcarboxamido)adenosine, and A(1) receptor agonist, N(6)-cyclopentyladenosine, in the absence and presence of selective adenosine receptor antagonists. Pharmacological antagonists, chemical ablation of airway sensory nerves using capsaicin, and passive sensitization of tissue with serum from subjects with atopy and asthma was used to investigate the mechanism of contraction. Human bronchial tissue contracted in a concentration-dependent manner to adenosine agonists that showed a rank order of activity of A(1) > A(2B) > A2(A) = A3. The maximum contractile response to N(6)-cyclopentyladenosine (231.0 ± 23.8 mg) was significantly reduced in tissues chemically treated with capsaicin to desensitize sensory nerves (desensitized: 101.6 ± 15.2 mg; P < 0.05). Passive sensitization significantly augmented the contraction induced by adenosine A(1) receptor activation (sensitized: 389.7 ± 52.8 mg versus nonsensitized; P < 0.05), which was linked to the release of leukotrienes, and not histamine (MK571: 25.5 ± 1.7 mg; epinastine 260.0 ± 22.2 mg versus control; P < 0.05). This study provides evidence for a role for adenosine A(1) receptors in eliciting human airway smooth muscle constriction, which, in part, is mediated by the action of capsaicin sensitive sensory nerves. PMID:21700958

Calzetta, Luigino; Spina, Domenico; Cazzola, Mario; Page, Clive P; Facciolo, Francesco; Rendina, Erino A; Matera, Maria G



Inhibition of adenosine kinase by phosphonate and bisphosphonate derivatives  

Microsoft Academic Search

The enzyme adenosine kinase (AK) plays a central role in regulating the intracellular and interstitial concentration of the\\u000a purine nucleoside adenosine (Ado). In view of the beneficial effects of Ado in protecting tissues from ischemia and other\\u000a stresses, there is much interest in developing AK inhibitors, which can regulate Ado concentration in a site- and event-specific\\u000a manner. The catalytic activity

Jae Park; Bhag Singh; Radhey S. Gupta



Adenosine release during seizures attenuates GABAA receptor-mediated depolarization.  


Seizure-induced release of the neuromodulator adenosine is a potent endogenous anticonvulsant mechanism, which limits the extension of seizures and mediates seizure arrest. For this reason several adenosine-based therapies for epilepsy are currently under development. However, it is not known how adenosine modulates GABAergic transmission in the context of seizure activity. This may be particularly relevant as strong activation of GABAergic inputs during epileptiform activity can switch GABA(A) receptor (GABA(A)R) signaling from inhibitory to excitatory, which is a process that plays a significant role in intractable epilepsies. We used gramicidin-perforated patch-clamp recordings to investigate the role of seizure-induced adenosine release in the modulation of postsynaptic GABA(A)R signaling in pyramidal neurons of rat hippocampus. Consistent with previous reports, GABA(A)R responses during seizure activity transiently switched from hyperpolarizing to depolarizing and excitatory. We found that adenosine released during the seizure significantly attenuated the depolarizing GABA(A)R responses and also reduced the extent of the after-discharge phase of the seizure. These effects were mimicked by exogenous adenosine administration and could not be explained by a change in chloride homeostasis mechanisms that set the reversal potential for GABA(A)Rs, or by a change in the conductance of GABA(A)Rs. Rather, A(1)R-dependent activation of potassium channels increased the cell's membrane conductance and thus had a shunting effect on GABA(A)R currents. As depolarizing GABA(A)R signaling has been implicated in seizure initiation and progression, the adenosine-induced attenuation of depolarizing GABA(A)R signaling may represent an important mechanism by which adenosine can limit seizure activity. PMID:22496577

Ilie, Andrei; Raimondo, Joseph V; Akerman, Colin J



Dicinnamoylquinides in roasted coffee inhibit the human adenosine transporter  

Microsoft Academic Search

Preliminary screening of a minor, non-xanthine constituent of roasted coffee, 3,4-diferuloyl-1,5-quinolactone (DIFEQ), showed inhibition of the adenosine transporter at low micromolar concentration. DIFEQ is a neutral derivative of the chlorogenic acids, i.e. isomeric mono- and di-substituted coumaroyl-, caffeoyl-, and feruloyl-esters of quinic acid, formed in the roasting process of coffee. Displacement of the adenosine transporter antagonist [3H](S)-(nitrobenzyl)-6-thioinosine binding by DIFEQ

Tomas de Paulis; Dennis E Schmidt; Aleksandra K Bruchey; Michael T Kirby; Michael P McDonald; Patricia Commers; David M Lovinger; Peter R Martin



[Sleep-wake regulation by prostaglandin D2 and adenosine].  


Prostaglandin (PG) D2 and adenosine are potent endogenous somnogens that accumulate in the brain during prolonged wakefulness. Lipocalin-type PGD synthase (L-PGDS) catalyzes the isomerization of PGH2, a common precursor of various prostanoids, to produce PGD2. L-PGDS is localized in the leptomeninges, choroid plexus, and oligodendrocytes of the central nervous system. PGD2 stimulates DP1 receptors localized in the basal forebrain and increases the local extracellular concentration of adenosine, a paracrine signaling molecule, to promote sleep. Adenosine activates adenosine A2A receptor-expressing neurons in the basal forebrain and ventrolateral preoptic area (VLPO) and inhibits adenosine A1 receptor-possessing arousal neurons. Sleep-promoting neurons in the VLPO send inhibitory signals to suppress the histaminergic neurons in the tuberomammillary nucleus (TMN); the histaminergic neurons contribute to arousal through histamine H1 receptors. GABAergic inhibition of TMN is involved in the induction of non-rapid eye movement (non-REM) sleep by PGD2 and adenosine A2A agonists. The neural network between the VLPO and TMN is considered to play a key role in regulation of vigilance states. Administering an L-PGD inhibitor (SeCl4), DP1 antagonist (ONO-4127Na), or adenosine A2A receptor antagonist (caffeine) suppresses both non-REM and REM sleep, indicating that the PGD2-adenosine system is crucial for maintaining physiological sleep. Selective gene-deletion strategies based on Cre/loxP technology and focal RNA interference have been used for silencing the expression of the A2A receptor by local infection with adeno-associated virus carrying Cre-recombinase or short hairpin RNA. The results of these studies have shown that the A2Asubreceptors in the shell region of the nucleus accumbens are responsible for the effect of caffeine on wakefulness. PMID:22647469

Nagata, Nanae; Urade, Yoshihiro



A 3 Adenosine Receptor: Pharmacology and Role in Disease  

Microsoft Academic Search

\\u000a The study of the A3 adenosine receptor (A3AR) represents a rapidly growing and intense area of research in the adenosine field. The present chapter will provide an\\u000a overview of the expression patterns, molecular pharmacology and functional role of this A3AR subtype under pathophysiological conditions. Through studies utilizing selective A3AR agonists and antagonists, or A3AR knockout mice, it is now clear

P. A. Borea; S. Gessi; S. Bar-Yehuda; P. Fishman


Pharmacology and Molecular Biology of A 3 Adenosine Receptors  

Microsoft Academic Search

\\u000a Adenosine is an important metabolite and a building block for many biologically relevant molecules. Most abundantly, it contributes\\u000a the purine base adenine and a ribose to ATP which as an energy-providing compound occurs in millimolar concentrations in every\\u000a cell. Such high concentrations of ATP are the basis for functionally significant levels of adenosine to occur in all cells\\u000a and in

Karl-Norbert Klotz


Hypoxia-Inducible Factors and Adenosine Signaling in Vascular Growth  

Microsoft Academic Search

\\u000a Low oxygen environment or hypoxia is conducive towards vascular growth and endothelial proliferation. Therefore it is an essential\\u000a element in both disease and development. Hypoxia stabilizes the hypoxia-inducible transcription factors -1? and -2? and also\\u000a increases adenosine levels thereby activating the adenosine receptor signaling pathways. While these pathways have been described\\u000a independently to a greater extent, increasing evidence suggests that

Aftab Ahmad; Carl W. White; Shama Ahmad


Proton transfer in oxidized adenosine self-aggregates.  


The UV-vis and the IR spectra of derivativized adenosine in dichloromethane have been recorded during potentiostatic oxidation at an optically transparent thin layer electrode. Oxidized adenosine shows a broad Zundel like absorption extending from 2800 up to 3600 cm(-1), indicating that a proton transfer process is occurring. Theoretical computations predict that proton transfer is indeed favored in oxidized 1:1 self-association complexes and allow to assign all the observed transient spectroscopic signals. PMID:24116647

Capobianco, Amedeo; Caruso, Tonino; Celentano, Maurizio; La Rocca, Mario Vincenzo; Peluso, Andrea



Proton transfer in oxidized adenosine self-aggregates  

NASA Astrophysics Data System (ADS)

The UV-vis and the IR spectra of derivativized adenosine in dichloromethane have been recorded during potentiostatic oxidation at an optically transparent thin layer electrode. Oxidized adenosine shows a broad Zundel like absorption extending from 2800 up to 3600 cm-1, indicating that a proton transfer process is occurring. Theoretical computations predict that proton transfer is indeed favored in oxidized 1:1 self-association complexes and allow to assign all the observed transient spectroscopic signals.

Capobianco, Amedeo; Caruso, Tonino; Celentano, Maurizio; La Rocca, Mario Vincenzo; Peluso, Andrea



Adenosine as inhibitor of myocardial effects of catecholamines  

Microsoft Academic Search

Infusion of adenosine into the coronary arteries of isolated guinea pig hearts produced a dosedependent inhibition of dP\\/dtmax caused by bolus injections of isoproterenol (4×10-11 moles). Threshold concentration of adenosine was 10-7 M and maximal inhibition (90%) occurred at 10-5 M. Coronary dilation induced by, papaverine did not influence the contractile response to catecholamines. In addition to its influence on

Jürgen Schrader; Gert Baumann; Eckehart Gerlach



Adenosine receptor subtype-selective antagonists in inflammation and hyperalgesia  

Microsoft Academic Search

In this study, we examined the effects of systemic and local administration of the subtype-selective adenosine receptor antagonists\\u000a PSB-36, PSB-1115, MSX-3, and PSB-10 on inflammation and inflammatory hyperalgesia. Pharmacological blockade of adenosine receptor\\u000a subtypes after systemic application of antagonists generally led to a decreased edema formation after formalin injection and,\\u000a with the exception of A3 receptor antagonism, also after the

Andras Bilkei-Gorzo; Osama M. Abo-Salem; Alaa M. Hayallah; Kerstin Michel; Christa E. Müller; Andreas Zimmer



[Adenosine deaminase activity in tuberculous and malignant pleural effusions].  


Measurement of pleural adenosine deaminase activity (ADA) is a useful diagnostic tool for tuberculous pleurisy, but false-positive findings from non-tuberculous effusions have been reported. In order to improve diagnostic value of ADA it is recommended to estimate activity of both ADA1 and ADA2 izoenzymes or 2'-deoxyadenosine/adenosine activity ratio. In order to evaluate ADA as a diagnostic parameter total ADA, with adenosine as a substrate, and 2'-deoxyadenosine/adenosine activity ratio were measured in tuberculous and malignant pleural effusions. Altogether, 26 pleural exudates (11 tuberculous and 15 malignant) were selected. ADA either with adenosine or 2'-deoxyadenosine was determined by colorimetric method of Giusti. Each pleural fluid sample was diluted prior to the assay (1:8) to avoid enzyme inhibition which was observed in nondiluted pleural effusions. The ADA level reached the diagnostic cut-off set for tuberculous effusions (40 U/L) in every 11 tuberculous exudates with the mean value of 85,3+/-47,1 U/L; in 9 of these the 2'-deoxyadenosine/adenosine ratio was less than 0,45. In the malignant group of patients, no one ADA level exceed 40 U/L, being estimated at 10,6+/-7,7 U/L (p<0,001). In 10 of these 15 exudates the 2'-deoxyadenosine/adenosine ratio was undetectable, in four it was less than 0,45 and only in one it was over 0,45. We concluded that ADA measured by the Giusti method proceeded by the dilution 1:8 of the pleural effusion samples very good differentiates tuberculous from malignant pleurisy, without the necessity to determine the 2'-deoxyadenosine/adenosine ratio. The investigation needs to be continued on the more numerous groups of patients. PMID:17175968

Safianowska, Aleksandra; Krenke, Rafa?; Dmowska-Sobstyl, Barbara; Bogacka-Zatorska, Elzbieta; Domaga?a-Kulawik, Joanna; Chazan, Ryszarda



Myocardial perfusion scintigraphy during maximal coronary artery vasodilation with adenosine  

SciTech Connect

Pharmacologic coronary vasodilation as an adjunct to thallium-201 myocardial perfusion scintigraphy provides an important alternative form of stress that has been increasingly used in patients unable to perform an exercise stress test. Although dipyridamole has traditionally been used for this purpose, there are several compelling reasons why adenosine may be a preferable agent. First, dipyridamole acts by blocking the reuptake and transport of adenosine, which is the effective substance responsible for coronary vasodilation. Second, exogenous adenosine has a very short half-life (less than 2 seconds), which explains its very short duration of action as well as the brief, self-limiting duration of its side effects. Third, the adenosine infusion is controllable and may be increased or decreased as desired. Fourth, the coronary vasodilation induced by the doses of adenosine we recommend (140 micrograms/kg/min) may be more profound than that induced by the standard dipyridamole dose. Our experience to date, with nearly 1,000 patients studied, shows the adenosine thallium-201 test to be practical and well tolerated, with high sensitivity (87%) and specificity (94%) for detecting coronary artery disease.

Verani, M.S.; Mahmarian, J.J. (Baylor College of Medicine, Houston, TX (USA))



Detrimental effects of adenosine signaling in sickle cell disease.  


Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A(2B) receptor (A(2B)R)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A(2B)R has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease. PMID:21170046

Zhang, Yujin; Dai, Yingbo; Wen, Jiaming; Zhang, Weiru; Grenz, Almut; Sun, Hong; Tao, Lijian; Lu, Guangxiu; Alexander, Danny C; Milburn, Michael V; Carter-Dawson, Louvenia; Lewis, Dorothy E; Zhang, Wenzheng; Eltzschig, Holger K; Kellems, Rodney E; Blackburn, Michael R; Juneja, Harinder S; Xia, Yang



Adenosine analogues decrease myocardial. beta. -adrenergic receptor affinity for isoproterenol  

SciTech Connect

Adenosine and its analogues have been shown to attenuate catecholamine-induced activation of adenylate cyclase in rat myocardial membranes via adenosine R/sub i/ (inhibitory) receptors. The effects of adenosine analogues on binding characteristics of ..beta..-adrenergic receptors (BAR) in rat heart ventricular membranes were examined in the present study. Neither phenylisopropyladenosine (PIA, nor 2-chloroadenosine (CADO, significantly influenced /sup 125/I-cyanopinodolol (ICYP) binding to membranes as assessed by BAR affinity (Kd, 20 pM) or concentration (B/sub max/, 35 fmol/mg protein). However, in isoproterenol (ISO)-ICYP competition experiments, PIA, an R/sub i/ agonist, significantly shifted the ISO competition curve to the right 3.6 fold. The IC/sub 50/s of control and PIA treated membranes were 5.04 x 10/sup -8/M, and 1.81 X 10/sup -7/M respectively. The slope of the control curve (-0.58) was also increased in the PIA treated membranes (-0.94). CADO, a less specific adenosine R/sub i/ receptor agonist, shifted the curve to the right only 2 fold and increased the slope from -0.5 to -0.75. 2',5'-dideoxyadenosine, an adenosine P-site agonist, had no significant effect on ISO binding. These data suggest that adenosine R/sub i/ agonists may attenuate catecholamine-induced activation of adenylate cyclase by decreasing the affinity of BAR for agonists.

Romano, F.D.; Fenton, R.A.; Dobson, J.G. Jr.



Enzymatic properties of Staphylococcus aureus adenosine synthase (AdsA)  

PubMed Central

Background Staphylococcus aureus is a human pathogen that produces extracellular adenosine to evade clearance by the host immune system, an activity attributed to the 5'-nucleotidase activity of adenosine synthase (AdsA). In mammals, conversion of adenosine triphosphate to adenosine is catalyzed in a two-step process: ecto-nucleoside triphosphate diphosphohydrolases (ecto-NTDPases) hydrolyze ATP and ADP to AMP, whereas 5'-nucleotidases hydrolyze AMP to adenosine. NTPDases harbor apyrase conserved regions (ACRs) that are critical for activity. Results NTPDase ACR motifs are absent in AdsA, yet we report here that recombinant AdsA hydrolyzes ADP and ATP in addition to AMP. Competition assays suggest that hydrolysis occurs following binding of all three substrates at a unique site. Alanine substitution of two amino acids, aspartic acid 127 and histidine 196 within the 5'-nucleotidase signature sequence, leads to reduced AMP or ADP hydrolysis but does not affect the binding of these substrates. Conclusion Collectively, these results provide insight into the unique ability of AdsA to produce adenosine through the consecutive hydrolysis of ATP, ADP and AMP, thereby endowing S. aureus with the ability to modulate host immune responses.



Intracellular ATP Concentration Contributes to the Cytotoxic and Cytoprotective Effects of Adenosine  

PubMed Central

Extracellular adenosine (Ade) interacts with cells by two pathways: by activating cell surface receptors at nanomolar/micromolar concentrations; and by interfering with the homeostasis of the intracellular nucleotide pool at millimolar concentrations. Ade shows both cytotoxic and cytoprotective effects; however, the underlying mechanisms remain unclear. In the present study, the effects of adenosine-mediated ATP on cell viability were investigated. Adenosine treatment was found to be cytoprotective in the low intracellular ATP state, but cytotoxic under the normal ATP state. Adenosine-mediated cytotoxicity and cytoprotection rely on adenosine-derived ATP formation, but not via the adenosine receptor pathway. Ade enhanced proteasome inhibition-induced cell death mediated by ATP generation. These data provide a new pathway by which adenosine exerts dual biological effects on cell viability, suggesting an important role for adenosine as an ATP precursor besides the adenosine receptor pathway.

Guo, Haiping; Liu, Shouting; Huang, Hongbiao; Liu, Ningning; Yang, Changshan; Tang, Ping; Liu, Jinbao



Hot spot mutations in adenosine deaminase deficiency.  

PubMed Central

We have previously characterized mutant adenosine deaminase (ADA; adenosine aminohydrolase, EC enzymes in seven children with partial ADA deficiency. Six children shared common origins, suggesting a common progenitor. However, we found evidence for multiple phenotypically different mutant enzymes. We hypothesized that many of the mutations would be at CpG dinucleotides, hot spots at which spontaneous deamination of 5-methylcytosine results in C to T or G to A transitions. Digestion of DNA from these children with Msp I and Taq I, enzymes recognizing CpG dinucleotides, identified three different mutations, each correlating with expression of a different mutant enzyme. Sequencing of cDNA clones and genomic DNA amplified by polymerase chain reaction confirmed the presence of C to T or G to A transitions at CpG dinucleotides (C226 to T, G446 to A, and C821 to T, resulting in Arg76 to Trp, Arg149 to Gln, and Pro274 to Leu). A "null" mutation, also found in two ADA-deficient severe combined immunodeficient children, was serendipitously detected as gain of a site for Msp I. Simultaneous loss of a site for Bal I defined the precise base substitution (T320 to C, Leu107 to Pro), confirmed by sequence analysis. To determine the true frequency of hot spot mutation in these children, consecutively ascertained through a newborn screening program, we sequenced cDNA from the remaining alleles. Two others were hot spot mutations (C631 to T and G643 to A, resulting in Arg211 to Cys and Ala215 to Thr), each again resulting in expression of a phenotypically different mutant enzyme. Only one additional mutation (previously identified by us) is not in a hot spot. These seven mutations account for all 14 chromosomes in these children. There is thus a very high frequency of hot spot mutations in partial ADA deficiency. Most of these children carry two different mutant alleles. We were able to correlate genotype and phenotype and to dissect the activity of individual mutant alleles. Images

Hirschhorn, R; Tzall, S; Ellenbogen, A



Dietary intake of chromium, copper, zinc, iron, manganese, calcium and magnesium: Duplicate plate technique - Measured and derived  

SciTech Connect

Duplicate plate technique is currently the most reliable method to measure dietary intake of nutrients. However, there is no control for alterations in the diet, conscious or subconscious, due to the collection process. Duplicate diet samples were collected by 19 adult subjects, 11 females (F) and 8 males (M), while consuming freely-chosen diets. Subjects were then placed on a controlled diet to determine actual caloric requirement. Most subjects consumed fewer calories during the freely-chosen diet collection day than their actual caloric requirement. The ratio of the determined caloric intake to the calories measured in the duplicate plate sample varied from 0.90 to 2.2. The data demonstrate that derived nutrient intake may be a better measurement of actual intake than duplicate technique alone.

Anderson, R.A.; Bryden, N.A.; Polansky, M.M. (Dept. of Agriculture, Beltsville, MD (United States))



Electrothermal behavior of sodium, potassium, calcium and magnesium in a tungsten coil atomizer and review of interfering effects  

NASA Astrophysics Data System (ADS)

The electrothermal behavior of Na, K, Ca and Mg in a 150-W tungsten coil atomizer was investigated in order to gather information about the atomization processes and the underlying factors responsible for chemical interferences of them on atomization of Al, Ba, Cd, Co, Cr, Pb and Yb. The interference effects were discussed considering the thermal stability of the species that could be formed in the condensed phase, the effect of protective gas composition in the atomization process and the pyrolysis temperature curves. Ca is the most serious interferent due to its high thermal stability (up to 1600°C) and to the possibility of double oxides formation. As hydrogen is decisive for the atomization of Na, K, Ca and Mg, some interference processes caused by these elements seem to be related to the competition towards hydrogen present in the protective gas composition. The knowledge of the correct temperature of the tungsten coil surface shows that most strategies for overcoming interferences based on chemical modifiers will fail for Cd and Pb, because tungsten acts as a natural permanent chemical modifier. It seems that in many applications previous separation and masking will be necessary.

Queiroz, Zilvanir F.; Krug, Francisco J.; Oliveira, Pedro V.; Silva, Márcia M.; Nóbrega, Joaquim A.



Dietary inulin intake and age can significantly affect intestinal absorption of calcium and magnesium in rats: a stable isotope approach  

PubMed Central

Background previous studies have shown that non-digestible inulin-type fructan intake can increase intestinal mineral absorption in both humans and animals. However, this stimulatory effect on intestinal absorption may depend on experimental conditions such as duration of fermentable fiber intake, mineral diet levels and animals' physiological status, in particular their age. Objectives the aim of this study was to determine the effect of inulin intake on Ca and Mg absorption in rats at different age stages. Methods eighty male Wistar rats of four different ages (2, 5, 10 and 20 months) were randomized into either a control group or a group receiving 3.75% inulin in their diet for 4 days and then 7.5% inulin for three weeks. The animals were fed fresh food and water ad libitum for the duration of the experiment. Intestinal absorption of Ca and Mg was determined by fecal monitoring using stable isotopic tracers. Ca and Mg status was also assessed. Results absorption of Ca and Mg was significantly lower in the aged rats (10 and 20 mo) than in the young and adult rat groups. As expected, inulin intake increased Ca and Mg absorption in all four rat groups. However, inulin had a numerically greater effect on Ca absorption in aged rats than in younger rats whereas its effect on Mg absorption remained similar across all four rat age groups. Conclusion the extent of the stimulatory effect of inulin on absorption of Ca may differ according to animal ages. Further studies are required to explore this effect over longer inulin intake periods, and to confirm these results in humans.

