This study demonstrates that three structurally distinct A1 receptor antagonists increase extracellular adenosine levels in two different types of cardiovascular cells, i.e., cardiac fibroblasts and vascular smooth muscle cells, and in two species, rats and humans. The extracellular adenosine responses to A1 receptor antagonists are concentration dependent, and are attenuated by pertussis toxin, a toxin that inactivates inhibitory G proteins, and by AMPCP, an inhibitor of ecto-5′-nucleotidase. This study also demonstrates that augmentation of extracellular adenosine levels