Coudray, Charles; Rambeau, Mathieu; Feillet-Coudray, Christine; Tressol, Jean Claude; Demigne, Christian; Gueux, Elyett; Mazur, Andrzej; Rayssiguier, Yves



Effect of titanium surface calcium and magnesium on adhesive activity of epithelial-like cells and fibroblasts.  


In the present study, we investigated the hydrothermal treatment of titanium with divalent cation solutions and its effect in promoting the adhesion of gingival epithelial cells and fibroblasts in vitro. Gingival keratinocyte-like Sa3 cells or fibroblastic NIH3T3 cells were cultured for 1 h on experimental titanium plates hydrothermally-treated with CaCl(2) (Ca) or MgCl(2) (Mg) solution, or distilled water (DW). The number and adhesive strengths of attached cells on the substrata were then analyzed. The number of Sa3 cells adhering to the Ca- and Mg-treated plates was significantly larger than in the DW group, but the strength of this adhesion did not differ significantly between groups. In contrast, NIH3T3 cell adhesion number and strength were increased in both the Ca and Mg groups compared to the DW group. Fluorescent microscopic observation indicated that, in all groups, Sa3 had identical expression levels of integrin ?4 and development of actin filaments, whereas NIH3T3 cells in the Ca and Mg groups displayed much stronger punctate cytoplasmic signals for vinculin and more bundle-shaped actin filaments than cells in the DW group. As a result, it was indicated that the hydrothermal treatment of titanium with Ca or Mg solution improved the integration of soft tissue cells with the substrata, which may facilitate the development of a soft tissue barrier around the implant. PMID:22589070

Okawachi, Hideyuki; Ayukawa, Yasunori; Atsuta, Ikiru; Furuhashi, Akihiro; Sakaguchi, Mami; Yamane, Koichi; Koyano, Kiyoshi



Extracellular Calcium and Magnesium, but Not Iron, Are Needed for Optimal Growth of Blastomyces dermatitidis Yeast Form Cells In Vitro  

PubMed Central

In the present study, we demonstrate that the yeast form of Blastomyces dermatitidis can proliferate for short periods of time in the absence of ferric iron but not in the absence of calcium or magnesium. The results of this study shed light on the resistance of B. dermatitidis to chelating agents, such as deferoxamine, and may explain how B. dermatitidis resists the iron-binding activity of serum transferrin.

Giles, Steven S.; Czuprynski, Charles J.



Fractionation of calcium and magnesium in honeys, juices and tea infusions by ion exchange and flame atomic absorption spectrometry.  


An analytical procedure was proposed to study the operational fractionation of Ca and Mg in bee honeys, fruit juices and tea infusions. The protocol devised was based on the solid phase extraction of distinct metal fractions on different sorbents, namely strong acidic cation exchanger Dowex 50W x 4, weak acidic cation exchanger Diaion WT01S and strong basic anion exchange resin Dowex 1 x 4. For the evaluation of the amounts of the metal fractions distinguished, a flame atomic absorption spectrometry was used off-line prior to the determination of Ca and Mg concentrations in the effluents obtained. It was established that Ca and Mg are mostly present in the analysed samples in the form of cationic species (96-100%). The accuracy of the entire fractionation scheme and sample preparation procedures involved was verified by the performance of the recovery tests. PMID:18970707

Pohl, P; Prusisz, B



Comparing the Effects of Sodium and Potassium Diet with Calcium and Magnesium Diet on Sex Ratio of Rats` Offspring  

Microsoft Academic Search

Sex determination has scientific basis for prevention of genetic sex linked diseases in addition to social backgrounds. There are many methods for sex determination. This study was designed to investigate the effects of adding different ions to the drinking water of rats on determination of rats' offspring sexes. In total, 72 female Vistar rats were chosen and randomly divided into



Novel sensors for potassium, calcium and magnesium ions based on a silicon transducer as a light-addressable potentiometric sensor  

Microsoft Academic Search

Potentiometric cation sensors using a silicon transducer, light-addressable potentiometric sensor (LAPS) and ion-recognition elements are described, and their performance are discussed. In the silicon transducer, an Al2O3 layer was used as an insulating layer. On the surface of the Al2O3 layer, ion-recognition element such as valinomycin, 18-crown-6 ether, bis[di(n-octylphenyl)phosphato]calcium(II) and ETH1117 were immobilized in the matrix of poly(vinyl chloride) film.

Atsushi Seki; Kentaro Motoya; Sinya Watanabe; Izumi Kubo



Calcium and Magnesium: Low Passive Permeability and Tubular Secretion in the Mouse Medullary Thick Ascending Limb of Henle's Loop (MTAL)  

Microsoft Academic Search

.   Recent studies from our laboratory have shown that in the mouse and rat nephron Ca2+ and Mg2+ are not reabsorbed in the medullary part of the thick ascending limb (mTAL) of Henle's loop. The aim of the present study\\u000a was to investigate whether the absence of transepithelial Ca2+ and Mg2+ transport in the mouse mTAL is due to its

M. Wittner; E. Desfleurs; S. Pajaud; G. Moine; C. de Rouffignac; A. Di Stefano



Thermodynamics of the conversion of calcium and magnesium fluorides to the parent metal oxides and hydrogen fluoride  

SciTech Connect

The authors have used thermodynamic modeling to examine the reaction of calcium fluoride (CaF{sub 2}) and magnesium fluoride (MgF{sub 2}) with water (H{sub 2}O) at elevated temperatures. The calculated, equilibrium composition corresponds to the global free-energy minimum for the system. Optimum, predicted reaction temperatures and reactant mole ratios are reported for the recovery of hydrogen fluoride (HF), a valuable industrial feedstock. Complete conversion of MgF{sub 2} is found at 1,000 C and a ratio of 40 moles of H{sub 2}O per 1 mole of MgF{sub 2}. For CaF{sub 2}, temperatures as high as 1,400 C are required for complete conversion at a corresponding mole ratio of 40 moles of H{sub 2}O per 1 mole of CaF{sub 2}. The authors discuss the presence of minor chemical constituents as well as the stability of various potential container materials for the pyrohydrolysis reactions at elevated temperatures. CaF{sub 2} and MgF{sub 2} slags are available as wastes at former uranium production facilities within the Department of Energy Complex and other facilities regulated by the Nuclear Regulatory Commission. Recovery of HF from these wastes is an example of environmental remediation at such facilities.

West, M.H.; Axler, K.M.



Effects of calcium and magnesium hardness on the fertilization and hatching success of channel X blue hybrid catfish eggs  

Technology Transfer Automated Retrieval System (TEKTRAN)

The aquifer used for hybrid catfish hatcheries is less than 10 mg/L of calcium hardness and 1- 25 mg/L of magnesium hardness. Embryonic development is deemed to be the most sensitive stage in the life cycle of a teleost. As egg development takes outside the fish’s body, water hardness is one abioti...


Ion antagonism between calcium and magnesium in phytochrome-mediated degradation of storage starch in Spirodela polyrhiza  

Microsoft Academic Search

Light and calcium regulation were studied in two processes running parallel in turions of Spirodela polyrhiza (L.) Schleiden: in germination and starch degradation. When germination of turions is induced by a single red light (R) pulse the response depends on exogenously applied Ca2+. This Ca2+ dependence is absent in continuous and intermittent R (hourly applied short R pulses that can

K.-J. Appenroth; Halina Gabrys



Estimation of calcified tissues hardness via calcium and magnesium ionic to atomic line intensity ratio in laser induced breakdown spectra  

NASA Astrophysics Data System (ADS)

Calcified tissues representing three different matrices, namely enamel of human teeth, shells and eggshell, have been studied via Laser Induced Breakdown Spectroscopy (LIBS) technique. The experimental CaII/CaI and MgII/MgI ratios have been measured, in view of the expected correlation between the extent of ionization caused by the laser induced shock wave (SW) and the hardness of the target. The ratio CaII/CaI between the ionic calcium line at 373.69 nm and the neutral line at 428.9 nm is obtained for enamel, shells and eggshell spectra, as well as the ratio MgII/MgI between the ionic magnesium line at 280.26 nm and the neutral line at 285.22 nm. The results show that such spectral lines intensities ratio differs for different matrices and is indeed related to the target materials hardness. It is also found that the MgII/MgI ratio is preferable as an indicator of hardness since these lines are less affected by self absorption. The SW front speed has been measured in the three cases and the obtained values confirm the proportionality to the target hardness. The results here obtained suggest the feasibility of the quantitative estimation of hardness for any other calcified tissues.

Abdel-Salam, Z. A.; Galmed, A. H.; Tognoni, E.; Harith, M. A.



Removal of hardness agents, calcium and magnesium, by natural and alkaline modified pumice stones in single and binary systems  

NASA Astrophysics Data System (ADS)

Natural and alkaline modified pumice stones were used for the adsorption of water hardening cations, Ca2+ and Mg2+. The adsorbents were characterized using XRF, XRD, SEM and FTIR instrumental techniques. At equilibrium time and for 150 mg/L of a given cation, removal efficiencies were 83% and 94% for calcium and 48% and 73% for magnesium for raw and modified pumices, respectively. The optimal pH for raw and modified pumices were found to be 6.0, leading to the removal of 79 and 96% of calcium and 51 and 93% of magnesium by 10 g/L of raw and modified pumice adsorbents, respectively. Maximum adsorption capacities were 57.27 and 62.34 mg/g for Ca2+ and 44.53 and 56.11 mg/g for Mg2+ on the raw and modified pumices, respectively. Ca2+ and Mg2+ adsorption capacities of the pumice adsorbents decreased in the presence of competing cations. Less than 300 min were needed to achieve 99 and 92% desorption of the adsorbed Ca2+ and 100 and 89% of the adsorbed Mg2+ from the natural and modified pumices, respectively. After treating synthetic water solution simulating an actual water stream with the alkali-modified pumice, total hardness of the treated sample met the required standard for drinking water, namely below 300 mg/L of CaCO3 (297.5 mg/L). The studied pumice adsorbents, and especially the treated pumice, can be therefore considered as promising low cost adsorbents, suitable for the removal of hardness ions from drinking water.

Sepehr, Mohammad Noori; Zarrabi, Mansur; Kazemian, Hossein; Amrane, Abdeltif; Yaghmaian, Kamiar; Ghaffari, Hamid Reza



Effects of two fermentable carbohydrates (inulin and resistant starch) and their combination on calcium and magnesium balance in rats.  


Resistant starch and inulin are complex carbohydrates that are fermented by the microflora and known to increase colonic absorption of minerals in animals. The fermentation of these substrates in the large bowel to short-chain fatty acids is the main reason for this increase in mineral absorption. The purpose of the present study was to examine the potential synergistic effect of a combination of these two fermentable carbohydrates. For this purpose, thirty-two adult male Wistar rats weighing 200 g were used in the present study. The rats were distributed into four groups, and fed for 21 d a fibre-free basal purified diet or diet containing 100 g inulin, or 150 g resistant starch (raw potato starch)/kg diet or a blend of 50 g inulin and 75 g resistant starch/kg diet. After an adaptation period of 14 d, the rats were then transferred to metabolic cages and dietary intake, faeces and urine were monitored for 5 d. The animals were then anaesthetized and caecal Ca and Mg absorption were measured. Finally, the rats were killed and blood, caecum and tissues were sampled. Ca and Mg levels were assessed in diets, faeces, urine, caecum and plasma by atomic absorption spectrometry. Our results confirmed that inulin and resistant starch ingestion led to considerable caecal fermentation in the three experimental groups compared with the control group diet. Moreover, both carbohydrates significantly increased the intestinal absorption and balance of Ca and Mg, without altering the plasma level of these two minerals. Interestingly, the combination of the studied carbohydrates increased significantly the caecal soluble Ca and Mg concentrations, the apparent intestinal absorption and balance of Ca, and non-significantly the plasma Mg level. In conclusion, a combination of different carbohydrates showed synergistic effects on intestinal Ca absorption and balance in rats. Further studies with other types of carbohydrate combinations should be carried out to extend these findings. PMID:11591235

Younes, H; Coudray, C; Bellanger, J; Demigné, C; Rayssiguier, Y; Rémésy, C



Acidic fermentation in the caecum increases absorption of calcium and magnesium in the large intestine of the rat.  


The effect of fermentation on colonic absorption of Ca and Mg was investigated in 8-week-old rats adapted to diets containing either digestible wheat starch (DS diets) or including resistant starch, i.e. 350 g raw potato starch/kg (RS diets). The dietary Ca level of the DS and RS diets was 2.5 or 7.5 g/kg. RS diets resulted in enlargements of the caecum together with hypertrophy of the caecal wall. Acidification of the caecal contents by microbial fermentation of RS was influenced by the dietary Ca level. Very acidic pH conditions and relatively low concentrations of short-chain fatty acids, in the presence of lactic acid fermentation, were observed with the 2.5 g Ca/kg level. Rats fed on RS diets had a higher percentage of soluble Ca (and inorganic phosphate) in the caecum, particularly of rats adapted to the high Ca level. As a result of the hypertrophy of the caecal wall and of an elevated concentration of soluble Ca, the caecal absorption of Ca was 5-6-fold higher in the RS groups than in the DS groups. The difference between dietary intake and faecal excretion (DI-FE) of Ca was higher in rats fed on RS diets than in those fed on DS diets, when the dietary Ca level was 2.5 g/kg. With the higher Ca intake the elevated rate of Ca absorption from the caecum in RS-fed rats was not paralleled by an enhanced DI-EE difference: this suggests a shift of the Ca absorption towards the large intestine. Feeding RS diets also enhanced Mg caecal absorption, resulting in a substantially higher DI-FE difference for Mg, especially with the 2.5 g Ca/kg diets, because a high Ca intake tends to inhibit Mg absorption. The present findings support the view that the large intestine may represent a major site of Ca (and Mg) absorption when acidic fermentations take place. This process could improve the digestive Ca balance when the dietary Ca supply is low; when the Ca supply is affluent, it rather shifts Ca absorption towards a more distal site of the digestive tract. PMID:8785206

Younes, H; Demigné, C; Rémésy, C



Calcium and magnesium isotope systematics in rivers draining the Himalaya-Tibetan-Plateau region: Lithological or fractionation control?  

NASA Astrophysics Data System (ADS)

In rivers draining the Himalaya-Tibetan-Plateau region, the 26Mg/ 24Mg ratio has a range of 2‰ and the 44Ca/ 42Ca ratio has a range of 0.6‰. The average ?26Mg values of tributaries from each of the main lithotectonic units (Tethyan Sedimentary Series (TSS), High Himalayan Crystalline Series (HHCS) and Lesser Himalayan Series (LHS)) are within 2 standard deviation analytical uncertainty (0.14‰). The consistency of average riverine ?26Mg values is in contrast to the main rock types (limestone, dolostone and silicate) which range in their average ?26Mg values by more than 2‰. Tributaries draining the dolostones of the LHS differ in their ?44Ca values compared to tributaries from the TSS and HHCS. The chemistry of these river waters is strongly influenced by dolostone (solute Mg/Ca close to unity) and both ?26Mg (-1.31‰) and ?44Ca (0.64‰) values are within analytical uncertainty of the LHS dolostone. These are the most elevated ?44Ca values in rivers and rock reported so far demonstrating that both riverine and bedrock ?44Ca values may show greater variability than previously thought. Although rivers draining TSS limestone have the lowest ?26Mgand?44Ca values at -1.41 and 0.42‰, respectively, both are offset to higher values compared to bedrock TSS limestone. The average ?26Mg value of rivers draining mainly silicate rock of the HHCS is -1.25‰, lower by 0.63‰ than the average silicate rock. These differences are consistent with a fractionation of ?26Mg values during silicate weathering. Given that the proportion of Mg exported from the Himalaya as solute Mg is small, the difference in 26Mg/ 24Mg ratios between silicate rock and solute Mg reflects the 26Mg/ 24Mg isotopic fractionation factor ( ?silicate-dissolvedMg) between silicate and dissolved Mg during incongruent silicate weathering. The value of ?silicate-dissolvedMg of 0.99937 implies that in the TSS, solute Mg is primarily derived from silicate weathering, whereas the source of Ca is overwhelmingly derived from carbonate weathering. The average ?44Ca value in HHCS rivers is within uncertainty of silicate rock at 0.39‰. The widespread hot springs of the High Himalaya have an average ?26Mg value of -0.46‰ and an average ?44Ca value of 0.5‰, distinct from riverine values for ?26Mg but similar to riverine ?44Ca values. Although rivers draining each major rock type have ?44Ca and ?26Mg values in part inherited from bedrock, there is no correlation with proxies for carbonate or silicate lithology such as Na/Ca ratios, suggesting that Ca and Mg are in part recycled. However, in spite of the vast contrast in vegetation density between the arid Tibetan Plateau and the tropical Lesser Himalaya, the isotopic fractionation factor for Ca and Mg between solute and rocks are not systematically different suggesting that vegetation may only recycle a small amount of Ca and Mg in these catchments. The discrepancy between solute and solid Ca and Mg isotope ratios in these rivers from diverse weathering environments highlight our lack of understanding concerning the origin and subsequent path of Ca and Mg, bound as minerals in rock, and released as cations in rivers. The fractionation of Ca and Mg isotope ratios may prove useful for tracing mechanisms of chemical alteration. Ca isotope ratios of solute riverine Ca show a greater variability than previously acknowledged. The variability of Ca isotope ratios in modern rivers will need to be better quantified and accounted for in future models of global Ca cycling, if past variations in oceanic Ca isotope ratios are to be of use in constraining the past carbon cycle.

Tipper, Edward T.; Galy, Albert; Bickle, Mike J.



Inhibition of calcium and magnesium-containing scale by a new antiscalant polymer in laboratory tests and a field trial  

Microsoft Academic Search

Membrane scaling is caused by the deposition of unsoluble salts as feedwater converted to brine, affectting the operation of seawater RO plants. Membrane scaling at the Dalian RO desalination plant was analyzed using Dalian seawater. Based on the characteristics of Dalian seawater, a new environmentally friendly, biodegradable antiscalant PAP-1 was synthesized in the laboratory. The performance of PAP-1 to inhibit

Hai-Yan Li; Wei Ma; Lu Wang; Ru Liu; Lin-Sen Wei; Qiang Wang



Individual effects of sodium, potassium, calcium, and magnesium chloride salts on Lactobacillus pentosus and Saccharomyces cerevisiae growth.  


A quantitative investigation on the individual effects of sodium (NaCl), potassium (KCl), calcium (CaCl2), and magnesium (MgCl2) chloride salts against Lactobacillus pentosus and Saccharomyces cerevisiae, two representative microorganisms of table olives and other fermented vegetables, was carried out. In order to assess their potential activities, both the kinetic growth parameters and dose-response profiles in synthetic media (deMan Rogosa Sharpe broth medium and yeast-malt-peptone-glucose broth medium, respectively) were obtained and analyzed. Microbial growth was monitored via optical density measurements as a function of contact time in the presence of progressive chloride salt concentrations. Relative maximum specific growth rate and lag-phase period were modeled as a function of the chloride salt concentrations. Moreover, for each salt and microorganism tested, the noninhibitory concentrations and the MICs were estimated and compared. All chloride salts exerted a significant antimicrobial effect on the growth cycle; particularly, CaCl2 showed a similar effect to NaCl, while KCl and MgCl2 were progressively less inhibitory. Microbial susceptibility and resistance were found to be nonlinearly dose related. PMID:18680941

Bautista-Gallego, J; Arroyo-López, F N; Durán-Quintana, M C; Garrido-Fernandez, A



Serum Zinc, Copper, Selenium, Calcium, and Magnesium Levels in Pregnant and Non-Pregnant Women in Gondar, Northwest Ethiopia  

Microsoft Academic Search

Pregnant women in developing countries are vulnerable to multiple micronutrient deficiencies. Studies assessing serum levels\\u000a of the micronutrients and magnitude of their deficiencies are very scarce in African subjects. This study was aimed at determining\\u000a serum levels of micronutrients in 375 pregnant (42 HIV seropositive) and 76 non-pregnant women (20 HIV seropositive) who visited\\u000a the University of Gondar Hospital, Gondar,

Afework Kassu; Tomoki Yabutani; Andargachew Mulu; Belay Tessema; Fusao Ota



Influence of Salt Stress on the Nutritional State of Cordyline fruticosa var. Red Edge, 2: Sodium, Potassium, Calcium, and Magnesium  

Microsoft Academic Search

The aim of this trial was to study the nutritional behavior generated by modifications in the salt concentration in the nutrient solution used for the fertigation of Cordyline fruticosa var. Red Edge plants. Four treatments were tested: T1 [control, 1.5 dS m, 14.3 mmol L sodium chloride (NaCl)]; T2 (2.5 dS m, 22.2 mmol L NaCl); T3 (3.5 dS m,

B. M. Plaza; S. Jiménez; M. T. Lao



A3 adenosine receptor signaling contributes to airway inflammation and mucus production in adenosine deaminase-deficient mice.  


Adenosine signaling has been implicated in chronic lung diseases such as asthma and chronic obstructive pulmonary disease; however, the specific roles of the various adenosine receptors in processes central to these disorders are not well understood. In this study, we have investigated the role(s) of the A(3) adenosine receptor in adenosine-dependent pulmonary inflammation observed in adenosine deaminase (ADA)-deficient mice. The A(3) receptor (A(3)R) was found to be expressed in eosinophils and mucus-producing cells in the airways of ADA-deficient mice. Treatment of ADA-deficient mice with MRS 1523, a selective A(3)R antagonist, prevented airway eosinophilia and mucus production. Similar findings were seen in the lungs of ADA/A(3) double knockout mice. Although eosinophils were decreased in the airways of ADA-deficient mice following antagonism or removal of the A(3)R, elevations in circulating and lung interstitial eosinophils persisted, suggesting signaling through the A(3)R is needed for the migration of eosinophils into the airways. These findings identify an important role for the A(3)R in regulating lung eosinophilia and mucus production in an environment of elevated adenosine. PMID:15240734

Young, Hays W J; Molina, Jose G; Dimina, Dawn; Zhong, Hongyan; Jacobson, Marlene; Chan, Lee-Nien L; Chan, Teh-Sheng; Lee, James J; Blackburn, Michael R



Biochemical characterization of putative central purinergic receptors by using 2-chloro[3H]adenosine, a stable analog of adenosine.  

PubMed Central

After pretreatment of rat brain synaptic membranes with adenosine deaminase to remove endogenous adenosine, 2-chloro[3H]adenosine, a stable analog of adenosine, binds to two sites with Kd values of 1.3 and 16 nM and corresponding Bmax values of 207 and 380 fmol/mg of protein. Binding is reversible, and the highest density of sites occurs in enriched synaptosomal fractions. In peripheral tissue, negligible binding is observed in heart, kidney, and liver, while testicle has 11 fmol of binding sites/mg of protein. In brain, caudate and hippocampus have the highest density of sites, and spinal cord and hypothalamus have the lowest. This high-affinity binding is stereospecific; the L diasteromer of N6-phenylisopropyladenosine is approximately 30-times more potent as a displacer of 2-chloro[3H]adenosine than the D isomer and is also sensitive to theophylline (IC50 = 8.8 microM) and other purine-related compounds. Several putative neurotransmitters, neurotransmitter antagonists, and other centrally active compounds have no effect on binding. The data are consistent with the hypothesis that 2-chloro[3H]adenosine is binding to central purinergic receptors.

Williams, M; Risley, E A



Hot spot mutations in adenosine deaminase deficiency  

SciTech Connect

The authors have previously characterized mutant adenosine deaminase enzymes in seven children with partial ADA deficiency. Six children shared common origins, suggesting a common progenitor. However, they found evidence for multiple phenotypically different mutant enzymes. They hypothesized that many of the mutations would be at CpG dinucleotides, hot spots at which spontaneous deamination of 5-methylcytosine results in C to T or G to A transitions. Digestion of DNA from these children with Msp I and Taq I, enzymes recognizing CpG dinucleotides, identified three different mutations, each correlating with expression of a different mutant enzyme. Sequencing of cDNA clones and genomic DNA amplified by polymerase chain reaction confirmed the presence of C to T or G to A transitions at CpG dinucleotides. To determine the true frequency of hot spot mutation in these children, consecutively ascertained through a newborn screening program, they sequenced cDNA from the remaining alleles. Two others were hot spot mutations each again resulting in expression of a phenotypically different mutant enzyme. These seven mutations account for all 14 chromosomes in these children. There is thus a very high frequency of hot spot mutations in partial ADA deficiency. They were able to correlate genotype and phenotype and to dissect the activity of individual mutant alleles.

Hirschhorn, R.; Tzall, S.; Ellenbogen, A. (New York Univ. Medical School, NY (USA))



Detecting adenosine triphosphate in the pericellular space.  


Release of adenosine triphosphate (ATP) into the extracellular space occurs in response to a multiplicity of physiological and pathological stimuli in virtually all cells and tissues. A role for extracellular ATP has been identified in processes as different as neurotransmission, endocrine and exocrine secretion, smooth muscle contraction, bone metabolism, cell proliferation, immunity and inflammation. However, ATP measurement in the extracellular space has proved a daunting task until recently. To tackle this challenge, some years ago, we designed and engineered a novel luciferase probe targeted to and expressed on the outer aspect of the plasma membrane. This novel probe was constructed by appending to firefly luciferase the N-terminal leader sequence and the C-terminal glycophosphatidylinositol anchor of the folate receptor. This chimeric protein, named plasma membrane luciferase, is targeted and localized to the outer side of the plasma membrane. With this probe, we have generated stably transfected HEK293 cell clones that act as an in vitro and in vivo sensor of the extracellular ATP concentration in several disease conditions, such as experimentally induced tumours and inflammation. PMID:23853707

Falzoni, Simonetta; Donvito, Giovanna; Di Virgilio, Francesco



Adenosine deaminase from Streptomyces coelicolor: recombinant expression, purification and characterization.  


The sequencing of the genome of Streptomyces coelicolor A3(2) identified seven putative adenine/adenosine deaminases and adenosine deaminase-like proteins, none of which have been biochemically characterized. This report describes recombinant expression, purification and characterization of SCO4901 which had been annotated in data bases as a putative adenosine deaminase. The purified putative adenosine deaminase gives a subunit Mr=48,400 on denaturing gel electrophoresis and an oligomer molecular weight of approximately 182,000 by comparative gel filtration. These values are consistent with the active enzyme being composed of four subunits with identical molecular weights. The turnover rate of adenosine is 11.5 s?ą at 30 °C. Since adenine is deaminated ?10ł slower by the enzyme when compared to that of adenosine, these data strongly show that the purified enzyme is an adenosine deaminase (ADA) and not an adenine deaminase (ADE). Other adenine nucleosides/nucleotides, including 9-?-D-arabinofuranosyl-adenine (ara-A), 5'-AMP, 5'-ADP and 5'-ATP, are not substrates for the enzyme. Coformycin and 2'-deoxycoformycin are potent competitive inhibitors of the enzyme with inhibition constants of 0.25 and 3.4 nM, respectively. Amino acid sequence alignment of ScADA with ADAs from other organisms reveals that eight of the nine highly conserved catalytic site residues in other ADAs are also conserved in ScADA. The only non-conserved residue is Asn317, which replaces Asp296 in the murine enzyme. Based on these data, it is suggested here that ADA and ADE proteins are divergently related enzymes that have evolved from a common ?/? barrel scaffold to catalyze the deamination of different substrates, using a similar catalytic mechanism. PMID:21511036

Pornbanlualap, Somchai; Chalopagorn, Pornchanok



Intravenous adenosine activates diffuse nociceptive inhibitory controls in humans.  


Experimentally induced pain can be attenuated by concomitant heterotopic nociceptive stimuli (counterirritation). Animal data indicate that this stems from supraspinal "diffuse noxious inhibitory controls" (DNICs) triggered by C and A? fibers. In humans, only noxious stimuli induce counterirritation. This points at C fibers, but the effects of pharmacologically stimulating C fibers have not been studied. Intravenous adenosine activates pulmonary C fibers and induces dyspnea. This study tests the hypothesis that putative activation of pulmonary C fibers by adenosine would trigger DNICs in humans and induce counterirritation. Twelve healthy volunteers were included (with valid results available in 9) and studied according to a double-blind, randomized, cross-over design (intravenous adenosine, 140 ?g·kg(-1)·min(-1), during 5 min vs. placebo). We measured ventilatory variables and end-tidal CO2 tension, dyspnea intensity by visual analog scale, and the intensity of putative chest pain. The primary outcome was the amplitude of the RIII component of the nociceptive flexor reflex recorded by biceps femoris electromyogram in response to painful electrical sural nerve stimulation (RIII), taken as a substitute for pain perception. Placebo did not induce any significant effect. Adenosine induced dyspnea, hyperpnea, tachycardia, and significant RIII inhibition (24 ± 8% at the 4th min, P < 0.0001). The temporal dynamics of adenosine-induced dyspnea and RIII inhibition differed (immediate onset followed by a slow decrease for dyspnea, slower onset for RIII inhibition). Intravenous adenosine in normal humans induces counterirritation, fueling the notion that C-fiber stimulation trigger DNICs in humans. The temporal dissociation between adenosine-induced dyspnea and RIII inhibition suggests that C fibers other than pulmonary ones might be involved. PMID:23869063

Morélot-Panzini, Capucine; Corvol, Jean-Christophe; Demoule, Alexandre; Raux, Mathieu; Fiamma, Marie-Noëlle; Willer, Jean-Claude; Similowski, Thomas



Auto-anti-idiotypic approach to adenosine receptors  

SciTech Connect

If an antibody (Abl) binds to and recognizes the same epitopes on a ligand that are recognized by a receptor, then among anti-idiotypic antibodies (Ab2) to Ab1, there may be some that have combining sites that mimic the ligand (internal image). In the case of the acetylcholine receptor and the glucocorticoid receptor these Ab2 antibodies could be raised through a naturally occurring idiotypic network by immunizing mice with the ligands of the receptors. To test the generality of this procedure and to raise antibodies to adenosine receptors, BALB/c mice were immunized with adenosine 6-aminocaproyl-BSA. Hyberidoma cell lines were raised. Cell lines which secreted antibodies that bound to rabbit anti-adenosine antibody were obtained. Two such mAbs, AA18 and AA21, inhibited the binding of (/sup 3/H)adenosine to rabbit anti-adenosine antibody. Furthermore, they bound to rat cerebral cortical membrane and binding could be inhibited by L-phenylisopropyladenosine (L-PIA), an adenosine receptor agonist. Rat cerebral membrane proteins were solubilized with 1% cholic acid, and analyzed by SDS-PAGE and Western blotting. Both AA18 and AA21 recognized a 62 kD band under non-reducing conditions, and 52 kD and 36 kD bands under reducing conditions. The 36 kD band is consistent with the A1 adenosine receptor binding subunit reported by Stiles, et al. The authors results extend the utility of the autoimmune approach for raising antibody to receptors without the necessity of using isolated receptor as immunogen.

Ku, H.H.; Erlanger, B.F.



Functional characterization of adenosine A2 receptors in Jurkat cells and PC12 cells using adenosine receptor agonists.  


The effect of several adenosine analogues on cyclic AMP accumulation was examined in the rat phaeochromocytoma cell PC12 and in the human T-cell leukaemia cell Jurkat, selected as prototypes of cells predominantly expressing adenosine A2A or A2B receptors. Using the reverse transcription-polymerase chain reaction it was, however, demonstrated that the Jurkat cell and the PC12 cell express both A2A and A2B receptor mRNA, albeit in different relative proportions. In PC12 cells the concentration required for half-maximal response (EC50) for the full agonist 5'-N-ethyl-carboxamidoadenosine (NECA) was 30 times lower than in Jurkat cells. There was no significant difference in the pA2 for the antagonist 5-amino-9-chloro-2-(2-furanyl)- 1,2,4-triazolo(1,5-C)quinazolinemonomethanesulphonate (CGS 15943) between the two cell types. In the presence of forskolin (1 microM in PC12 cells; 10 microM in Jurkat cells) the EC50 value for NECA was reduced two-to sixfold. Forskolin also increased the maximal cAMP accumulation twofold in PC12 cells and sevenfold in Jurkat cells. A series of 2-substituted adenosine analogues CV 1808 (2-phenylamino adenosine), CV 1674 [2-(4-methoxyphenyl)adenosine], CGS 21680 ż2-[p-(2-carbonylethyl)phenylethylamino]-5'-N-ethyl- carboxamido adenosineż, and four 2-substituted isoguanosines, SHA 40 [2-(2-phenylethoxy)adenosine; PEA], SHA 91 [2-(2-cyclohexylethoxy)adenosine; CEA], SHA 118 ż2-[2-(p-methylphenyl)ethoxy]adenosine; MPEAż, and SHA 125 (2-hexyloxyadenosine; HOA), all raised cAMP accumulation in PC12 cells, but had minimal or no effect in Jurkat cells. In the PC12 cells the addition of forskolin (1 microM) reduced the EC50 by a factor of 2(CV 1808) to 12 (SHA 125). In Jurkat cells all the analogues gave a significant, but submaximal, cAMP response in the presence of forskolin (10 microM), but they were essentially inactive in its absence. The results show that a series of 2-substituted adenosine analogues can be used to discriminate between A2A and A2B receptors. The two receptor subtypes appear to coexist, even in clonal cells selected for typical pharmacology. A2 receptor pharmacology can therefore be complex. PMID:8692279

van der Ploeg, I; Ahlberg, S; Parkinson, F E; Olsson, R A; Fredholm, B B



Adenosine A 1 receptors using 8-dicyclopropylmethyl-1-[ 11 C]methyl-3-propylxanthine PET in Alzheimer’s disease  

Microsoft Academic Search

Objective  Adenosine is an endogenous modulator of synaptic functions in the central nervous system. The effects of adenosine are mediated\\u000a by at least four adenosine receptor subtypes. Decreased density of adenosine A1 receptors, which is a major subtype adenosine\\u000a receptor in the hippocampus, has been reported in vitro in Alzheimer’s disease. We evaluated adenosine A1 receptor in the\\u000a brain of elderly

Nobuyoshi Fukumitsu; Kenji Ishii; Yuichi Kimura; Keiichi Oda; Masaya Hashimoto; Masahiko Suzuki; Kiichi Ishiwata



Engineered adenosine-releasing cells for epilepsy therapy: Human mesenchymal stem cells and human embryonic stem cells  

Microsoft Academic Search

Summary  Adenosine is a modulator of neuronal activity with anticonvulsant and neuroprotective properties. Conversely, focal deficiency\\u000a in adenosine contributes to ictogenesis. Thus, focal reconstitution of adenosine within an epileptogenic brain region constitutes\\u000a a rational therapeutic approach, whereas systemic augmentation of adenosine is precluded by side effects. To meet the therapeutic\\u000a goal of focal adenosine augmentation, genetic disruption of the adenosine metabolizing

Detlev Boison



Mechanism of adenylate kinase. Dose adenosine 5'-triphosphate bind to the adenosine 5'-monophosphate site  

SciTech Connect

Although the subtrate binding properties of adenylate kinase (AK) have been studied extensively by various biochemical and biophysical techniques, it remains controversial whether uncomplexed adenosine 5'-triphosphate (ATP) binds to the adenosine 5'-monophosphate (AMP) site of AK. The authors present two sets of experiments which argue against binding of ATP to the AMP site. (a) /sup 31/P nuclear magnetic resonance titration of ATP with AK indicated a 1:1 stoichiometry on the basis of changes in coupling constants and line widths. This ruled out binding of ATP to both sites. (b) ATP and MgATP were found to behave similarly by protecting AK from spontaneous inactivation while AMP showed only a small degree of protection. Such inactivation could also be protected or reversed by dithioerythritol and is most likely due to oxidation of sulfhydryl groups, one of which (cysteine-25) is located near the MgATP site. The results support binding of ATP to the MgATP site predominantly, instead of the AMP site, in the absence of Mg/sup 2 +/.

Shyy, Y.J.; Tian, G.; Tsai, M.D.



Inhibition of adenosine and thymidylate kinases by bisubstrate analogs.  


Potential bisubstrate analogs, in which the 5'-hydroxyl group of adenosine was joined to the phosphoryl group acceptor by polyphosphoryl bridges of varying length (ApnX, where n is the number of phosphoryl groups and X is the nucleoside moiety of the acceptor), were tested as inhibitors of human liver adenosine kinase and of thymidylate kinase from peripheral blast cells of patients with acute myelocytic leukemia. Adenosine kinase was most strongly inhibited by P1,P4-(diadenosine 5')-tetraphosphate (Kd = 30 nM) and P1,P5-(diadenosine 5')-pentaphosphate (Kd = 73 nM). Thymidylate kinase was most strongly inhibited by P1-(adenosine 5')-P5-(thymidine 5')-pentaphosphate (Kd = 120 nM) and by P1(adenosine 5')-P6-(thymidine 5')-hexaphosphate (Kd = 43 nM). In these enzymes, as in adenylate and thymidylate kinases, strongest inhibition was achieved in compounds containing one or two more phosphoryl groups than the substrates combined. These results support the view that nucleoside and nucleotide kinases mediate direct transfer of phosphoryl groups from ATP to acceptors, rather than acting by a double displacement mechanism. PMID:3023350

Bone, R; Cheng, Y C; Wolfenden, R



Adenosine Kinase of Arabidopsis. Kinetic Properties and Gene Expression1  

PubMed Central

To assess the functional significance of adenosine salvage in plants, the cDNAs and genes encoding two isoforms of adenosine kinase (ADK) were isolated from Arabidopsis. The ADK1- and ADK2-coding sequences are very similar, sharing 92% and 89% amino acid and nucleotide identity, respectively. Each cDNA was overexpressed in Escherichia coli, and the catalytic activity of each isoform was determined. Both ADKs had similar catalytic properties with a Km and Vmax/Km for adenosine of 0.3 to 0.5 ?m and 5.4 to 22 L min?1 mg?1 protein, respectively. The Km and Vmax/Km for the cytokinin riboside N6(isopentenyl) adenosine are 3 to 5 ?m and 0.021 to 0.14 L min?1 mg?1 protein, respectively, suggesting that adenosine is the preferred substrate for both ADK isoforms. In Arabidopsis plants, both ADK genes are expressed constitutively, with the highest steady-state mRNA levels being found in stem and root. ADK1 transcript levels were generally higher than those of ADK2. ADK enzyme activity reflected relative ADK protein levels seen in immunoblots for leaves, flowers, and stems but only poorly so for roots, siliques, and dry seeds. The catalytic properties, tissue accumulation, and expression levels of these ADKs suggest that they play a key metabolic role in the salvage synthesis of adenylates and methyl recycling in Arabidopsis. They may also contribute to cytokinin interconversion.

Moffatt, Barbara A.; Wang, Li; Allen, Mike S.; Stevens, Yvonne Y.; Qin, Wensheng; Snider, Jamie; von Schwartzenberg, Klaus



Characterization of Two Adenosine Analogs as Fluorescence Probes in RNA  

PubMed Central

The fluorescence properties of two adenosine analogs, 2-(3-phenylpropyl)adenosine [A-3CPh] and 2-(4-phenylbutyl)adenosine [A-4CPh], are reported. As monomers, the quantum yields and the mean lifetimes are 0.011 and 6.22 ns for A-3CPh and 0.007 and 7.13 ns for A-4CPh, respectively. Surprisingly, the quantum yields of the two probes are enhanced 11–82 fold upon incorporation into RNA, while the mean lifetimes decrease 23–40%. The data suggest that a subpopulation of molecules is responsible for the fluorescence characteristics and that the distribution of emitting and non-emitting structures is altered upon incorporation of the probes into RNA. Thus, although both adenosine analogs have low quantum yields as monomers, their fluorescence signals are significantly enhanced in RNA. Thermodenaturation experiments and CD spectroscopy indicate that incorporation of the adenosine analogs into three different RNAs does not alter their global structure or stability. Therefore, these probes should be useful for probing events occurring close to the site of modification.

Zhao, Ying; Knee, Joseph L.; Baranger, Anne M.



Selective adenosine-A 2A activation reduces lung reperfusion injury following transplantation  

Microsoft Academic Search

Background: The adenosine-A2A receptor on the neutrophil is responsible for several anti-inflammatory actions. We hypothesized that DWH-146e, a selective adenosine-A2A agonist, would reduce lung reperfusion injury following transplantation.

Scott D Ross; Curtis G Tribble; Joel Linden; James J Gangemi; Brendan C Lanpher; Andrew Y Wang; Irving L Kron



Role of Adenosine Analogs and Growth Hormone in Waking and Sleep.  

National Technical Information Service (NTIS)

The role of adenosine in sleep has been further investigated using electroencephalography to document the dose response effects of newly developed specific adenosine A1 and A2 receptor stimulants and 8-cyclopropyltheophylline (CPRT), a substituted xanthin...

M. Radulovacki



Adenosine and protection from acute kidney injury  

PubMed Central

Purpose of Review Acute Kidney Injury (AKI) is a major clinical problem without effective therapy. Development of AKI among hospitalized patients drastically increases mortality, and morbidity. With increases in complex surgical procedures together with a growing elderly population, the incidence of AKI is rising. Renal adenosine receptor (AR) manipulation may have great therapeutic potential in mitigating AKI. In this review, we discuss renal AR biology and potential clinical therapies for AKI. Recent Findings The 4 AR subtypes (A1AR, A2AAR, A2BAR and A3AR) have diverse effects on the kidney. The pathophysiology of AKI may dictate the specific AR subtype activation needed to produce renal protection. The A1AR activation in renal tubules and endothelial cells produces beneficial effects against ischemia and reperfusion (IR) injury by modulating metabolic demand, decreasing necrosis, apoptosis and inflammation. The A2AAR protects against AKI by modulating leukocyte-mediated renal and systemic inflammation whereas the A2BAR activation protects by direct activation of renal parenchymal ARs. In contrast, the A1AR antagonism may play a protective role in nephrotoxic AKI and radiocontrast induced nephropathy by reversing vascular constriction and inducing naturesis and diuresis. Furthermore, as the A3AR-activation exacerbates apoptosis and tissue damage due to renal IR, selective A3AR antagonism may hold promise to attenuate renal IR injury. Finally, renal A1AR activation also protects against renal endothelial dysfunction caused by hepatic IR injury. Summary Despite the current lack of therapies for the treatment and prevention of AKI, recent research suggests that modulation of renal ARs holds promise in treating AKI and extrarenal injury.

Yap, Steven C.; Lee, H. Thomas



Concentration dependence of adenosine and the protection of rat cortical neurones during anoxia.  


Aglycaemic/anoxic slices of rat olfactory cortex lose all electrical activity. On reoxygenation, 10 microM adenosine enhanced recovery from 23 +/- 7% to 53 +/- 12%; an increased tissue endurance of 5-7 min. 100 microM adenosine slightly depressed recovery to 11.5 +/- 2.1%. Dipyridamole increased whereas adenosine deaminase reduced recovery. These observations question the therapeutic effectiveness of high adenosine concentrations. PMID:7804833

Donaghy, K M; Scholfield, C N



Subclasses of adenosine receptors in the central nervous system: Interaction with caffeine and related methylxanthines  

Microsoft Academic Search

1.The potencies of caffeine and related methylxanthines as adenosine antagonists were assessed with respect to three apparent subtypes of adenosine receptors in rat brain preparations: (i) the A1-adenosine receptor which binds with a very high affinity the ligand [3H]cyclohexyladenosine (KD, 1 nM) in rat brain membranes; (ii) a ubiquitous low-affinity A2-adenosine receptor which activates cyclic AMP accumulation in rat brain

John W. Daly; Pamela Butts-Lamb; William Padgett



A Novel Action for Adenosine: Apoptosis of Astroglial Cells in Rat-Brain Primary Cultures  

Microsoft Academic Search

2-chloro-adenosine induced apoptosis of astroglial cells in rat brain cultures, as shown by flow cytometry and morphological analysis. The adenosine analogue was far more potent than several previously characterized sugars (including 2-deoxy-D-ribose and D-ribose, the sugar moiety of 2-chloro-adenosine), which trigger apoptosis in a variety of cell-lines [8-10], suggesting that the effects of 2-chloro-adenosine are only partially dictated by its

M. P. Abbracchio; S. Ceruti; D. Barbieri; C. Franceschi; W. Malorni; L. Biondo; G. Burnstock; F. Cattabeni



A2B Receptors Mediate the Antimitogenic Effects of Adenosine in Cardiac Fibroblasts  

Microsoft Academic Search

Adenosine inhibits growth of cardiac fibroblasts; however, the adenosine receptor subtype that mediates this antimitogenic effect remains undefined. Therefore, the goals of this study were to determine which adenosine receptor subtype mediates the antimitogenic effects of adenosine and to investigate the signal transduction mechanisms involved. In rat left ventricular cardiac fibroblasts, PDGF-BB (25 ng\\/mL) stimulated DNA synthesis (3H-thymidine incorpora- tion),

Raghvendra K. Dubey; Delbert G. Gillespie; Lefteris C. Zacharia; Zaichuan Mi; Edwin K. Jackson


[Adenosine deaminase as costimulatory molecule and marker of cellular immunity].  


Adenosine deaminase (ADA) is an enzyme of purine metabolism which has been the subject of much interest because the congenital defect of this enzyme causes severe combined immunodeficiency syndrome. One of the three isoforms of the enzyme (ecto-ADA) is capable of binding to the glycoprotein CD26 and adenosine receptors A1 and A2B. ADA-CD26 interaction produces a costimulatory signal in the events of T cell activation and secretion of IFN-gamma, TNF-alpha and IL-6. During this activation, the enzyme activity is regulated positively by IL-2 and IL-12 and negatively by IL-4, based on the mechanism of translocation. Diverse studies suggest that seric and plasmatic levels of ADA rise in some diseases caused by microorganisms infecting mainly the macrophages and in hypertensive disorders, which may represent a compensatory mechanism resulting from increased adenosine levels and the release of hormones and inflammatory mediators estimulated by hipoxia. PMID:21365880

Pérez-Aguilar, Mary Carmen; Goncalves, Loredana; Ibarra, Alba; Bonfante-Cabarcas, Rafael



Delayed onset adenosine deaminase deficiency associated with acute disseminated encephalomyelitis.  


Acute disseminated encephalomyelitis (ADEM) is a monophasic, immune-mediated demyelinating disorder that can appear after either immunizations or, more often, infections. Magnetic resonance imaging of patients shows inflammatory lesions in the brain and spinal cord. An immune-mediated mechanism may play a role in this disease, although its precise pathogenesis remains unclear. In this study, a 2-year-old boy presented with ADEM, and he showed improvement on treatment with high-dose intravenous corticosteroids. At the age of 3 years, the presence of recurrent bronchitis, bronchiectasia, and lymphopenia suggested that the patient was suffering from combined immunodeficiency. The patient was finally diagnosed with delayed onset adenosine deaminase deficiency. Delayed onset adenosine deaminase deficiency is frequently associated with autoimmune diseases, including thyroiditis and cytopenia, both of which were observed in the patient. The ADEM in this patient may be a presentation of delayed onset adenosine deaminase deficiency. PMID:22447032

Nakaoka, Hideyuki; Kanegane, Hirokazu; Taneichi, Hiromichi; Miya, Kazushi; Yang, Xi; Nomura, Keiko; Takezaki, Shunichiro; Yamada, Masafumi; Ohara, Osamu; Kamae, Chikako; Imai, Kohsuke; Nonoyama, Shigeaki; Wada, Taizo; Yachie, Akihiro; Hershfield, Michael S; Ariga, Tadashi; Miyawaki, Toshio



Release of Adenosine and ATP During Ischemia and Epilepsy  

PubMed Central

Eighty years ago Drury & Szent-Györgyi described the actions of adenosine, AMP (adenylic acid) and ATP (pyrophosphoric or diphosphoric ester of adenylic acid) on the mammalian cardiovascular system, skeletal muscle, intestinal and urinary systems. Since then considerable insight has been gleaned on the means by which these compounds act, not least of which in the distinction between the two broad classes of their respective receptors, with their many subtypes, and the ensuing diversity in cellular consequences their activation invokes. These myriad actions are of course predicated on the release of the purines into the extracellular milieu, but, surprisingly, there is still considerable ambiguity as to how this occurs in various physiological and pathophysiological conditions. In this review we summarise the release of ATP and adenosine during seizures and cerebral ischemia and discuss mechanisms by which the purines adenosine and ATP may be released from cells in the CNS under these conditions.

Dale, Nicholas; Frenguelli, Bruno G



Effect of adenosine and inosine on ureagenesis in hepatocytes.  

PubMed Central

Adenosine and inosine produced a dose-dependent stimulation of ureagenesis in isolated rat hepatocytes. Hypoxanthine, xanthine and uric acid were without effect. Half-maximally effective concentrations were 0.08 microM for adenosine and 5 microM for inosine. Activation of ureagenesis by both nucleosides had the following characteristics: (a) it was observed with either glutamine or (NH4)2CO3, provided that glucose was present; (b) it was not detected when glucose was replaced by lactate plus oleate; (c) it was mutually antagonized by glucagon, but not by adrenaline; and (d) it was dependent on Ca2+. We suggest that the action of adenosine and inosine on ureagenesis might be of physiological significance.

Guinzberg, R; Laguna, I; Zentella, A; Guzman, R; Pina, E



Correlation between blood adenosine metabolism and sleep in humans.  


Blood adenosine metabolism, including metabolites and metabolizing enzymes, was studied during the sleep period in human volunteers. Searching for significant correlations among biochemical parameters found: adenosine with state 1 of slow-wave sleep (SWS); activity of 5'-nucleotidase with state 2 of SWS; inosine and AMP with state 3-4 of SWS; and activity of 5'-nucleotidase and lactate with REM sleep. The correlations were detected in all of the subjects that presented normal hypnograms, but not in those who had fragmented sleep the night of the experiment. The data demonstrate that it is possible to obtain information of complex brain operations such as sleep by measuring biochemical parameters in blood. The results strengthen the notion of a role played by adenosine, its metabolites and metabolizing enzymes, during each of the stages that constitute the sleep process in humans. PMID:11382880

Díaz-Muńoz, M; Hernández-Muńoz, R; Suárez, J; Vidrio, S; Yááńez, L; Aguilar-Roblero, R; Rosenthal, L; Villalobos, L; Fernández-Cancino, F; Drucker-Colín, R; Chagoya De Sanchez, V



Adenosine induces growth-cone turning of sensory neurons  

PubMed Central

The formation of appropriate connections between neurons and their specific targets is an essential step during development and repair of the nervous system. Growth cones are located at the leading edges of the growing neurites and respond to environmental cues in order to be guided to their final targets. Directional information can be coded by concentration gradients of substrate-bound or diffusible-guidance molecules. Here we show that concentration gradients of adenosine stimulate growth cones of sensory neurons (dorsal root ganglia) from chicken embryos to turn towards the adenosine source. This response is mediated by adenosine receptors. The subsequent signal transduction process involves cAMP. It may be speculated that the in vivo function of this response is concerned with the formation or the repair and regeneration of the peripheral nervous system. Electronic supplementary material The online version of this article (doi:10.1007/s11302-008-9121-3) contains supplementary material, which is available to authorised users.

Grau, Benjamin; Eilert, John-Christian; Munck, Sebastian



Induction of atrioventricular nodal reentry tachycardia with intravenous adenosine.  


Adenosine, used to terminate paroxysmal supraventricular tachycardia (SVT), is often useful in understanding the mechanism of tachycardia. This case report describes induction of SVT with adenosine in a 36-year-old man presenting with recurrent palpitations. After a short run of conduction via both slow and fast pathways, SVT was induced following a long PR interval. The long PR interval resulted by conduction via the slow pathway due to the preferential conduction block by adenosine over fast pathway. The notching at the terminal part of QRS during antegrade slow pathway conduction and during tachycardia indicated activation of the atrium via retrograde fast pathway. This electrocardiographical feature confirmed the mechanism of the tachycardia as atrioventricular nodal reentrant tachycardia. PMID:17453083

Dora, S K; Namboodiri, N; Valaparambil, A K; Tharakan, J A



Increased extracellular adenosine in Drosophila that are deficient in adenosine deaminase activates a release of energy stores leading to wasting and death.  


Extracellular adenosine is an important signaling molecule in neuromodulation, immunomodulation and hypoxia. Adenosine dysregulation can cause various pathologies, exemplified by a deficiency in adenosine deaminase in severe combined immunodeficiency. We have established a Drosophila model to study the effects of increased adenosine in vivo by mutating the main Drosophila adenosine deaminase-related growth factor (ADGF-A). Using a genetic screen, we show here that the increased extracellular adenosine in the adgf-a mutant is associated with hyperglycemia and impairment in energy storage. The adenosine works in this regard through the adenosine receptor as an anti-insulin hormone in parallel to adipokinetic hormone, a glucagon counterpart in flies. If not regulated properly, this action can lead to a loss of energy reserves (wasting) and death of the organism. Because adenosine signaling is associated with the immune response and the response to stress in general, our results mark extracellular adenosine as a good candidate signal involved in the wasting syndrome that accompanies various human pathologies. PMID:20940317

Zuberova, Monika; Fenckova, Michaela; Simek, Petr; Janeckova, Lucie; Dolezal, Tomas



Potential roles of adenosine deaminase-2 in diabetic retinopathy.  


The early activation of microglia that induces retinal inflammation in DR may serve as a target for therapeutic intervention of DR. Our demonstration that retinal inflammation is attenuated via adenosine receptor A(2A)AR supports the hypothesis that a mechanism to maintain extracellular concentrations of adenosine important in normal physiology is impaired in DR. Extracellular concentrations of adenosine are regulated by the interplay of equiliberative nucleoside transporter (ENT)s with enzymes of adenosine metabolism including adenosine deaminase-1 (ADA1), adenosine kinase (AK) and CD73. In the vertebrates but not rodents, a macrophage-associated ADA2 is identified. The role of ADA2 is, therefore, understudied as the sequencing probes or antibodies to mouse ADA2 are not available. We identified increased ADA2 expression and activity in human and porcine retinas with diabetes, and in Amadori glycated albumin (AGA)- or hyperglycemia-treated porcine and human microglia. In rodent as well as porcine cells, modulation of TNF-? release is mediated by A(2A)AR. Quantitative analysis of normal and diabetic porcine retinas reveals that while the expression levels of ADA2, A2AAR, ENT1, TNF-? and MMP9 are increased, the levels of AK are reduced during inflammation as an endogenous protective mechanism. To determine the role of ADA2, we found that AGA induces ADA2 expression, ADA2 activity and TNF-? release, and that TNF-? release is blocked by ADA2-neutralizing antibody or ADA2 siRNA, but not by scrambled siRNA. These results suggest that retinal inflammation in DR is mediated by ADA2, and that the anti-inflammatory activity of A(2A)AR signaling is impaired in diabetes due to increased ADA2 activity. PMID:23685153

Elsherbiny, Nehal M; Naime, Mohammad; Ahmad, Saif; Elsherbini, Ahmed M; Mohammad, Shuaib; Fulzele, Sadanand; El-Remessy, Azza B; Al-Gayyar, Mohammed M; Eissa, Laila A; El-Shishtawy, Mamdouh M; Han, Guichun; White, Richard; Haroldo, Toque Flores; Liou, Gregory I



Adenosine A 1 receptors decrease thalamic excitation of inhibitory and excitatory neurons in the barrel cortex  

Microsoft Academic Search

Caffeine is consumed worldwide to enhance wakefulness, but the cellular mechanisms are poorly understood. Caffeine blocks adenosine receptors suggesting that adenosine decreases cortical arousal. Given the widespread innervation of the cerebral cortex by thalamic fibers, adenosine receptors on thalamocortical terminals could provide an efficient method of limiting thalamic activation of the cortex. Using a mouse thalamocortical slice preparation and whole-cell

D. E. Fontanez; J. T. Porter



Intravascular Source of Adenosine During Forearm Ischemia in Humans Implications for Reactive Hyperemia  

Microsoft Academic Search

It is believed that adenosine is released in ischemic tissues and contributes to reactive hyperemia. We tested this hypothesis in the human forearm using microdialysis to estimate interstitial and intravascular levels of adenosine and caffeine withdrawal to potentiate endogenous adenosine and determine its effect on reactive hyperemia. Forearm blood flow response to ischemia was measured by air plethysmography before and

Fernando Costa; Mark Angel; Virginia Haile; Brian Christman; Italo Biaggioni


Adenosine nucleotide “energy charge” ratios as an ecophysiological index for microplankton communities  

Microsoft Academic Search

Energy charge (EC) ratios of microplankton samples have been measured from their adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) contents, according to a method based on enzymatic tranformations of ADP and AMP into ATP, and the subsequent quantitative analysis of the latter by the bioluminescent reaction of a firefly lantern extract (Photinus pyralis). Interference caused by other

J.-C. Romano; R. Daumas



Adenosine Regulation of Cystic Fibrosis Transmembrane Conductance Regulator through Prostenoids in Airway Epithelia  

Microsoft Academic Search

Cystic fibrosis is caused by dysfunction of the cystic fibrosis trans- membrane conductance regulator (CFTR) protein, leading to al- tered ion transport, chronic infection, and excessive inflammation. Here we investigated regulation of CFTR in airway cell monolayers by adenosine, adenosine receptors, and arachidonic acid. Our stud- ies demonstrate that the A2B adenosine receptor is expressed at high levels relative to

Yao Li; Wei Wang; William Parker; J. P. Clancy


Adenosine and IFN  synergistically increase IFN  production of human NK cells  

Microsoft Academic Search

Prevention of overwhelming immune reactions is essential for an organism to survive. Adenosine, a ribonucleoside produced by various cell types during inflammatory processes, has been shown to inhibit effector functions of different im- mune cells. Here, we show that the adenosine A3 receptor agonist iodobenzyl methylcarboxamido- adenosine potently inhibited proliferation, IFN- production, and cytotoxicity of activated human lymphoid cells. Stimulation

Florian Jeffe; Kerstin A. Stegmann; Felix Broelsch; Michael P. Manns; Markus Cornberg; Heiner Wedemeyer



Neuronal transporter and astrocytic ATP exocytosis underlie activity-dependent adenosine release in the hippocampus.  


The neuromodulator adenosine plays an important role in many physiological and pathological processes within the mammalian CNS. However, the precise mechanisms of how the concentration of extracellular adenosine increases following neural activity remain contentious. Here we have used microelectrode biosensors to directly measure adenosine release induced by focal stimulation in stratum radiatum of area CA1 in mouse hippocampal slices. Adenosine release was both action potential and Ca˛? dependent and could be evoked with low stimulation frequencies and small numbers of stimuli. Adenosine release required the activation of ionotropic glutamate receptors and could be evoked by local application of glutamate receptor agonists. Approximately 40% of stimulated-adenosine release occurred by translocation of adenosine via equilibrative nucleoside transporters (ENTs). This component of release persisted in the presence of the gliotoxin fluoroacetate and thus results from the direct release of adenosine from neurons. A reduction of adenosine release in the presence of NTPDase blockers, in slices from CD73(-/-) and dn-SNARE mice, provides evidence that a component of adenosine release arises from the extracellular metabolism of ATP released from astrocytes. This component of release appeared to have slower kinetics than the direct ENT-mediated release of adenosine. These data suggest that activity-dependent adenosine release is surprisingly complex and, in the hippocampus, arises from at least two distinct mechanisms with different cellular sources. PMID:23713028

Wall, Mark J; Dale, Nicholas



The 2?,3?-cAMP-adenosine pathway  

PubMed Central

Our recent studies employing HPLC-tandem mass spectrometry to analyze venous perfusate from isolated, perfused kidneys demonstrate that intact kidneys produce and release into the extracellular compartment 2?,3?-cAMP, a positional isomer of the second messenger 3?,5?-cAMP. To our knowledge, this represents the first detection of 2?,3?-cAMP in any cell/tissue/organ/organism. Nuclear magnetic resonance experiments with isolated RNases and experiments in isolated, perfused kidneys suggest that 2?,3?-cAMP likely arises from RNase-mediated transphosphorylation of mRNA. Both in vitro and in vivo kidney experiments demonstrate that extracellular 2?,3?-cAMP is efficiently metabolized to 2?-AMP and 3?-AMP, both of which can be further metabolized to adenosine. This sequence of reactions is called the 2?,3?-cAMP-adenosine pathway (2?,3?-cAMP ? 2?-AMP/3?-AMP ? adenosine). Experiments in rat and mouse kidneys show that metabolic poisons increase extracellular levels of 2?,3?-cAMP, 2?-AMP, 3?-AMP, and adenosine; however, little is known regarding the pharmacology of 2?,3?-cAMP, 2?-AMP, and 3?-AMP. What is known is that 2?,3?-cAMP facilitates activation of mitochondrial permeability transition pores, a process that can lead to apoptosis and necrosis, and inhibits proliferation of vascular smooth muscle cells and glomerular mesangial cells. In summary, there is mounting evidence that at least some types of cellular injury, by triggering mRNA degradation, engage the 2?,3?-cAMP-adenosine pathway, and therefore this pathway should be added to the list of biochemical pathways that produce adenosine. Although speculative, it is possible that the 2?,3?-cAMP-adenosine pathway may protect against some forms of acute organ injury, for example acute kidney injury, by both removing an intracellular toxin (2?,3?-cAMP) and increasing an extracellular renoprotectant (adenosine).



Adenosine A 3 Receptor Signaling in the Central Nervous System  

Microsoft Academic Search

\\u000a Adenosine A3 receptors are widely distributed in the central nervous system but are expressed at a low level and have lower affinity for\\u000a adenosine in comparison to the A1 and A2A receptors. Nevertheless, they appear to tonically modulate motor activity as pointed out in A3 receptor-deleted mice.\\u000a \\u000a \\u000a The role of A3 receptor in several pathophysiological conditions is often controversial. In

Felicita Pedata; Anna Maria Pugliese; Ana M. Sebastiăo; Joaquim A. Ribeiro


Graphene oxide based fluorescent aptasensor for adenosine deaminase detection using adenosine as the substrate.  


We present a novel fluorescent aptasensor for simple and accurate detection of adenosine deaminase (ADA) activity and inhibition on the basis of graphene oxide (GO) using adenosine (AD) as the substrate. This aptasensor consists of a dye-labeled single-stranded AD specific aptamer, GO and AD. The fluorescence intensity of the dye-labeled AD specific aptamer is quenched very efficiently by GO as a result of strong ?-? stacking interaction and excellent electronic transference of GO. In the presence of AD, the fluorescence of the GO-based probe is recovered since the competitive binding of AD and GO with the dye-labeled aptamer prevents the adsorption of dye-labeled aptamer on GO. When ADA was introduced to this GO-based probe solution, the fluorescence of the probe was quenched owing to ADA can convert AD into inosine which has no affinity to the dye-labeled aptamer, thus allowing quantitative investigation of ADA activity. The as-proposed sensor is highly selective and sensitive for the assay of ADA activity with a detection limit of 0.0129U/mL in clean buffer, which is more than one order of magnitude lower than the previous reports. Meanwhile, a good linear relationship with the correlation coefficient of R=0.9922 was obtained by testing 5% human serum containing a series of concentrations of ADA. Additionally, the inhibition effect of erythro-9-(2-hydroxy-3-nonyl) adenine on ADA activity was investigated in this design. The GO-based fluorescence aptasensor not only provides a simple, cost-effective and sensitive platform for the detection of ADA and its inhibitor but also shows great potential in the diagnosis of ADA-relevant diseases and drug development. PMID:22613226

Xing, Xiao-Jing; Liu, Xue-Guo; Yue-He; Luo, Qing-Ying; Tang, Hong-Wu; Pang, Dai-Wen



Phosphorylation of adenosine in renal brush-border membrane vesicles by an exchange reaction catalysed by adenosine kinase.  

PubMed Central

Uptake of [3H]adenosine in brush-border membrane (BBM) vesicles from either rat or pig kidney leads to an accumulation of intravesicular [3H]AMP. The lack of significant levels of ATP and the presence of AMP in BBM indicated that a phosphotransfer between [3H]adenosine and AMP occurs. The phosphotransfer activity is inhibited by iodotubercidin, which suggests that it is performed by adenosine kinase acting in an ATP-independent manner. The existence of a similar phosphotransferase activity was demonstrated in membrane-free extracts from pig kidney. From the compounds tested it was shown that a variety of mononucleotides could act as phosphate donors. The results suggest that phosphotransfer reactions may be physiologically relevant in kidney.

Sayos, J; Solsona, C; Mallol, J; Lluis, C; Franco, R



Ecto-5'-nucleotidase (CD73)-mediated formation of adenosine is critical for the striatal adenosine A2A receptor functions.  


Adenosine is a neuromodulator acting through inhibitory A1 receptors (A1Rs) and facilitatory A2ARs, which have similar affinities for adenosine. It has been shown that the activity of intracellular adenosine kinase preferentially controls the activation of A1Rs, but the source of the adenosine activating A2ARs is unknown. We now show that ecto-5'-nucleotidase (CD73), the major enzyme able to convert extracellular AMP into adenosine, colocalizes with A2ARs in the basal ganglia. In addition to astrocytes, striatal CD73 is prominently localized to postsynaptic sites. Notably, CD73 coimmunoprecipitated with A2ARs and proximity ligation assays confirmed the close proximity of CD73 and A2ARs in the striatum. Accordingly, the cAMP formation in synaptosomes as well as the hypolocomotion induced by a novel A2AR prodrug that requires CD73 metabolization to activate A2ARs were observed in wild-type mice, but not in CD73 knock-out (KO) mice or A2AR KO mice. Moreover, CD73 KO mice displayed increased working memory performance and a blunted amphetamine-induced sensitization, mimicking the phenotype of global or forebrain-A2AR KO mice, as well as upon pharmacological A2AR blockade. These results show that CD73-mediated formation of extracellular adenosine is responsible for the activation of striatal A2AR function. This study points to CD73 as a new target that can fine-tune A2AR activity, and a novel therapeutic target to manipulate A2AR-mediated control of striatal function and neurodegeneration. PMID:23843511

Augusto, Elisabete; Matos, Marco; Sévigny, Jean; El-Tayeb, Ali; Bynoe, Margaret S; Müller, Christa E; Cunha, Rodrigo A; Chen, Jiang-Fan



Human suction blister interstitial fluid prevents metal ion-dependent oxidation of low density lipoprotein by macrophages and in cell-free systems.  

PubMed Central

LDL in the circulation is well protected against oxidation by the highly efficient antioxidant defense mechanisms of human plasma. LDL oxidation contributing to atherosclerosis, therefore, has been hypothesized to take place in the interstitial fluid of the arterial wall. We investigated the antioxidant composition and the capacity to inhibit LDL oxidation of human suction blister interstitial fluid (SBIF), a suitable representative of interstitial fluid. We found that the concentrations in SBIF of the aqueous small-molecule antioxidants ascorbate and urate were, respectively, significantly higher (P < 0.05) and identical to plasma concentrations. In contrast, lipoprotein-associated lipids and lipid-soluble antioxidants (alpha-tocopherol, ubiquinol-10, lycopene, and beta-carotene) were present at only 8-23% of the concentrations in plasma. No lipid hydroperoxides could be detected ( < 5 nM) in either fluid. The capacity of serum and SBIF to protect LDL from oxidation was investigated in three metal ion-dependent systems: copper, iron, and murine macrophages in Ham's F-10 medium. In all three systems, addition of > or = 6% (vol/vol) of either serum or SBIF inhibited LDL oxidation by > 90%. The concentration that inhibited macrophage-mediated LDL oxidation by 50% was as low as 0.3% serum and 0.7% SBIF. The enzymatic or physical removal of ascorbate or urate and other low molecular weight components did not affect the ability of either fluid to prevent LDL oxidation, and the high molecular weight fraction was as protective as whole serum or SBIF. These data demonstrate that both serum and SBIF very effectively protect LDL from metal ion-dependent oxidation, most probably because of a cumulative metal-binding effect of several proteins. Our data suggest that LDL in the interstitial fluid of the arterial wall is very unlikely to get modified by metal ion-mediated oxidation. Images

Dabbagh, A J; Frei, B



A2A receptor dependent and A2A receptor independent effects of extracellular adenosine on murine thymocytes in conditions of adenosine deaminase deficiency  

Microsoft Academic Search

Adenosine deaminase (ADA) deficiency causes severe combined immunodefi- ciency (SCID) and is accompanied by T-cell depletion and accumulation of both intracellular and extracellular adenosine (extAdo) and deoxyadenosine. To better understand the causes of T-cell depletion in vivo and to discriminate between extracellular and intracellular effects of exogenously added adenosine in vitro, we investigated mechanisms of 2 differ- ent effects of

Sergey Apasov; Jiang-Fan Chen; Patrick Smith; Michail Sitkovsky



Activation of adenosine A 1 receptor-induced neural stem cell proliferation via MEK\\/ERK and Akt signaling pathways  

Microsoft Academic Search

Adenosine, a modulator of neuronal function in the mammalian central nervous system, exerts a neuropro- tective effect via the adenosine A1 receptor; however, its effect on neural stem cells (NSCs) remains unclear. Because adenosine is released in response to patho- logical conditions and NSCs play a key role in neurore- generation, we tested the hypothesis that adenosine is capable of

Hideyuki Migita; Katsuya Kominami; Mami Higashida; Rumi Maruyama; Nobuko Tuchida; Fiona McDonald; Fumiki Shimada; Kazuhiro Sakurada



Crystal Structures of T. b. rhodesiense Adenosine Kinase Complexed with Inhibitor and Activator: Implications for Catalysis and Hyperactivation  

Microsoft Academic Search

BackgroundThe essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP) utilizing adenosine triphosphate (ATP)

Sabine Kuettel; Jason Greenwald; Dirk Kostrewa; Shaheen Ahmed; Leonardo Scapozza; Remo Perozzo



Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency  

Microsoft Academic Search

Background We investigated the long-term outcome of gene therapy for severe combined immu- nodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. Methods We infused autologous CD34+ bone marrow cells transduced with a retroviral vec- tor containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked

Alessandro Aiuti; Federica Cattaneo; Stefania Galimberti; Ulrike Benninghoff; Barbara Cassani; Luciano Callegaro; Samantha Scaramuzza; Grazia Andolfi; Massimiliano Mirolo; Immacolata Brigida; Antonella Tabucchi; Filippo Carlucci; Martha Eibl; Memet Aker; Shimon Slavin; Hamoud Al-Mousa; Abdulaziz Al Ghonaium; Alina Ferster; Andrea Duppenthaler; Luigi Notarangelo; Uwe Wintergerst; Rebecca H. Buckley; Marco Bregni; Sarah Marktel; Maria Grazia Valsecchi; Paolo Rossi; Fabio Ciceri; Roberto Miniero; Claudio Bordignon; Maria-Grazia Roncarolo



Sensorineural deafness in siblings with adenosine deaminase deficiency  

Microsoft Academic Search

Two siblings with adenosine deaminase deficiency were successfully treated with allogeneic bone marrow transplantation without conditioning. Although the patients were free from infections after immumologic reconstitution, both showed sensorineural deafness at 1 year of age. Because there were no structural abnormalities in the inner and middle ears, no evidence of prenatal infections of rubella, cytomegalovirus or toxoplasma, and no postnatal

Chitose Tanaka; Toshiro Hara; Ichiro Suzaki; Yoshihiro Maegaki; Kenzo Takeshita



Caffeine withdrawal affects central adenosine receptors but not benzodiazepine receptors  

Microsoft Academic Search

Summary The effects of chronic caffeine administration on both adenosine and benzodiazepine receptors were studied in mouse brain membranes. Animals were fed on a diet enriched with caffeine (600 mg\\/kg diet) for 15 days and sacrificed 2, 4, 8 and 15 days after withdrawal. Compared with controls fed on a regular diet, animals receiving a caffeine-enriched diet showed an increase

J.-P. Boulenger; P. J. Marangos



Involvement of adenosine in cerebral hypoxic hyperemia in the dog.  


Theophylline, a competitive adenosine antagonist, was used to evaluate the role of adenosine in cerebral hypoxic hyperemia. Cerebral venous outflow was measured by the Rapela-Green technique in mongrel dogs anesthetized with pentobarbital sodium and ventilated artificially. Theophylline was infused locally into the cerebral arterial system during moderate [cerebral venous O2 tension (PO2) 27-29 mmHg] or severe (cerebral venous PO2 = 10-15 mmHg) hypoxia; theophylline had no direct vascular effects at the concentration used. Cerebral hyperemia was completely reversed during moderate hypoxia, but only partially reversed during severe hypoxia when theophylline was infused during maintained hypoxia. Theophylline had no effect on cerebral; perfusion pressure, blood flow, or vascular resistance during normoxia. In another group, theophylline had no effect on the cerebral hyperemia induced by hypercapnia. In separate experiments, local cerebral arterial infusion of adenosine or AMP during normoxia had no effect on cerebral hemodynamics at any infusion rate tested (up to 100 micrograms/min). This study supports the hypothesis that adenosine is involved in the hyperemia associated with cerebral hypoxia. However, the degree of involvement may be dependent on the degree of hypoxia. PMID:7270701

Emerson, T E; Raymond, R M



Adrenomedullin Mediates Coronary Vasodilation through Adenosine Receptors and K ATPChannels  

Microsoft Academic Search

The following experiments were conducted to determine whether, and the mechanisms through which, endogenous peptides alter coronary artery blood flow. Ultrasonic transit time probes were placed around the ascending aorta and left anterior descending coronary artery in groups of anesthetized, open-chest dogs. A Millar pressure catheter monitored left ventricular developed pressure. Intracoronary artery bolus injections of adenosine (a purinergic receptor

Braulio L. Sabates; John D. Pigott; Ella U. Choe; Mark P. Cruz; Howard L. Lippton; Albert L. Hyman; Lewis M. Flint; John J. Ferrara



Transgenic overexpression of adenosine kinase aggravates cell death in ischemia.  


Adenosine is an endogenous neuromodulator with anticonvulsive and neuroprotective activity. Adenosine levels are normally kept in the range of 20 to 200 nmol/L by low basal expression of its main metabolic enzyme, adenosine kinase (ADK). Dysfunction of the adenosinergic system has been demonstrated to contribute to epileptogenesis. To investigate whether upregulation of ADK may render the brain more susceptible to ischemic cell death, mutant mice overexpressing an Adk transgene in brain were subjected to middle cerebral artery occlusion (MCAO). One day after either 15 or 60 mins of MCAO, wild-type (WT) animals had infarct areas encompassing about 5% and 50% of their ischemic hemisphere, respectively. In marked contrast, the volume of the infarcts increased three-fold in Adk transgenic mutants after 15 mins of MCAO, and after 60 mins of MCAO all mutants died within 24 h. Pretreatment of the mutants with the ADK inhibitor 5-iodotubercidin led to lesions similar to those in WT mice. Thus, low levels of ADK are essential to maintain adenosine-mediated neuroprotection. We conclude that pathologic overexpression of ADK as in epilepsy may also render the brain more susceptible to injury from ischemia. Consequently, ADK emerges as a rational therapeutic target to enhance neuroprotection. PMID:16685255

Pignataro, Giuseppe; Simon, Roger P; Boison, Detlev



Role of Extracellular Adenosine in Acute Lung Injury  

NSDL National Science Digital Library

Acute lung injury (ALI) is a lung disease characterized by pulmonary edema and severe hypoxia. The past decade hosted a search for endogenous mechanisms controlling lung inflammation and pulmonary edema during ALI. As such, recent evidence indicates extracellular adenosine in orchestrating the resolution of pulmonary edema and inflammation during ALI.

Tobias Eckle (University of Colorado Denver Anesthesiology, Mucosal Inflammation Program); Michael Koeppen (University of Colorado Denver Anesthesiology); Holger K. Eltzschig (University of Colorado Denver Anesthesiology)



Adenosine-mediated Killing of Cultured Epithelial Cancer Cells1  

Microsoft Academic Search

Because micromolar concentrations of adenosine (Ado) have been doc- umented recently in the interstitial fluid of carcinomas growing in ani- mals, we examined the effects of low concentrations of Ado on the growth of cultured human carcinoma cells. Ado alone had little effect upon cell growth. In the presence of one of a number of Ado deaminase (ADA) inhibitors, Ado

Catherine P. Barry; Stuart E. Lind



Clinical expression, genetics and therapy of adenosine deaminase (ADA) deficiency  

Microsoft Academic Search

Adenosine deaminase (ADA) deficiency was the first known cause of primary immunodeficiency. Over the past 25 years the basis for immune deficiency has largely been established. Now it appears that ADA deficiency may also cause hepatic toxicity, raising new questions about its pathogenesis. The ADA gene has been sequenced and the ADA three-dimensional structure solved. The relationship between genotype and

M. S. Hershfield; F. X. Arredondo-Vega; I. Santisteban



Host A(2B) adenosine receptors promote carcinoma growth.  


Recent studies suggest that tumor-infiltrating immune cells can benefit the tumor by producing factors that promote angiogenesis and suppress immunity. Because the tumor microenvironment is characterized by high adenosine levels, we hypothesized that the low-affinity A(2B) adenosine receptor located on host immune cells may participate in these effects. In the current study, we tested this hypothesis in a Lewis lung carcinoma isograft model using A(2B) receptor knockout (A(2B)KO) mice. These mice exhibited significantly attenuated tumor growth and longer survival times after inoculation with Lewis lung carcinoma compared to wild type (WT) controls. Lewis lung carcinoma tumors in A(2B)KO mice contained significantly lower levels of vascular endothelial growth factor (VEGF) compared to tumors growing in WT animals. This difference was due to VEGF production by host cells, which comprised 30 +/- 2% of total tumor cell population. Stimulation of adenosine receptors on WT tumor-infiltrating CD45+ immune cells increased VEGF production fivefold, an effect not seen in tumor-associated CD45+ immune cells lacking A(2B) receptors. In contrast, we found no significant difference in VEGF production between CD45- tumor cells isolated from WT and A(2B)KO mice. Thus, our data suggest that tumor cells promote their growth by exploiting A(2B) adenosine receptor-dependent regulation of VEGF in host immune cells. PMID:18714400

Ryzhov, Sergey; Novitskiy, Sergey V; Zaynagetdinov, Rinat; Goldstein, Anna E; Carbone, David P; Biaggioni, Italo; Dikov, Mikhail M; Feoktistov, Igor



Human brain endothelial cells are responsive to adenosine receptor activation.  


The blood-brain barrier (BBB) of the central nervous system (CNS) consists of a unique subset of endothelial cells that possess tight junctions which form a relatively impervious physical barrier to a large variety of blood components. Until recently, there have been no good in vitro models for studying the human BBB without the co-culture of feeder cells. The hCMEC/D3 cell line is the first stable, well-differentiated human brain endothelial cell line that grows independently in culture with characteristics that closely resemble those of resident human brain endothelial cells. As our previously published findings demonstrated the importance of adenosine receptor (AR) signaling for lymphocyte entry into the CNS, we wanted to determine if human brain endothelial cells possess the capacity to generate and respond to extracellular adenosine. Utilizing the hCMEC/D3 cell line, we determined that these cells express CD73, the cell surface enzyme that converts extracellular AMP to adenosine. When grown under normal conditions, these cells also express the A(1), A(2A), and A(2B) AR subtypes. Additionally, hCMEC/D3 cells are responsive to extracellular AR signaling, as cAMP levels increase following the addition of the broad spectrum AR agonist 5'-N-ethylcarboxamidoadenosine (NECA). Overall, these results indicate that human brain endothelial cells, and most likely the human BBB, have the capacity to synthesize and respond to extracellular adenosine. PMID:21484089

Mills, Jeffrey H; Alabanza, Leah; Weksler, Babette B; Couraud, Pierre-Olivier; Romero, Ignacio A; Bynoe, Margaret S



CD39/Adenosine Pathway Is Involved in AIDS Progression  

PubMed Central

HIV-1 infection is characterized by a chronic activation of the immune system and suppressed function of T lymphocytes. Regulatory CD4+ CD25high FoxP3+CD127low T cells (Treg) play a key role in both conditions. Here, we show that HIV-1 positive patients have a significant increase of Treg-associated expression of CD39/ENTPD1, an ectoenzyme which in concert with CD73 generates adenosine. We show in vitro that the CD39/adenosine axis is involved in Treg suppression in HIV infection. Treg inhibitory effects are relieved by CD39 down modulation and are reproduced by an adenosine-agonist in accordance with a higher expression of the adenosine A2A receptor on patients' T cells. Notably, the expansion of the Treg CD39+ correlates with the level of immune activation and lower CD4+ counts in HIV-1 infected patients. Finally, in a genetic association study performed in three different cohorts, we identified a CD39 gene polymorphism that was associated with down-modulated CD39 expression and a slower progression to AIDS.

Limou, Sophie; Younas, Mehwish; Kok, Ayrin; Hue, Sophie; Seddiki, Nabila; Hulin, Anne; Delaneau, Olivier; Schuitemaker, Hanneke; Herbeck, Joshua T.; Mullins, James I.; Muhtarova, Maria; Bensussan, Armand; Zagury, Jean-Francois; Lelievre, Jean-Daniel; Levy, Yves



CD39/adenosine pathway is involved in AIDS progression.  


HIV-1 infection is characterized by a chronic activation of the immune system and suppressed function of T lymphocytes. Regulatory CD4+ CD25(high) FoxP3+CD127(low) T cells (Treg) play a key role in both conditions. Here, we show that HIV-1 positive patients have a significant increase of Treg-associated expression of CD39/ENTPD1, an ectoenzyme which in concert with CD73 generates adenosine. We show in vitro that the CD39/adenosine axis is involved in Treg suppression in HIV infection. Treg inhibitory effects are relieved by CD39 down modulation and are reproduced by an adenosine-agonist in accordance with a higher expression of the adenosine A2A receptor on patients' T cells. Notably, the expansion of the Treg CD39+ correlates with the level of immune activation and lower CD4+ counts in HIV-1 infected patients. Finally, in a genetic association study performed in three different cohorts, we identified a CD39 gene polymorphism that was associated with down-modulated CD39 expression and a slower progression to AIDS. PMID:21750674

Nikolova, Maria; Carriere, Matthieu; Jenabian, Mohammad-Ali; Limou, Sophie; Younas, Mehwish; Kök, Ayrin; Huë, Sophie; Seddiki, Nabila; Hulin, Anne; Delaneau, Olivier; Schuitemaker, Hanneke; Herbeck, Joshua T; Mullins, James I; Muhtarova, Maria; Bensussan, Armand; Zagury, Jean-François; Lelievre, Jean-Daniel; Lévy, Yves



Pharmacological blockade of adenosine A2A receptors diminishes scarring  

PubMed Central

Adenosine A2A receptor (A2AR) stimulation promotes wound healing and is required for the development of fibrosis in murine models of scleroderma and cirrhosis. Nonetheless, the role of A2AR in the formation of scars following skin trauma has not been explored. Here, we examined the effect of pharmacological blockade of A2AR, with the selective adenosine A2AR-antagonist ZM241385 (2.5 mg/ml), in a murine model of scarring that mimics human scarring. We found that application of the selective adenosine A2AR antagonist ZM241385 decreased scar size and enhanced the tensile strength of the scar. Within the scar itself, collagen alignment and composition (marked reduction in collagen 3), but not periostin, biglycan, or fibronectin accumulation, was improved by application of ZM241385. Moreover, A2AR blockade reduced the number of myofibroblasts and angiogenesis but not macrophage infiltration in the scar. Taken together, our work strongly suggests that pharmacological A2AR blockade can be used to diminish scarring while improving the collagen composition and tensile strength of the healed wound.—Perez-Aso, M., Chiriboga, L., Cronstein, B. N. Pharmacological blockade of adenosine A2A receptors diminishes scarring.

Perez-Aso, Miguel; Chiriboga, Luis; Cronstein, Bruce N.



Laser photobleaching leads to a fluorescence grade adenosine deaminase  

SciTech Connect

The enzyme adenosine deaminase (adenosine aminohydrolase EC from calf intestinal mucosa is commercially available at high purity grade yet, at the sensitivity at which fluorescence studies may be undertaken, a nonpeptidic fluorescence is detectable at lambda exmax = 350 nm and lambda emmax = 420 nm. A sevenfold decrease of this nonpeptidic fluorescence was obtained upon irradiation by the third harmonic (355 nm) of a Nd:YAG laser for 16 min, at 5 mJ/pulse, with a pulse width of 6 ns at a repetition rate of 10 Hz. The decline of fluorescence was accompanied by a negligible loss of enzymatic activity. Moreover, the integrity of the protein was ascertained by (i) its fluorescence (lambda exmax = 305 nm, lambda emmax = 335 nm) and lifetime distribution and (ii) its kinetics in the presence of the substrate adenosine and two inhibitors, all of which remained essentially unaltered. Laser photobleaching is a simple way to achieve a fluorescence grade adenosine deaminase.

Parola, A.H.; Caiolfa, V.R.; Bar, I.; Rosenwaks, S. (Ben Gurion Univ. of the Negev, Beer Sheva (Israel))



Dynein: A Protein with Adenosine Triphosphatase Activity from Cilia  

Microsoft Academic Search

The adenosine triphosphatase protein from cilia of Tetrahymena pyriformis consists of 30S and 14S fractions. The 30S fraction consists of rod-like particles, 70 to 90 angstroms in diameter, which are linear polymers of globular 14S units. The 14S units have a molecular weight of approximately 600,000. The enzymatic properties of the two fractions are similar.

I. R. Gibbons; A. J. Rowe



[The antihypoxic and radioprotective properties of selective adenosine receptor agonists].  


The selective A1- and A2-receptor agonists L-PIA (ED50 = 0.55-0.78 mmole/kg) and NEGA (D50 = 0.05-0.1 mmole/kg) possess high antihypoxic and radioprotective effects. A2-subtype receptors may be involved in the antihypoxic and radioprotective effects of adenosine analogs. PMID:1458173

Ol'khovski?, I A; Kulinski?, V I; Klimova, A D; Lidak, M Iu; Tsalmane, L V


2-(1-Hexyn-1-yl)adenosine-induced intraocular hypertension is mediated via K + channel opening through adenosine A 2A receptor in rabbits  

Microsoft Academic Search

The present study was performed to clarify the mechanism of change in intraocular pressure by 2-(1-hexyn-1-yl)adenosine (2-H-Ado), a selective adenosine A2 receptor agonist, in rabbits. 2-H-Ado (0.1%, 50 ?l)-induced ocular hypertension (Emax: 7.7 mm Hg) was inhibited by an adenosine A2A receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine, ATP-sensitive K+ channel blocker glibenclamide or 5-hydroxydecanoic acid, but not by an adenosine A1 receptor antagonist

Takashi Konno; Takehiro Uchibori; Akihiko Nagai; Kentaro Kogi; Norimichi Nakahata



Pharmacokinetics of adenosine and cordycepin, a bioactive constituent of Cordyceps sinensis in rat.  


Cordycepin is a bioactive constituent of Cordyceps sinensis that has been shown to regulate homeostatic function. As an adenosine analogue, it is possible cordycepin goes through a similar metabolic pathway to that of adenosine. To investigate this hypothesis, a sensitive liquid chromatography with photodiode-array detector (HPLC-PDA) coupled to a microdialysis sampling system was developed to monitor cordycepin and adenosine in rat blood and liver. Other endogenous nucleosides were simultaneously measured to further understand the downstream metabolic pathway. The experiments were divided into six parallel groups for drug administration: (1) normal saline vehicle, (2) adenosine, (3) cordycepin, (4) normal saline + erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; a potent adenosine deaminase inhibitor), (5) adenosine + EHNA, and (6) cordycepin + EHNA. The pharmacokinetic results suggest that the levels of both adenosine and cordycepin decreased rapidly in blood around 30 min after drug administration. When adenosine was given, the concentrations of adenosine metabolites, hypoxanthinosine and hypoxanthine, increased in rat blood. This phenomenon was inhibited by EHNA pretreatment. An unidentified peak was observed in the blood and liver samples after cordycepin administration. The decline of this unidentified peak paralleled the decreased of the concentration of cordycepin, and it was not observed in the presence of the adenosine deaminase inhibitor. It is concluded that adenosine and cordycepin had short elimination half-lives and high rates of clearance and their biotransformation was suppressed by EHNA. PMID:20302371

Tsai, Yung-Jen; Lin, Lie-Chwen; Tsai, Tung-Hu



Transendothelial transport and metabolism of adenosine and inosine in the intact rat aorta  

SciTech Connect

This study was aimed at defining the role of vascular endothelium in the transport and metabolism of adenosine. For this purpose, endothelium-intact and endothelium-denuded isolated rat aortas, perfused at constant flow (2 ml/min), were prelabeled with 3H-adenosine or 3H-inosine for 10 minutes at concentrations of 0.012-100 microM. Sequestration of adenosine by endothelium was determined from radioactivity recovered during selective endothelial cell removal with deoxycholic acid (0.75% for 15 seconds). In the physiological concentration range of adenosine (0.012-1 microM), fractional sequestration by endothelium was 90-92% of the total adenosine incorporation by the aorta. Endothelial sequestration of inosine at 0.1 microM was 85%. At 100 microM adenosine or inosine, fractional sequestration by aortic endothelium was 33% and 39%, respectively. Analysis of the specific radioactivity of adenine nucleotides extracted from prelabeled aortas indicated that most of the adenosine was incorporated into endothelial adenine nucleotides. Incorporation of inosine into endothelial ATP was approximately 15% that of adenosine. Inhibition of aortic adenosine deaminase with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) did not influence sequestration of 0.1 microM adenosine, but resulted in a 49% reduction of total endothelial incorporation at 100 microM adenosine. Transfer of radioactive purines from the endothelium to underlying smooth muscle after prelabeling was equivalent to only 1%/hr of total endothelial radioactivity.

Kroll, K.; Kelm, M.K.; Buerrig, K.F.S.; Schrader, J.



Multi-objective evolutionary design of adenosine receptor ligands.  


A novel multiobjective evolutionary algorithm (MOEA) for de novo design was developed and applied to the discovery of new adenosine receptor antagonists. This method consists of several iterative cycles of structure generation, evaluation, and selection. We applied an evolutionary algorithm (the so-called Molecule Commander) to generate candidate A1 adenosine receptor antagonists, which were evaluated against multiple criteria and objectives consisting of high (predicted) affinity and selectivity for the receptor, together with good ADMET properties. A pharmacophore model for the human A1 adenosine receptor (hA1AR) was created to serve as an objective function for evolution. In addition, three support vector machine models based on molecular fingerprints were developed for the other adenosine receptor subtypes (hA2A, hA2B, and hA3) and applied as negative objective functions, to aim for selectivity. Structures with a higher evolutionary fitness with respect to ADMET and pharmacophore matching scores were selected as input for the next generation and thus developed toward overall fitter ("better") compounds. We finally obtained a collection of 3946 unique compounds from which we derived chemical scaffolds. As a proof-of-principle, six of these templates were selected for actual synthesis and subsequently tested for activity toward all adenosine receptors subtypes. Interestingly, scaffolds 2 and 3 displayed low micromolar affinity for many of the adenosine receptor subtypes. To further investigate our evolutionary design method, we performed systematic modifications on scaffold 3. These modifications were guided by the substitution patterns as observed in the set of generated compounds that contained scaffold 3. We found that an increased affinity with appreciable selectivity for hA1AR over the other adenosine receptor subtypes was achieved through substitution of the scaffold; compound 3a had a Ki value of 280 nM with approximately 10-fold selectivity with respect to hA2AR, while 3g had a 1.6 ?M affinity for hA1AR with negligible affinity for the hA2A, hA2B, and hA3 receptor subtypes. PMID:22647079

van der Horst, Eelke; Marqués-Gallego, Patricia; Mulder-Krieger, Thea; van Veldhoven, Jacobus; Kruisselbrink, Johannes; Aleman, Alexander; Emmerich, Michael T M; Brussee, Johannes; Bender, Andreas; Ijzerman, Adriaan P



Insulin resistance and vasodilation in essential hypertension. Studies with adenosine.  

PubMed Central

Insulin-mediated vasodilation has been proposed as a determinant of in vivo insulin sensitivity. We tested whether sustained vasodilation with adenosine could overcome the muscle insulin resistance present in mildly overweight patients with essential hypertension. Using the forearm technique, we measured the response to a 40-min local intraarterial infusion of adenosine given under fasting conditions (n = 6) or superimposed on a euglycemic insulin clamp (n = 8). In the fasting state, adenosine-induced vasodilation (forearm blood flow from 2.6 +/- 0.6 to 6.0 +/- 1.2 ml min-1dl-1, P < 0.001) was associated with a 45% rise in muscle oxygen consumption (5.9 +/- 1.0 vs 8.6 +/- 1.7 mumol min-1dl-1, P < 0.05), and a doubling of forearm glucose uptake (0.47 +/- 0.15 to 1.01 +/- 0.28 mumol min-1dl-1, P < 0.05). The latter effect remained significant also when expressed as a ratio to concomitant oxygen balance (0.08 +/- 0.03 vs 0.13 +/- 0.04 mumol mumol-1, P < 0.05), whereas for all other metabolites (lactate, pyruvate, FFA, glycerol, citrate, and beta-hydroxybutyrate) this ratio remained unchanged. During euglycemic hyperinsulinemia, whole-body glucose disposal was stimulated (to 19 +/- 3 mumol min-1kg-1), but forearm blood flow did not increase significantly above baseline (2.9 +/- 0.2 vs 3.1 +/- 0.2 ml min-1dl-1, P = NS). Forearm oxygen balance increased (by 30%, P < 0.05) and forearm glucose uptake rose fourfold (from 0.5 to 2.3 mumol min-1dl-1, P < 0.05). Superimposing an adenosine infusion into one forearm resulted in a 100% increase in blood flow (from 2.9 +/- 0.2 to 6.1 +/- 0.9 ml min-1dl-1, P < 0.001); there was, however, no further stimulation of oxygen or glucose uptake compared with the control forearm. During the clamp, the ratio of glucose to oxygen uptake was similar in the control and in the infused forearms (0.27 +/- 0.11 and 0.23 +/- 0.09, respectively), and was not altered by adenosine (0.31 +/- 0.9 and 0.29 +/- 0.10). We conclude that in insulin-re15-76sistant patients with hypertension, adenosine-induced vasodilation recruits oxidative muscle tissues and exerts a modest, direct metabolic effect to promote muscle glucose uptake in the fasting state. Despite these effects, however, adenosine does not overcome muscle insulin resistance. Images

Natali, A; Bonadonna, R; Santoro, D; Galvan, A Q; Baldi, S; Frascerra, S; Palombo, C; Ghione, S; Ferrannini, E



Adenosine in cold blood cardioplegia - a placebo-controlled study  

PubMed Central

OBJECTIVE Adenosine as an additive in blood cardioplegia is cardioprotective in animal studies, but its clinical role in myocardial protection remains controversial. The aim of this study was to investigate whether the addition of adenosine in continuous cold blood cardioplegia would enhance myocardial protection. METHODS In a prospective double-blind study comparing adenosine 400 ?mol l?1 to placebo in continuous cold blood cardioplegia, 80 patients undergoing isolated aortic valve replacement were randomized into four groups: antegrade cardioplegia with adenosine (n = 19), antegrade cardioplegia with placebo (n = 21), retrograde cardioplegia with adenosine (n = 21) and retrograde cardioplegia with placebo (n = 19). Myocardial arteriovenous differences in oxygen and lactate were measured before, during and after aortic occlusion. Myocardial concentrations of adenine nucleotides and lactate were determined from left ventricular biopsies obtained before aortic occlusion, after bolus cardioplegia, at 60 min of aortic occlusion and at 20 min after aortic occlusion. Plasma creatine kinase (CK-MB) and troponin T were measured at 1, 3, 6, 9, 12 and 24 h after aortic occlusion. Haemodynamic profiles were obtained before surgery and 1, 8 and 24 h after cardiopulmonary bypass. Repeated-measures analysis of variance was used for significance testing. RESULTS Adenosine had no effects on myocardial metabolism of oxygen, lactate and adenine nucleotides, postoperative enzyme release or haemodynamic performance. When compared with the antegrade groups, the retrograde groups showed higher myocardial oxygen uptake (17.3 ± 11.4 versus 2.5 ± 3.6 ml l?1 at 60 min of aortic occlusion, P < 0.001) and lactate accumulation (43.1 ± 20.7 versus 36.3 ± 23.0 µmol g?1 at 60 min of aortic occlusion, P = 0.052) in the myocardium during aortic occlusion, and lower postoperative left ventricular stroke work index (27.2 ± 8.4 versus 30.1 ± 7.9 g × m × m?2, P = 0.034). CONCLUSIONS Adenosine 400 ?mol l?1 in cold blood cardioplegia showed no cardioprotective effects on the parameters studied. Myocardial ischaemia was more pronounced in patients receiving retrograde cardioplegia.

Ahlsson, Anders; Sobrosa, Claudio; Kaijser, Lennart; Jansson, Eva; Bomfim, Vollmer



Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture  

PubMed Central

Acupuncture is an invasive procedure commonly used to relieve pain. Acupuncture is practiced worldwide, despite difficulties in reconciling its principles with evidence-based medicine. We found that adenosine, a neuromodulator with anti-nociceptive properties, was released during acupuncture in mice and that its anti-nociceptive actions required adenosine A1 receptor expression. Direct injection of an adenosine A1 receptor agonist replicated the analgesic effect of acupuncture. Inhibition of enzymes involved in adenosine degradation potentiated the acupuncture-elicited increase in adenosine, as well as its anti-nociceptive effect. These observations indicate that adenosine mediates the effects of acupuncture and that interfering with adenosine metabolism may prolong the clinical benefit of acupuncture.

Goldman, Nanna; Chen, Michael; Fujita, Takumi; Xu, Qiwu; Peng, Weiguo; Liu, Wei; Jensen, Tina K; Pei, Yong; Wang, Fushun; Han, Xiaoning; Chen, Jiang-Fan; Schnermann, Jurgen; Takano, Takahiro; Bekar, Lane; Tieu, Kim; Nedergaard, Maiken



Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity  

PubMed Central

Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of adenosine remains unclear. We report here that multiple enzymes degrade extracellular ATP in brain tissue, whereas only Nt5e degrades AMP to adenosine. However, endogenous A1 receptor activation during cortical seizures in vivo or heterosynaptic depression in situ is independent of Nt5e activity, and activation of astrocytic ATP release via Ca2+ photolysis does not trigger synaptic depression. In contrast, selective activation of postsynaptic CA1 neurons leads to release of adenosine and synaptic depression. This study shows that adenosine-mediated synaptic depression is not a consequence of astrocytic ATP release, but is instead an autonomic feedback mechanism that suppresses excitatory transmission during prolonged activity.

Lovatt, Ditte; Xu, Qiwu; Liu, Wei; Takano, Takahiro; Smith, Nathan A.; Schnermann, Jurgen; Tieu, Kim; Nedergaard, Maiken



Regional haemodynamic responses to adenosine receptor activation vary across time following lipopolysaccharide treatment in conscious rats  

PubMed Central

Background and purpose: Studies using adenosine receptor antagonists have shown that adenosine-mediated vasodilatations play an important role in the maintenance of regional perfusion during sepsis, but it is unclear whether vascular sensitivity to adenosine is affected. Here, we assessed regional haemodynamic responses to adenosine agonists and antagonists in normal and lipopolysaccharide (LPS)-treated rats to investigate a possible role for adenosine in the haemodynamic sequelae. Experimental approach: Male Sprague–Dawley rats were chronically instrumented with pulsed Doppler flow probes to measure regional haemodynamic responses to adenosine-receptor agonists (adenosine, 2-choloro-N6-cyclopentyladenosine (CCPA)) and antagonists (8-phenyltheophylline (8-PT), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)), at selected time points in control and LPS-treated rats. Key results: The responses to 8-PT were consistent with endogenous adenosine causing bradycardia, and renal and hindquarters vasodilatation in control rats, whereas in LPS-treated rats, there was evidence for endogenous adenosine causing renal (at 1.5?h) and hindquarters (at 6?h) vasoconstriction. In control animals, exogenous adenosine caused hypotension, tachycardia and widespread vasodilatation, whereas in LPS-treated rats, the adenosine-induced renal (at 1.5?h) and hindquarters (at 6?h) vasodilatations were abolished. As enhanced A1 receptor-mediated vasoconstriction could explain the results in LPS-treated rats, vascular responsiveness to a selective A1-receptor agonist (CCPA) or antagonist (DPCPX) was assessed. There was no evidence for enhanced vasoconstrictor responsiveness to CCPA in LPS-treated rats, but DPCPX caused renal vasodilatation, consistent with endogenous adenosine mediating renal vasoconstriction under these conditions. Conclusions and implications: The results show changes in adenosine receptor-mediated cardiovascular effects in endotoxaemia that may have implications for the use of adenosine-based therapies in sepsis.

Jolly, L; March, J E; Kemp, P A; Bennett, T; Gardiner, S M



Feedback Effects of Host-Derived Adenosine on Enteropathogenic Escherichia coli  

PubMed Central

Enteropathogenic Escherichia coli (EPEC) is a common cause of watery diarrhea in children in developing countries. After adhering intimately to small intestinal cells, EPEC secretes effector proteins into host cells, altering host cell functions and causing cell damage and death. We previously showed that EPEC infection triggers the release of adenosine triphosphate (ATP) from host cells and that ATP is broken down to ADP, AMP, and adenosine. Adenosine produced from the breakdown of extracellular ATP triggers fluid secretion in cultured intestinal monolayers and may be an important mediator of EPEC-induced diarrhea. In this study we examined whether adenosine has any effects on EPEC bacteria themselves. Adenosine stimulated EPEC growth in several types of media in vitro. Adenosine also altered the pattern of EPEC adherence to cultured cells from a classic localized adherence pattern to a more diffuse adherence pattern. Adenosine changed the pattern of expression of virulence factors in EPEC, inhibiting the expression of the bundle-forming pilus (BFP) and enhancing expression of the EPEC secreted proteins (Esps). The ability of adenosine to inhibit BFP was dependent on the Plasmid-encoded Regulator (Per). In vivo, experimental manipulations of adenosine levels had strong effects on the outcome of EPEC infection in rabbit intestinal loops. Reduction in adenosine levels by addition of exogenous adenosine deaminase (ADA) reduced numbers of EPEC bacteria recovered by over 10-fold in rabbit intestine in vivo. Conversely, inhibitors of ADA increased EPEC-induced fluid secretion, the number of EPEC bacteria recovered from intestinal fluid, and increased the in vivo expression of espA and espB. In addition to its previously reported effects on host cells and tissues, adenosine also has strong effects on EPEC bacteria, stimulating EPEC growth, altering its adherence pattern, and changing the expression of several important virulence genes. Adenosine is released from host cells in response to EPEC infection, and it appears that EPEC has the ability to sense and respond to the adenosine produced.

Crane, John K.; Shulgina, Irina



Enhanced airway inflammation and remodeling in adenosine deaminase-deficient mice lacking the A2B adenosine receptor.  


Adenosine is a signaling nucleoside that is generated in response to cellular injury and orchestrates the balance between tissue protection and the progression to pathological tissue remodeling. Adenosine deaminase (ADA)-deficient mice develop progressive airway inflammation and remodeling in association with adenosine elevations, suggesting that adenosine can promote features of chronic lung disease. Furthermore, pharmacological studies in ADA-deficient mice demonstrate that A(2B)R antagonism can attenuate features of chronic lung disease, implicating this receptor in the progression of chronic lung disease. This study examines the contribution of A(2B)R signaling in this model by generating ADA/A(2B)R double-knockout mice. Our hypothesis was that genetic removal of the A(2B)R from ADA-deficient mice would lead to diminished pulmonary inflammation and damage. Unexpectedly, ADA/A(2B)R double-knockout mice exhibited enhanced pulmonary inflammation and airway destruction. Marked loss of pulmonary barrier function and excessive airway neutrophilia are thought to contribute to the enhanced tissue damage observed. These findings support an important protective role for A(2B)R signaling during acute stages of lung disease. PMID:19494329

Zhou, Yang; Mohsenin, Amir; Morschl, Eva; Young, Hays W J; Molina, Jose G; Ma, Wenbin; Sun, Chun-Xiao; Martinez-Valdez, Hector; Blackburn, Michael R



Mechanism of A2 adenosine receptor activation. I. Blockade of A2 adenosine receptors by photoaffinity labeling  

SciTech Connect

It has previously been shown that covalent incorporation of the photoreactive adenosine derivative (R)-2-azido-N6-p-hydroxy-phenylisopropyladenosine ((R)-AHPIA) into the A1 adenosine receptor of intact fat cells leads to a persistent activation of this receptor, resulting in a reduction of cellular cAMP levels. In contrast, covalent incorporation of (R)-AHPIA into human platelet membranes, which contain only stimulatory A2 adenosine receptors, reduces adenylate cyclase stimulation via these receptors. This effect of (R)-AHPIA is specific for the A2 receptor and can be prevented by the adenosine receptor antagonist theophylline. Binding studies indicate that up to 90% of A2 receptors can be blocked by photoincorporation of (R)-AHPIA. However, the remaining 10-20% of A2 receptors are sufficient to mediate an adenylate cyclase stimulation of up to 50% of the control value. Similarly, the activation via these 10-20% of receptors occurs with a half-life that is only 2 times longer than that in control membranes. This indicates the presence of a receptor reserve, with respect to both the extent and the rate of adenylate cyclase stimulation. These observations require a modification of the models of receptor-adenylate cyclase coupling.

Lohse, M.J.; Klotz, K.N.; Schwabe, U.



Adenosine-induced release of cyclic adenosine 3',5'-monophosphate from the left ventricle in the anaesthetized intact dog.  

PubMed Central

1. The influence of adenosine on the release of cyclic adenosine 3',5'-monophosphate (cyclic AMP) from the heart was examined in twenty-two anaesthetized intact dogs. The animals were pre-treated with propranolol and vagotomized. The rate of nucleotide release from the left ventricle was determined as the product of the left ventricular myocardial plasma flow and the coronary veno-arterial difference in plasma nucleotide concentration. 2. Adenosine was infused into the left ventricle during three successive 15 min periods at rates of 25, 50 and 100 n-mole/kg. min, respectively. The mean blood pressure in the ascending aorta was prevented from falling by inflating a balloon placed into the thoracic aorta. The measurements were performed before the infusion and at the 10th min of each infusion period. The values given are means +/- S.E. 3. During the 45 min infusion of adenosine at increasing rate, the cyclic AMP concentration in arterial plasma increased from 7.0 +/- 0.3 to 14.0 +/- 0.9 p-mole/ml. The nucleotide was released from the left ventricle at rates increasing from 48.2 +/- 7.1 to 206.5 +/- 56.2 p-mole/100 g. min while the left ventricular myocardial blood flow increased from 127 +/- 6 to 399 +/- 33 ml./100 g.min. The oxygen consumption of the left ventricle was not modified. 4. When adenosine was infused at a rate of 100 n-mol/kg.min, the thorax was opened and the apex of the heart and the left atrial appendage were removed for nucleotide assay. The cardiac cyclic AMP concentration did not differ from that observed in control dogs. 5. The results suggest that cyclic AMP is likely to be involved in the membrane and cellular events underlying the relaxant effect of adenosine on the coronary smooth muscle. The lack of change in cardiac cyclic AMP concentration, as determined by whole tissue extractions, is consistent with a study by others showing that, under normoxic conditions, cyclic AMP is released from a small, compartmentalized fraction of the cyclic AMP content of the heart. The elevation of the plasma nucleotide concentration could result from adenosine effects on various cell systems or organs, in addition to the observed release from the heart.

Huynh-Thu, T; Lammerant, J



Spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors, are involved in antinociception by systemically administered amitriptyline.  


The present study explored a link between spinal 5-HT(7) and adenosine A(1) receptors in antinociception by systemic amitriptyline in normal and adenosine A(1) receptor knock-out mice using the 2% formalin test. In normal mice, antinociception by systemic amitriptyline 3mg/kg was blocked by intrathecal administration of the selective adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) 10 nmol. Blockade was also seen in adenosine A(1) receptor +/+ mice, but not in -/- mice lacking these receptors. In both normal and adenosine A(1) receptor +/+ mice, the selective 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB269970) 3 ?g blocked antinociception by systemic amitriptyline, but it did not prevent antinociception in adenosine A(1) receptor -/- mice. In normal mice, flinching was unaltered when the selective 5-HT(7) receptor agonist (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS-19) 20 ?g was administered alone, but increased when co-administered intrathecally with DPCPX 10 nmol or SB269970 3 ?g. Intrathecal AS-19 decreased flinching in adenosine A(1) receptor +/+ mice compared to -/- mice. Systemic amitriptyline appears to reduce nociception by activating spinal adenosine A(1) receptors secondarily to 5-HT(7) receptors. Spinal actions constitute only one aspect of antinociception by amitriptyline, as intraplantar DPCPX 10 nmol blocked antinociception by systemic amitriptyline in normal and adenosine A(1) receptor +/+, but not -/- mice. Adenosine A(1) receptor interactions are worthy of attention, as chronic oral caffeine (0.1, 0.3g/L, doses considered relevant to human intake levels) blocked antinociception by systemic amitriptyline in normal mice. In conclusion, adenosine A(1) receptors contribute to antinociception by systemic amitriptyline in both spinal and peripheral compartments. PMID:23142373

Liu, Jean; Reid, Allison R; Sawynok, Jana



Sustained adenosine exposure causes lung endothelial apoptosis: a possible contributor to cigarette smoke-induced endothelial apoptosis and lung injury.  


Pulmonary endothelial cell (EC) apoptosis has been implicated in the pathogenesis of emphysema. Cigarette smoke (CS) causes lung EC apoptosis and emphysema. In this study, we show that CS exposure increased lung tissue adenosine levels in mice, an effect associated with increased lung EC apoptosis and the development of emphysema. Adenosine has a protective effect against apoptosis via adenosine receptor-mediated signaling. However, sustained elevated adenosine increases alveolar cell apoptosis in adenosine deaminase-deficient mice. We established an in vitro model of sustained adenosine exposure by incubating lung EC with adenosine in the presence of an adenosine deaminase inhibitor, deoxycoformicin. We demonstrated that sustained adenosine exposure caused lung EC apoptosis via nucleoside transporter-facilitated intracellular adenosine uptake, subsequent activation of p38 and JNK in mitochondria, and ultimately mitochondrial defects and activation of the mitochondria-mediated intrinsic pathway of apoptosis. Our results suggest that sustained elevated adenosine may contribute to CS-induced lung EC apoptosis and emphysema. Our data also reconcile the paradoxical effects of adenosine on apoptosis, demonstrating that prolonged exposure causes apoptosis via nucleoside transporter-mediated intracellular adenosine signaling, whereas acute exposure protects against apoptosis via activation of adenosine receptors. Inhibition of adenosine uptake may become a new therapeutic target in treatment of CS-induced lung diseases. PMID:23316066

Lu, Qing; Sakhatskyy, Pavlo; Newton, Julie; Shamirian, Paul; Hsiao, Vivian; Curren, Sean; Gabino Miranda, Gustavo Andres; Pedroza, Mesias; Blackburn, Michael R; Rounds, Sharon



Adenosine protected against pulmonary edema through transporter- and receptor A2-mediated endothelial barrier enhancement  

PubMed Central

We have previously demonstrated that adenosine plus homocysteine enhanced endothelial basal barrier function and protected against agonist-induced barrier dysfunction in vitro through attenuation of RhoA activation by inhibition of isoprenylcysteine-O-carboxyl methyltransferase. In the current study, we tested the effect of elevated adenosine on pulmonary endothelial barrier function in vitro and in vivo. We noted that adenosine alone dose dependently enhanced endothelial barrier function. While adenosine receptor A1 or A3 antagonists were ineffective, an adenosine transporter inhibitor, NBTI, or a combination of DPMX and MRS1754, antagonists for adenosine receptors A2A and A2B, respectively, partially attenuated the barrier-enhancing effect of adenosine. Similarly, inhibition of both A2A and A2B receptors with siRNA also blunted the effect of adenosine on barrier function. Interestingly, inhibition of both transporters and A2A/A2B receptors completely abolished adenosine-induced endothelial barrier enhancement. The adenosine receptor A2A and A2B agonist, NECA, also significantly enhanced endothelial barrier function. These data suggest that both adenosine transporters and A2A and A2B receptors are necessary for exerting maximal effect of adenosine on barrier enhancement. We also found that adenosine enhanced Rac1 GTPase activity and overexpression of dominant negative Rac1 attenuated adenosine-induced increases in focal adhesion complexes. We further demonstrated that elevation of cellular adenosine by inhibition of adenosine deaminase with Pentostatin significantly enhanced endothelial basal barrier function, an effect that was also associated with enhanced Rac1 GTPase activity and with increased focal adhesion complexes and adherens junctions. Finally, using a non-inflammatory acute lung injury (ALI) model induced by ?-naphthylthiourea, we found that administration of Pentostatin, which elevated lung adenosine level by 10-fold, not only attenuated the development of edema before ALI but also partially reversed edema after ALI. The data suggest that adenosine deaminase inhibition may be useful in treatment of pulmonary edema in settings of ALI.

Lu, Qing; Harrington, Elizabeth O.; Newton, Julie; Casserly, Brian; Radin, Gregory; Warburton, Rod; Zhou, Yang; Blackburn, Michael R.



Activation of murine lung mast cells by the adenosine A3 receptor.  


Adenosine has been implicated to play a role in asthma in part through its ability to influence mediator release from mast cells. Most physiological roles of adenosine are mediated through adenosine receptors; however, the mechanisms by which adenosine influences mediator release from lung mast cells are not understood. We established primary murine lung mast cell cultures and used real-time RT-PCR and immunofluorescence to demonstrate that the A(2A), A(2B), and A(3) adenosine receptors are expressed on murine lung mast cells. Studies using selective adenosine receptor agonists and antagonists suggested that activation of A(3) receptors could induce mast cell histamine release in association with increases in intracellular Ca(2+) that were mediated through G(i) and phosphoinositide 3-kinase signaling pathways. The function of A(3) receptors in vivo was tested by exposing mice to the A(3) receptor agonist, IB-MECA. Nebulized IB-MECA directly induced lung mast cell degranulation in wild-type mice while having no effect in A(3) receptor knockout mice. Furthermore, studies using adenosine deaminase knockout mice suggested that elevated endogenous adenosine induced lung mast cell degranulation by engaging A(3) receptors. These results demonstrate that the A(3) adenosine receptor plays an important role in adenosine-mediated murine lung mast cell degranulation. PMID:12817016

Zhong, Hongyan; Shlykov, Sergiy G; Molina, Jose G; Sanborn, Barbara M; Jacobson, Marlene A; Tilley, Stephen L; Blackburn, Michael R



Adenosine and inosine increase cutaneous vasopermeability by activating A(3) receptors on mast cells.  


Adenosine has potent effects on both the cardiovascular and immune systems. Exposure of tissues to adenosine results in increased vascular permeability and extravasation of serum proteins. The mechanism by which adenosine brings about these physiological changes is poorly defined. Using mice deficient in the A(3) adenosine receptor (A(3)AR), we show that increases in cutaneous vascular permeability observed after treatment with adenosine or its principal metabolite inosine are mediated through the A(3)AR. Adenosine fails to increase vascular permeability in mast cell-deficient mice, suggesting that this tissue response to adenosine is mast cell-dependent. Furthermore, this response is independent of activation of the high-affinity IgE receptor (FcepsilonR1) by antigen, as adenosine is equally effective in mediating these changes in FcepsilonR1 beta-chain-deficient mice. Together these results support a model in which adenosine and inosine induce changes in vascular permeability indirectly by activating mast cells, which in turn release vasoactive substances. The demonstration in vivo that adenosine, acting through a specific receptor, can provoke degranulation of this important tissue-based effector cell, independent of antigen activation of the high-affinity IgE receptor, supports an important role for this nucleoside in modifying the inflammatory response. PMID:10675362

Tilley, S L; Wagoner, V A; Salvatore, C A; Jacobson, M A; Koller, B H



Adenosine Regulation of Cystic Fibrosis Transmembrane Conductance Regulator through Prostenoids in Airway Epithelia  

PubMed Central

Cystic fibrosis is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, leading to altered ion transport, chronic infection, and excessive inflammation. Here we investigated regulation of CFTR in airway cell monolayers by adenosine, adenosine receptors, and arachidonic acid. Our studies demonstrate that the A2B adenosine receptor is expressed at high levels relative to the other adenosine receptor subtypes, with a characteristic low-affinity profile for adenosine-stimulated CFTR Cl? currents in both Calu-3 cells and CFBE41o- airway cell monolayers stably transduced with wild-type CFTR. The levels of adenosine found in sputum from patients with cystic fibrosis with moderate to severe lung disease stimulated apical prostaglandin release in Calu-3 and CFBE41o- cells, implicating adenosine regulation of phospholipase A2 (PLA2) activity. A2B adenosine receptor and arachidonic acid stimulation produced CFTR-dependent currents in airway monolayers and increased cAMP levels that were sensitive to cyclooxygenase inhibition. Arachidonic acid demonstrated dual regulation of CFTR, stimulating CFTR and Cl? currents in intact airway monolayers, and potently inhibiting PKA-activated Cl? currents in excised membrane patches. Cl? currents produced by arachidonic acid were sensitive to inhibition of PKA, cyclooxygenase, and 5-lipoxygenase. Together, the results provide a converging mechanism to link regulation of CFTR and airway cell inflammation through adenosine and adenosine receptors.

Li, Yao; Wang, Wei; Parker, William; Clancy, J. P.



Presynaptic K-channel blockade counteracts the depressant effect of adenosine in olfactory cortex.  


Slices of isolated olfactory cortex from guinea-pig have been used to study the action of adenosine at synapses between axons of the lateral olfactory tract and neurons in the olfactory cortex. Adenosine depressed the excitatory postsynaptic potential, and, with paired or multiple stimuli, the reduced excitatory postsynaptic potentials in adenosine showed more synaptic facilitation. Very small excitatory postsynaptic potentials which were estimated not to be affected by postsynaptic membrane conductance changes were highly sensitive to adenosine. Both observations indicate a presynaptic action of adenosine. To test whether a conductance increase to potassium ions mediated adenosine action, the K-channel blockers, 3,4-diaminopyridine (1-100 mumol/l) or 4-aminopyridine (100-500 mumol/l) were applied or Cs partially substituted for K. These substances reduced or prevented adenosine from having its depressant effect on synaptic transmission. These particular K-channel blockers also prolonged the action potential propagating along the lateral olfactory tract. When the increased excitability was counteracted by high Mg or low concentrations of tetrodotoxin, 3,4-diaminopyridine still blocked adenosine action. UO2 ions prolonged the lateral olfactory tract action potential without blockade of K-conductance, but still supported an adenosine depression of the excitatory postsynaptic potential. Veratridine also supported the adenosine depression. These observations suggest that the action of 3,4-diaminopyridine on adenosine was not solely the result of increased tissue excitability. In contrast, tetraethylammonium (20 mmol/l), Ba (0.5-4 mmol/l) or Rb replacement for K had a negligible effect on the duration of the presynaptic action potential and had no effect on the depressant action of adenosine. These data are compatible with the idea that adenosine enhances an aminopyridine-sensitive potassium conductance in nerve terminals and changes in Ca influx are consequential to this. PMID:2452996

Scholfield, C N; Steel, L



In vivo evidence against a role for adenosine in the exercise pressor reflex in humans.  


The pressor response to exercise is of great importance in both physiology and pathophysiology. Whether endogenous adenosine is a trigger for this reflex remains controversial. Muscle interstitial adenosine concentration can be determined by microdialysis. However, there are indications that local muscle cell damage by the microdialysis probe confounds these measurements in exercising muscle. Therefore, we used the nucleoside uptake inhibitor dipyridamole as pharmacological tool to bypass this confounding. We used microdialysis probes to measure endogenous adenosine in forearm skeletal muscle of healthy volunteers during two cycles of 15 min of intermittent isometric handgripping. During the second contraction, dipyridamole (12 microg.min(-1).dl forearm(-1)) was administered into the brachial artery. Dipyridamole potentiated the exercise-induced increase in dialysate adenosine from 0.30 +/- 0.08 to 0.48 +/- 0.10 micromol/l (n = 9, P < 0.05), but it did not potentiate the exercise-induced increase in blood pressure. A time-control study without dipyridamole revealed no difference in exercise-induced increase in adenosine between both contractions (n = 8). To exclude the possibility that the dipyridamole-induced increase in dialysate adenosine originates from extravasation of increased circulating adenosine, we simultaneously measured adenosine with microdialysis probes in forearm muscle and antecubital vein. In a separate group of nine volunteers, simultaneous intrabrachial infusion of 100 microg.min(-1).dl(-1) dipyridamole and 5 microg.min(-1).dl(-1) adenosine increased dialysate adenosine from the intravenous but not the interstitial probe, indicating preserved endothelial barrier function for adenosine. We conclude that dipyridamole significantly inhibits uptake of interstitial adenosine without affecting the pressor response to exercise, suggesting that interstitial adenosine is not involved in the pressor response to rhythmic isometric exercise. PMID:15817726

Riksen, Niels P; van Ginneken, Egidia E M; van den Broek, Petra H H; Smits, Paul; Rongen, Gerard A



Study of the substrate-binding properties of bovine liver adenosine kinase and inhibition by fluorescent nucleoside analogues.  


Adenosine kinase (AK) catalyzes the phosphorylation of adenosine to AMP with ATP as phosphate donor. Intrinsic fluorescence of bovine liver AK was shown previously to be a sensitive probe to quantify the binding of substrates to the enzyme [Elaloui, A., Divita, G., Maury, G., Imbach, J.-L. & Goody, R. S. (1994) Eur. J Biochem. 221, 839-846]. AK contains two catalytic, sites: a high-affinity site, which binds adenosine and AMP selectively; and a site for ATP and ADP. In the present work, these two sites were characterized by combining the quenching of protein fluorescence induced by the binding of the ligands and the fluorescence enhancement observed upon binding of the N-methylanthraniloyl-derivated nucleotides or adenosine. A new fluorescent analog of adenosine, 5'-N-methylanthraniloyl-adenosine, was synthesized and shown to bind selectively to the high-affinity adenosine-binding site with an affinity similar to that of adenosine (Kd 1 microM). In contrast, 2'(3')-N-methylanthraniloyl derivatives of ATP, adenosine (5')tetraphospho(5')adenosine (Ap4A), and adenosine (5')pentaphospho(5')adenosine (Ap5A), bind to the enzyme at the ATP site. Methylantraniloyl derivatives of ATP and adenosine were used as tools for selective characterization of a series of adenosine analogues. The bisubstrate inhibitors Ap4A and Ap5A bind to the ATP site with high affinity and apparently not to the adenosine site, thus acting more as ATP analogues than true bisubstrate ligands. The binding properties of a series of adenosine analogues were strongly dependent on the structural modifications on adenosine. The analogues modified at positions 2' or 3' show similar affinities for AK as that of adenosine, whereas adenosine analogues modified at the base present a relatively low affinity for the enzyme. PMID:9342249

Pelicano, H; Maury, G; Elalaoui, A; Shafiee, M; Imbach, J L; Goody, R S; Divita, G



Adenosine induced pulmonary fibrosis and the contribution of the adenosine A2B receptor to the induction of osteopontin in a mouse model of pulmonary fibrosis  

Microsoft Academic Search

Pulmonary fibrosis is a devastating and lethal lung disease with no current cure. Research into cellular signaling pathways able to modulate aspects of pulmonary inflammation and fibrosis will aid in the development of effective therapies for its treatment. Our laboratory has generated a transgenic\\/knockout mouse with systemic elevations in adenosine due to the partial lack of its metabolic enzyme, adenosine

Janci Lee Chunn



Characterization of cardiac adenosine receptors using N/sup 6/-phenyladenosines and a new radioligand, (/sup 125/I)-(m-aminophenyl)adenosine  

SciTech Connect

The chick heart contains adenosine receptors with characteristics similar to the R adenosine receptors found in the CNS. They have synthesized several N/sup 6/-phenyladenosines and tested their potencies for inhibiting the binding of (/sup 125/I)(p-aminobenzyl)adenosine )(/sup 125/I)ABA) to chick heart membranes. Of the 12 compounds tested, N/sup 6/-(p-aminobenzyl) adenosine (ABA) was the least potent (IC/sub 50/ approx. 40 nM) while N/sup 6/-(m-nitrophenyl)adenosine(MNPA) was the most potent (IC/sub 50/ approx. 1 nM). The IC/sub 50/ of N/sup 6/-(m-aminophenyl)adenosine(MAPA) was greater than that of N/sup 6/-phenyladenosine(PA) while that of MNPA was less than that of PA. The effects of these electron-releasing (-NH/sub 2/) and electron-withdrawing (-NO/sub 2/) groups along with data obtained with other phenyl-substituted N/sup 6/-phenyladenosines suggest that the electron density of the N/sup 6/-nitrogen may affect the affinities of these compounds for the cardiac adenosine receptor. MAPA can be iodinated to produce a new ligand, (/sup 125/I)MAPA. This iodination, like that of ABA, increases the affinity of the compound and produces a ligand with good affinity and low nonspecific binding suitable for studies on tissues with low concentrations of adenosine receptors.

Kwatra, M.M.; Hosey, M.M.; Green, R.



Role of central and peripheral adenosine receptors in the cardiovascular responses to intraperitoneal injections of adenosine A1 and A2A subtype receptor agonists.  


1. The cardiovascular effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the adenosine A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) were investigated in rats implanted with telemetry transmitters for the measurement of blood pressure and heart rate. 2. Intraperitoneal (i.p.) injections of the adenosine A1 receptor agonist CPA led to dose-dependent decreases in both blood pressure and heart rate. These effects of 0.3 mg kg(-1) CPA were antagonized by i.p. injections of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethyl-xanthine (CPT), but not by i.p. injections of the adenosine A2A receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3). Injections (i.p.) of the peripherally acting nonselective adenosine antagonist 8-sulfophenyltheophylline (8-SPT) and the purported nonselective adenosine antagonist caffeine also antagonized the cardiovascular effects of CPA. 3. The adenosine A2A agonist CGS 21680 given i.p. produced a dose-dependent decrease in blood pressure and an increase in heart rate. These effects of 0.5 mg kg(-1) CGS 21680 were antagonized by i.p. injections of the adenosine A2A receptor antagonist MSX-3, but not by i.p. injections of the antagonists CPT, 8-SPT or caffeine. 4. Central administration (intracerebral ventricular) of CGS 21680 produced an increase in heart rate, but no change in blood pressure. MSX-3 given i.p. antagonized the effects of the central injection of CGS 21680. 5. These results suggest that adenosine A1 receptor agonists produce decreases in blood pressure and heart rate that are mediated by A1 receptors in the periphery, with little or no contribution of central adenosine A1 receptors to those effects. 6. The heart rate increasing effect of adenosine A2A agonists appears to be mediated by adenosine A2A receptors in the central nervous system. The blood pressure decreasing effect of adenosine A2A agonists is most probably mediated in the periphery. PMID:15678095

Schindler, Charles W; Karcz-Kubicha, Marzena; Thorndike, Eric B; Müller, Christa E; Tella, Srihari R; Ferré, Sergi; Goldberg, Steven R



Novel adenosine A(2A) receptor ligands: a synthetic, functional and computational investigation of selected literature adenosine A(2A) receptor antagonists for extending into extracellular space.  


Growing evidence has suggested a role in targeting the adenosine A2A receptor for the treatment of Parkinson's disease. The literature compounds KW 6002 (2) and ZM 241385 (5) were used as a starting point from which a series of novel ligands targeting the adenosine A2A receptor were synthesized and tested in a recombinant human adenosine A2A receptor functional assay. In order to further explore these molecules, we investigated the biological effects of assorted linkers attached to different positions on selected adenosine A2A receptor antagonists, and assessed their potential binding modes using molecular docking studies. The results suggest that linking from the phenolic oxygen of selected adenosine A2A receptor antagonists is relatively well tolerated due to the extension towards extracellular space, and leads to the potential of attaching further functionality from this position. PMID:23602401

Jörg, Manuela; Shonberg, Jeremy; Mak, Frankie S; Miller, Neil D; Yuriev, Elizabeth; Scammells, Peter J; Capuano, Ben



Soluble Ecto-5'-nucleotidase (5'-NT), Alkaline Phosphatase, and Adenosine Deaminase (ADA1) Activities in Neonatal Blood Favor Elevated Extracellular Adenosine.  


Extracellular adenosine, a key regulator of physiology and immune cell function that is found at elevated levels in neonatal blood, is generated by phosphohydrolysis of adenine nucleotides released from cells and catabolized by deamination to inosine. Generation of adenosine monophosphate (AMP) in blood is driven by cell-associated enzymes, whereas conversion of AMP to adenosine is largely mediated by soluble enzymes. The identities of the enzymes responsible for these activities in whole blood of neonates have been defined in this study and contrasted to adult blood. We demonstrate that soluble 5'-nucleotidase (5'-NT) and alkaline phosphatase (AP) mediate conversion of AMP to adenosine, whereas soluble adenosine deaminase (ADA) catabolizes adenosine to inosine. Newborn blood plasma demonstrates substantially higher adenosine-generating 5'-NT and AP activity and lower adenosine-metabolizing ADA activity than adult plasma. In addition to a role in soluble purine metabolism, abundant AP expressed on the surface of circulating neonatal neutrophils is the dominant AMPase on these cells. Plasma samples from infant observational cohorts reveal a relative plasma ADA deficiency at birth, followed by a gradual maturation of plasma ADA through infancy. The robust adenosine-generating capacity of neonates appears functionally relevant because supplementation with AMP inhibited whereas selective pharmacologic inhibition of 5'-NT enhanced Toll-like receptor-mediated TNF-? production in neonatal whole blood. Overall, we have characterized previously unrecognized age-dependent expression patterns of plasma purine-metabolizing enzymes that result in elevated plasma concentrations of anti-inflammatory adenosine in newborns. Targeted manipulation of purine-metabolizing enzymes may benefit this vulnerable population. PMID:23897810

Pettengill, Matthew; Robson, Simon; Tresenriter, Megan; Millán, José Luis; Usheva, Anny; Bingham, Taiese; Belderbos, Mirjam; Bergelson, Ilana; Burl, Sarah; Kampmann, Beate; Gelinas, Laura; Kollmann, Tobias; Bont, Louis; Levy, Ofer



Genetic removal of the A2A adenosine receptor enhances pulmonary inflammation, mucin production, and angiogenesis in adenosine deaminase-deficient mice.  


Adenosine is generated at sites of tissue injury where it serves to regulate inflammation and damage. Adenosine signaling has been implicated in the regulation of pulmonary inflammation and damage in diseases such as asthma and chronic obstructive pulmonary disease; however, the contribution of specific adenosine receptors to key immunoregulatory processes in these diseases is still unclear. Mice deficient in the purine catabolic enzyme adenosine deaminase (ADA) develop pulmonary inflammation and mucous metaplasia in association with adenosine elevations making them a useful model for assessing the contribution of specific adenosine receptors to adenosine-mediated pulmonary disease. Studies suggest that the A(2A) adenosine receptor (A(2A)R) functions to limit inflammation and promote tissue protection; however, the contribution of A(2A)R signaling has not been examined in the ADA-deficient model of adenosine-mediated lung inflammation. The purpose of the current study was to examine the contribution of A(2A)R signaling to the pulmonary phenotype seen in ADA-deficient mice. This was accomplished by generating ADA/A(2A)R double knockout mice. Genetic removal of the A(2A)R from ADA-deficient mice resulted in enhanced inflammation comprised largely of macrophages and neutrophils, mucin production in the bronchial airways, and angiogenesis, relative to that seen in the lungs of ADA-deficient mice with the A(2A)R. In addition, levels of the chemokines monocyte chemoattractant protein-1 and CXCL1 were elevated, whereas levels of cytokines such as TNF-alpha and IL-6 were not. There were no compensatory changes in the other adenosine receptors in the lungs of ADA/A(2A)R double knockout mice. These findings suggest that the A(2A)R plays a protective role in the ADA-deficient model of pulmonary inflammation. PMID:17601796

Mohsenin, Amir; Mi, Tiejuan; Xia, Yang; Kellems, Rodney E; Chen, Jiang-Fan; Blackburn, Michael R



Soluble Ecto-5?-nucleotidase (5?-NT), Alkaline Phosphatase, and Adenosine Deaminase (ADA1) Activities in Neonatal Blood Favor Elevated Extracellular Adenosine*  

PubMed Central

Extracellular adenosine, a key regulator of physiology and immune cell function that is found at elevated levels in neonatal blood, is generated by phosphohydrolysis of adenine nucleotides released from cells and catabolized by deamination to inosine. Generation of adenosine monophosphate (AMP) in blood is driven by cell-associated enzymes, whereas conversion of AMP to adenosine is largely mediated by soluble enzymes. The identities of the enzymes responsible for these activities in whole blood of neonates have been defined in this study and contrasted to adult blood. We demonstrate that soluble 5?-nucleotidase (5?-NT) and alkaline phosphatase (AP) mediate conversion of AMP to adenosine, whereas soluble adenosine deaminase (ADA) catabolizes adenosine to inosine. Newborn blood plasma demonstrates substantially higher adenosine-generating 5?-NT and AP activity and lower adenosine-metabolizing ADA activity than adult plasma. In addition to a role in soluble purine metabolism, abundant AP expressed on the surface of circulating neonatal neutrophils is the dominant AMPase on these cells. Plasma samples from infant observational cohorts reveal a relative plasma ADA deficiency at birth, followed by a gradual maturation of plasma ADA through infancy. The robust adenosine-generating capacity of neonates appears functionally relevant because supplementation with AMP inhibited whereas selective pharmacologic inhibition of 5?-NT enhanced Toll-like receptor-mediated TNF-? production in neonatal whole blood. Overall, we have characterized previously unrecognized age-dependent expression patterns of plasma purine-metabolizing enzymes that result in elevated plasma concentrations of anti-inflammatory adenosine in newborns. Targeted manipulation of purine-metabolizing enzymes may benefit this vulnerable population.

Pettengill, Matthew; Robson, Simon; Tresenriter, Megan; Millan, Jose Luis; Usheva, Anny; Bingham, Taiese; Belderbos, Mirjam; Bergelson, Ilana; Burl, Sarah; Kampmann, Beate; Gelinas, Laura; Kollmann, Tobias; Bont, Louis; Levy, Ofer



Phosphorylation of Adenosine with Trimetaphosphate Under Simulated Prebiotic Conditions  

Microsoft Academic Search

The phosphorylation of adenosine withtrimetaphosphate in solution, in solid phase and usingwet-dry cycles was carried out and it was found thatwet-dry cycles were the most efficient. The catalytic effectsof some metal ions on the phosphorylation were alsostudied and it was discovered that Ni(II) is the mosteffective. The combination of wet-dry cycles (4 cycles)and catalysis by Ni(II) led to an unprecedented

Changmei Cheng; Chang Fan; Rong Wan; Chunyuan Tong; Zhiwei Miao; Jing Chen; Yufen Zhao



Severe combined immunodeficiency due to adenosine deaminase deficiency.  


Severe Combined Immunodeficiency is the term applied to a group of rare genetic disorders characterised by defective or absent T and B cell functions. Patients usually present in first 6 months of life with respiratory/gastrointestinal tract infections and failure to thrive. Among the various types of severe combined immunodeficiency, enzyme deficiencies are relatively less common. We report the case of a 6 years old girl having severe combined immunodeficiency due to adenosine deaminase deficiency. PMID:22764473

Hussain, Waqar; Batool, Asma; Ahmed, Tahir Aziz; Bashir, Muhammad Mukarram



Capillary Electrophoresis in Diagnosis and Monitoring of Adenosine Deaminase Deficiency  

Microsoft Academic Search

Background: The diagnosis and monitoring of severe combined immunodeficiency disease (SCID) attribut- able to adenosine deaminase (ADA) deficiency requires measurements of ADA, purine nucleoside phosphory- lase (PNP), and S-adenosyl-L-homocysteine-hydrolase (SAHH) activity and of deoxyadenosine metabolites. We developed capillary electrophoresis (CE) methods for the detection of key diagnostic metabolites and evalua- tion of enzyme activities. Methods: Deoxyadenosine metabolites were separated in

Filippo Carlucci; Antonella Tabucchi; Alessandro Aiuti; Francesca Rosi; Federica Floccari; Roberto Pagani; Enrico Marinello


Gene therapy for adenosine-deaminase-deficient severe combined immunodeficiency  

Microsoft Academic Search

Adenosine-deaminase-deficient SCID was the first inherited disease to be treated with gene therapy. This life-threatening disorder is characterized by a purine defect that leads to impaired immune functions, recurrent infections and systemic metabolic abnormalities. The early gene therapy trials showed the safety and feasibility of engineering haematopoietic stem cells and peripheral blood lymphocytes using retroviral vectors. However, all patients were

Alessandro Aiuti



Adenosine signaling in striatal circuits and alcohol use disorders.  


Adenosine signaling has been implicated in the pathophysiology of alcohol use disorders and other psychiatric disorders such as anxiety and depression. Numerous studies have indicated a role for A1 receptors (A1R) in acute ethanol-induced motor incoordination, while A2A receptors (A2AR) mainly regulate the rewarding effect of ethanol in mice. Recent findings have demonstrated that dampened A2AR-mediated signaling in the dorsomedial striatum (DMS) promotes ethanol-seeking behaviors. Moreover, decreased A2AR function is associated with decreased CREB activity in the DMS, which enhances goal-oriented behaviors and contributes to excessive ethanol drinking in mice. Interestingly, caffeine, the most commonly used psychoactive substance, is known to inhibit both the A1R and A2AR. This dampened adenosine receptor function may mask some of the acute intoxicating effects of ethanol. Furthermore, based on the fact that A2AR activity plays a role in goal-directed behavior, caffeine may also promote ethanol-seeking behavior. The A2AR is enriched in the striatum and exclusively expressed in striatopallidal neurons, which may be responsible for the regulation of inhibitory behavioral control over drug rewarding processes through the indirect pathway of the basal ganglia circuit. Furthermore, the antagonistic interactions between adenosine and dopamine receptors in the striatum also play an integral role in alcoholism and addiction-related disorders. This review focuses on regulation of adenosine signaling in striatal circuits and the possible implication of caffeine in goal-directed behaviors and addiction. PMID:23912595

Nam, Hyung Wook; Bruner, Robert C; Choi, Doo-Sup



The A2b adenosine receptor protects against vascular injury  

Microsoft Academic Search

The A2b adenosine receptor (A2bAR) is highly abundant in bone marrow macrophages and vascular smooth muscle cells (VSMC). To examine the functional significance of this receptor expression, we applied a femoral artery injury model to A2bAR knockout (KO) mice and showed that the A2bAR prevents vascular lesion formation in an injury model that resembles human restenosis after angioplasty. While considering

Dan Yang; Milka Koupenova; Donald J. McCrann; Katherine J. Kopeikina; Herbert M. Kagan; Barbara M. Schreiber; Katya Ravid



A 3 Adenosine Receptor in the Pulmonary System  

Microsoft Academic Search

\\u000a A3 adenosine receptor (A3AR) is highly expressed in the airways of both man and other species. Within the human lungs, A3AR appears mostly on circulating and resident inflammatory cells, particularly granular leukocytes such as eosinophils, neutrophils\\u000a and monocytes. The human A3AR mediates anti-inflammatory cell responses upon its activation on these cells, via direct effect on cell migration, degranulation\\u000a or the

Yifat Klein; Idit Matot


Adenosine Diphosphate as an Intracellular Regulator of Insulin Secretion  

Microsoft Academic Search

Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels couple the cellular metabolic state to electrical activity and are a critical link between blood glucose concentration and pancreatic insulin secretion. A mutation in the second nucleotide-binding fold (NBF2) of the sulfonylurea receptor (SUR) of an individual diagnosed with persistent hyperinsulinemic hypoglycemia of infancy generated KATP channels that could be opened by diazoxide but

C. G. Nichols; S.-L. Shyng; A. Nestorowicz; B. Glaser; J. P. Clement IV; G. Gonzalez; L. Aguilar-Bryan; M. A. Permutt; J. Bryan



Induction of senescence by adenosine suppressing the growth of lung cancer cells.  


Extracellular adenosine is well reported to suppress tumor growth by induction of apoptosis. However, in this study we found that adenosine treatment results in cellular senescence in A549 lung cancer cells both in vitro and in vivo; adenosine induces cell cycle arrest and senescence in a p53/p21 dependent manner; adenosine elevates the level of phosphor-?H2AX, pCHK2 and pBRCA1, the markers for prolonged DNA damage response which are likely responsible for initiating the cellular senescence. Our study first demonstrates that adenosine suppresses growth of cancer cells by inducing senescence and provides additional evidence that adenosine could act as an effective anticancer agent for targeted cancer therapy. PMID:24051088

Yang, Dongqin; Song, Junyao; Wu, Lijun; Ma, Yunfang; Song, Chunhua; Dovat, Sinisa; Nishizaki, Tomoyuki; Liu, Jie



Nuclear Factor ?B and Adenosine Receptors: Biochemical and Behavioral Profiling  

PubMed Central

Adenosine is produced primarily by the metabolism of ATP and mediates its physiological actions by interacting primarily with adenosine receptors (ARs) on the plasma membranes of different cell types in the body. Activation of these G protein-coupled receptors promotes activation of diverse cellular signaling pathways that define their tissue-specific functions. One of the major actions of adenosine is cytoprotection, mediated primarily via two ARs - A1 (A1AR) and A3 (A3AR). These ARs protect cells exposed to oxidative stress and are also regulated by oxidative stress. Stress-mediated regulation of ARs involves two prominent transcription factors - activator protein-1 (AP-1) and nuclear factor (NF)-?B – that mediate the induction of genes important in cell survival. Mice that are genetically deficient in the p50 subunit of NF-?B (i.e., p50 knock-out mice) exhibit altered expression of A1AR and A2AAR and demonstrate distinct behavioral phenotypes under normal conditions or after drug challenges. These effects suggest an important role for NF-?B in dictating the level of expression of ARs in vivo, in regulating the cellular responses to stress, and in modifying behavior.

Ramkumar, Vickram; Jhaveri, Krishna A; Xie, Xiaobin; Jajoo, Sarvesh; Toth, Linda A



Pathophysiological roles for purines: adenosine, caffeine and urate  

PubMed Central

The motor symptoms of Parkinson's disease (PD) are due primarily to the degeneration of the dopaminergic neurons in the nigrostriatal pathway. However, several other brain areas and neurotransmitters other than dopamine such as noradrenaline, 5-hydroxytryptamine and acetylcholine are affected in the disease. Moreover, adenosine because of the extensive interaction of its receptors with the dopaminergic system has been implicated in the in the pathophysiology of the disease. Based on the involvement of these nondopaminergic neurotransmitters in PD and the sometimes severe adverse effects that limit the mainstay use of dopamine-based antiparkinsonian treatments, recent assessments have called for a broadening of therapeutic options beyond the traditional dopaminergic drug arsenal. In this review we describe the interactions between dopamine and adenosine receptors that underpin the preclinical and clinical rationale for pursuing adenosine A2A receptor antagonists as symptomatic and potentially neuroprotective treatment of PD. The review will pay particular attention to recent results regarding specific A2A receptor-receptor interactions and recent findings identifying urate, the end product of purine metabolism, as a novel prognostic biomarker and candidate neuroprotectant in PD.

Morelli, Micaela; Carta, Anna R; Kachroo, Anil; Schwarzschild, Michael A.



Estradiol Inhibits Smooth Muscle Cell Growth in Part by Activating the cAMP-Adenosine Pathway  

Microsoft Academic Search

Estradiol inhibits smooth muscle cell growth; however, the mechanisms involved remain unclear. Because estradiol stimulates cAMP synthesis and adenosine inhibits cell growth, we hypothesized that the conversion of cAMP to adenosine (ie, the cAMP-adenosine pathway) mediates in part the inhibitory effects of estradiol on vascular smooth muscle cell growth. To test this hypothesis, we examined the effects of estradiol (0.001

Raghvendra K. Dubey; Delbert G. Gillespie; Zaichuan Mi; Marinella Rosselli; Paul J. Keller; Edwin K. Jackson



Adenosine-induced depression of synaptic transmission in the isolated olfactory cortex: receptor identification  

Microsoft Academic Search

1.We have investigated the type of purine receptor in the guinea-pig olfactory cortex, using pial surface slices maintained in vitro.2.Adenosine (0.1 to 100 µmol\\/l) bath applied in the presence of the uptake inhibitor nitrobenzylthioinosine, depressed the evoked potentials in a dose related fashion.3.Synthetic and uptake resistant adenosine analogues had the same effect as adenosine and the order of potency of

J. McCabe; C. N. Scholfield



GABAergic involvement in motor effects of an adenosine A 2A receptor agonist in mice  

Microsoft Academic Search

Adenosine A2A agonists are known to induce catalepsy and inhibit dopamine mediated motor hyperactivity. An antagonistic interaction between adenosine A2A and dopamine D2 receptors is known to regulate GABA-mediated neurotransmission in striatopallidal neurons. Stimulation of adenosine A2A and dopamine D2 receptors has been shown to increase and inhibit GABA release respectively in pallidal GABAergic neurons. However, the role of GABAergic

R. T Khisti; C. T Chopde; Elessy Abraham



Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture  

Microsoft Academic Search

Acupuncture is an invasive procedure commonly used to relieve pain. Acupuncture is practiced worldwide, despite difficulties in reconciling its principles with evidence-based medicine. We found that adenosine, a neuromodulator with anti-nociceptive properties, was released during acupuncture in mice and that its anti-nociceptive actions required adenosine A1 receptor expression. Direct injection of an adenosine A1 receptor agonist replicated the analgesic effect

Nanna Goldman; Michael Chen; Takumi Fujita; Qiwu Xu; Weiguo Peng; Wei Liu; Tina K Jensen; Yong Pei; Fushun Wang; Xiaoning Han; Jiang-Fan Chen; Jurgen Schnermann; Takahiro Takano; Kim Tieu; Maiken Nedergaard



Deoxyadenosine Triphosphate as a Potentially Toxic Metabolite in Adenosine Deaminase Deficiency  

Microsoft Academic Search

The inherited deficiency of adenosine deaminase (adenosine aminohydrolase; EC activity in humans is associated with an immunodeficiency. Some of the immunodeficient and enzyme-deficient patients respond immunologically to periodic infusions of irradiated erythrocytes containing adenosine deaminase. It has been previously reported that erythrocytes and lymphocytes from immunodeficient and enzyme-deficient children contained increased concentrations of ATP, and in the one child

Amos Cohen; Rochelle Hirschhorn; Sheldon D. Horowitz; Arieh Rubinstein; Stephen H. Polmar; Richard Hong; David W. Martin



Simple and Sensitive Binding Assay for Measurement of Adenosine Using Reduced S-Adenosylhomocysteine Hydrolase  

Microsoft Academic Search

Background: Adenosine has been suggested to play an important role in the regulation of renal function. We developed a simple and sensitive binding assay for the detection of adenosine based on the displacement of (3H)adenosine from S-adenosylhomocysteine (SAH) hy- drolase in its reduced form. Methods: SAH hydrolase was purified to apparent homogeneity from bovine kidney by standard chro- matographic methods.

Doris Kloor; Kozo Yao; Ursula Delabar; Hartmut Osswald



Cytoprotective effects of adenosine and inosine in an in vitro model of acute tubular necrosis  

PubMed Central

Background and purpose: We have established an in vitro model of acute tubular necrosis in rat kidney tubular cells, using combined oxygen-glucose deprivation (COGD) and screened a library of 1280 pharmacologically active compounds for cytoprotective effects. Experimental approach: We used in vitro cell-based, high throughput, screening, with cells subjected to COGD using hypoxia chambers, followed by re-oxygenation. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and the Alamar Blue assay measured mitochondrial respiration and the lactate dehydrogenase assay was used to indicate cell death. ATP levels were measured using a luminometric assay. Key results: Adenosine markedly reduced cellular injury, with maximal cytoprotective effect at 100 µM and an EC50 value of 14 µM. Inosine was also found to be cytoprotective. The selective A3 adenosine receptor antagonist MRS 1523 attenuated the protective effects of adenosine and inosine, while an A3 adenosine receptor agonist provided a partial protective effect. Adenosine deaminase inhibition attenuated the cytoprotective effect of adenosine but not of inosine during COGD. Inhibition of adenosine kinase reduced the protective effects of both adenosine and inosine during COGD. Pretreatment of the cells with adenosine or inosine markedly protected against the fall in cellular ATP content in the cells subjected to COGD. Conclusions and implications: The cytoprotection elicited by adenosine and inosine in a model of renal ischaemia involved both interactions with cell surface adenosine receptors on renal tubular epithelial cells and intracellular metabolism and conversion of adenosine to ATP.

Modis, Katalin; Gero, Domokos; Nagy, Nora; Szoleczky, Petra; Toth, Zoltan Dori; Szabo, Csaba



Increase in plasma free fatty acids and natriuresis by xanthines may reflect adenosine antagonism  

Microsoft Academic Search

The hypothesis has been examined that adenosine is involved in the diuretic and free fatty acid (FFA) — releasing action of xanthines. The effects of theophylline (T), a potent adenosine antagonist, were compared with those of enprofylline (3-propyl xanthine, E), which exerts negligible antagonism of adenosine. Eight healthy male volunteers were given E 1.5 mg\\/kg, T 5.0mg\\/kg or placebo 0.9%

K.-E. Andersson; N. Johannesson; B. Karlberg; C. G. A. Persson



S-Adenosylhomocysteine hydrolase as a target for intracellular adenosine action  

Microsoft Academic Search

S-Adenosylhomocysteine hydrolase (AdoHcyase) controls intracellular levels of S-adenosylhomocysteine (AdoHcy). AdoHcy is a potent product inhibitor of some S-adenosylmethionine-dependent methyltransferases. Pharmacological modulation of AdoHcyase to indirectly inhibit methyltransferases can be guided by the fact that adenosine binds with high affinity to AdoHcyase and inhibits enzyme activity. cAMP can compete with adenosine and can counteract the adenosine-induced inhibition of AdoHcyase. Thus, the

Doris Kloor; Hartmut Osswald



Mast cell desensitization to IgE fails to induce a parallel adenosine receptor desensitization  

Microsoft Academic Search

Desensitization induced by challenge of mast cells with antigen is specific for IgE-dependent signals. During the secretory process mast cells release adenosine, which can induce a desensitization of adenosine receptors. To determine whether adenosine receptors may de desensitized from a previous antigen challenge, mast cells were sensitized with anti-DNP IgE antibody, challenged with DNP-BSA antigen, returned to culture overnight, resensitized,

D. L. Marquardt; A. Lwin; L. L. Walker



Adenosine can mediate its actions through generation of reactive oxygen species  

PubMed Central

Adenosine is an important cerebral vasodilator, but mediating mechanisms are not understood. We investigated the expression of adenosine receptor subtypes in isolated cerebral arterial muscle cells (CAMCs), and their role in adenosine-induced superoxide (O2?) generation and reduction in cerebral arterial tone. Reverse transcriptase-PCR, western blotting, and immunofluorescence studies have shown that CAMCs express transcript and protein for A1, A2A, A2B, and A3 adenosine receptors. Stimulation of CAMCs with adenosine or the A2A agonist CGS-21680 increased the generation of O2? that was attenuated by the inhibition of A2A and A2B adenosine receptor subtypes, or by the peptide inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase gp91ds-tat, or by the mitochondria uncoupler 2,4-dinitrophenol. Application of adenosine or CGS-21680 dilated pressure-constricted cerebral arterial segments that were prevented by the antioxidants superoxide dismutase (SOD) conjugated to polyethylene glycol (PEG) and PEG-catalase or by the A2B adenosine receptor antagonist MRS-1754, or by the mixed A2A and A2B antagonist ZM-241385. Antagonism of the A2A and A2B adenosine receptors had no effect on cerebral vasodilatation induced by nifedipine. These findings indicate that adenosine reduces pressure-induced cerebral arterial tone through stimulation of A2A and A2B adenosine receptors and generation of O2? from NADPH oxidase and mitochondrial sources. This signaling pathway could be one of the mediators of the cerebral vasodilatory actions of adenosine.

Gebremedhin, Debebe; Weinberger, Brian; Lourim, David; Harder, David R



Reduced appetite for caffeine in adenosine A 2A receptor knockout mice  

Microsoft Academic Search

Adenosine A2A receptor knockout mice (A2AR KO) were compared to wild-type controls (A2AR WT) in a caffeine intake paradigm. When mice had ad libitum access to caffeine (0.3 g\\/l) and water in a two-bottle paradigm for 12 consecutive days, adenosine A2AR KO mice drank less caffeinated solution, demonstrating a reduced appetite for caffeine as compared to adenosine A2AR WT mice.

Malika El Yacoubi; Catherine Ledent; Marc Parmentier; Jean Costentin; Jean-Marie Vaugeois



The A2a adenosine receptor modulates the reinforcement efficacy and neurotoxicity of MDMA  

Microsoft Academic Search

Adenosine is an endogenous purine nucleoside that plays a neuromodulatory role in the central nervous system. A2a adenosine receptors have been involved in reward-related processes, inflammatory phenomena and neurotoxicity reactions. In the present study, we investigated the role of A2a adenosine receptors on the acute pharmacological effects, reinforcement and neuroinflammation induced by MDMA administration. First, the acute effects of MDMA

Jessica Ruiz-Medina; Catherine Ledent; Olga Carretón; Olga Valverde



The Role of IL6 in Adenosine-Mediated Pulmonary Fibrosis  

Microsoft Academic Search

Adenosine is a purinergic signaling molecule that regulates various aspects of inflammation and has been implicated in the pathogenesis of chronic lung diseases. Previous studies have demonstrated that adenosine up-regulates IL-6 production through the engagement of the A2B adenosine receptor in various cell types, including alveolar macrophages. IL-6 is elevated in mouse models and humans with chronic lung disease, suggesting

Mesias Pedroza



The A3 Adenosine Receptor as a New Target for Cancer Therapy and Chemoprotection  

Microsoft Academic Search

Adenosine, a purine nucleoside, acts as a regulatory molecule, by binding to specific G-protein-coupled A1, A2A, A2B, and A3 cell surface receptors. We have recently demonstrated that adenosine induces a differential effect on tumor and normal cells. While inhibiting in vitro tumor cell growth, it stimulates bone marrow cell proliferation. This dual activity was mediated through the A3 adenosine receptor.

Pnina Fishman; Sara Bar-Yehuda; Faina Barer; Lea Madi; Asha S. Multani; Sen Pathak



Adenosine A 1 receptor antagonist versus montelukast on airway reactivity and inflammation  

Microsoft Academic Search

Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating adenosine A1 receptors. Previously, it is reported that a high dose of L-97-1, a water-soluble, small molecule adenosine A1 receptor antagonist, blocks early and late allergic responses, and bronchial hyper-responsiveness to histamine in a hyper-responsive rabbit model of allergic asthma. Effects of a lower dose of L-97-1 are compared

Ahmed Nadeem; Peter C. M. Obiefuna; Constance N. Wilson; S. Jamal Mustafa



Adenosine: An endogenous modulator of innate immune system with therapeutic potential  

Microsoft Academic Search

Adenosine is a purine nucleoside, which is produced inside the body under metabolic stress like hypoxic conditions, acute or chronic inflammatory tissue insults. The synthesis of adenosine involves the catabolism of adenine nucleotides (ATP, ADP and AMP) by the action of extracellular ectonucleotidases i.e. CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5?-ectonucleotidase. Once adenosine is released in the

Vijay Kumar; Ambika Sharma



2- and 8-alkynyl-9-ethyladenines: Synthesis and biological activity at human and rat adenosine receptors  

Microsoft Academic Search

The synthesis of a series of 9-ethyladenine derivatives bearing alkynyl chains in 2- or 8-position was undertaken, based on\\u000a the observation that replacement of the sugar moiety in adenosine derivatives with alkyl groups led to adenosine receptor\\u000a antagonists. All the synthesized compounds were tested for their affinity at human and rat A1, A2A, and A3 adenosine receptors in binding assays;

Rosaria Volpini; Stefano Costanzi; Catia Lambertucci; Sauro Vittori; Claudia Martini; M. Letizia Trincavelli; Karl-Norbert Klotz; Gloria Cristalli



Biosynthesis of nebularine (purine 9-?- d-ribofuranoside) involves enzymic release of hydroxylamine from adenosine  

Microsoft Academic Search

Biosynthesis of the antibiotic nebularine (purine-9-?-d-ribofuranoside) by Lepista nebularis and Streptomyces yokosukanensis has been studied and a novel enzymic activity is described which deaminates adenosine to release hydroxylamine. Use of 14C-labelled nucleosides showed that adenosine was the more immediate precursor of nebularine. That formation of nebularine involves direct incorporation of adenosine and does not involve prior catabolism and re-use of

Eric G. Brown; Muhsin Konuk



Modulation of Hippocampal Glutamatergic Transmission by ATP Is Dependent on Adenosine A1 Receptors  

PubMed Central

Excitatory glutamatergic synapses in the hippocampal CA1 region of rats are potently inhibited by purines, including adenosine, ATP, and ATP analogs. Adenosine receptors are A1 known to mediate at least part of the response to adenine nucleotides, either because adenine nucleotides activate A1 receptors directly, or activate them secondarily upon the nucleotides’ conversion to adenosine. In the present studies, the inhibitory effects of adenosine, ATP, the purportedly stable ATP analog adenosine-5?-O-(3-thio)triphosphate (ATP?S), and cyclic AMP were examined in mice with a null mutation in the adenosine A1 receptor gene. ATP?S displaced the binding of A1-selective ligands to intact brain sections and brain homogenates from adenosine A1 receptor wild-type animals. In homogenates, but not in intact brain sections, this displacement was abolished by adenosine deaminase. In hippocampal slices from wild-type mice, purines abolished synaptic responses, but slices from mice lacking functional A1 receptors showed no synaptic modulation by adenosine, ATP, cAMP, or ATP?S. In slices from heterozygous mice the dose-response curve for both adenosine and ATP was shifted to the right. In all cases, inhibition of synaptic responses by purines could be blocked by prior treatment with the competitive adenosine A1 receptor antagonist 8-cyclopentyltheophylline. Taken together, these results show that even supposedly stable adenine nucleotides are rapidly converted to adenosine at sites close to the A1 receptor, and that inhibition of synaptic transmission by purine nucleotides is mediated exclusively by A1 receptors.

Masino, Susan A.; Diao, Lihong; Illes, Peter; Zahniser, Nancy R.; Larson, Gaynor A.; Johansson, Bjorn; Fredholm, Bertil B.; Dunwiddie, Thomas V.



Adenosine stimulates CREB activation in macrophages via a p38 MAPK-mediated mechanism  

Microsoft Academic Search

Adenosine is an endogenously released autocoid that has potent receptor-mediated modulatory effects on macrophage function. The intracellular pathways mediating these effects are incompletely understood. Since adenosine receptor occupancy has been associated with activation of the cAMP–PKA system as well as of p38 MAPK and p42\\/44 MAPK, all of which can activate the CREB transcription factor system, we hypothesized that adenosine

Zoltán H Németh; S. Joseph Leibovich; Edwin A Deitch; Beáta Sperlágh; László Virág; E. Sylvester Vizi; Csaba Szabó; György Haskó



Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction  

Microsoft Academic Search

OBJECTIVESThe Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial was designed to test the hypothesis that adenosine as an adjunct to thrombolysis would reduce myocardial infarct size.BACKGROUNDReperfusion therapy for acute myocardial infarction (MI) has been shown to reduce mortality, but reperfusion itself also may have deleterious effects.METHODSThe AMISTAD trial was a prospective, open-label trial of thrombolysis with randomization to adenosine

Kenneth W Mahaffey; Joseph A Puma; N. Alejandro Barbagelata; Marcelo F DiCarli; Massoud A Leesar; Kevin F Browne; Paul R Eisenberg; Roberto Bolli; A. Cecilia Casas; Victor Molina-Viamonte; Cesare Orlandi; Roger Blevins; Raymond J Gibbons; Robert M Califf; Christopher B Granger



John Montgomery's Legacy: Carbocyclic Adenosine Analogues as Sah Hydrolase Inhibitors with Broad-Spectrum Antiviral Activity  

Microsoft Academic Search

Ever since the S-adenosylhomocysteine (AdoHcy, SAH) hydrolase was recognized as a pharmacological target for antiviral agents (J. A. Montgomery et al., J. Med. Chem. 25:626–629, 1982), an increasing number of adenosine, acyclic adenosine, and carbocyclic adenosine analogues have been described as potent SAH hydrolase inhibitors endowed with broad-spectrum antiviral activity. The antiviral activity spectrum of the SAH hydrolase inhibitors include

E. De Clercq



Optimization of Adenosine 5?-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening  

PubMed Central

Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse agonists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational optimization of agonists, however, remains to be assessed. In this study of adenosine 5? derivatives, we evaluated the performance of an agonist-bound A2A adenosine receptor (AR) structure in retrieval of known agonists and then employed the structure to screen for new fragments optimally fitting the corresponding subpocket. Biochemical and functional assays demonstrate high affinity of new derivatives that include polar heterocycles. The binding models also explain modest selectivity gain for some substituents toward the closely related A1AR subtype and the modified agonist efficacy of some of these ligands. The study suggests further applicability of in silico fragment screening to rational lead optimization in GPCRs.

Tosh, Dilip K.; Phan, Khai; Gao, Zhan-Guo; Gakh, Andrei A.; Xu, Fei; Deflorian, Francesca; Abagyan, Ruben; Stevens, Raymond C.; Jacobson, Kenneth A.; Katritch, Vsevolod



Optimization of adenosine 5'-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment screening.  


Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse agonists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational optimization of agonists, however, remains to be assessed. In this study of adenosine 5' derivatives, we evaluated the performance of an agonist-bound A(2A) adenosine receptor (AR) structure in retrieval of known agonists and then employed the structure to screen for new fragments optimally fitting the corresponding subpocket. Biochemical and functional assays demonstrate high affinity of new derivatives that include polar heterocycles. The binding models also explain modest selectivity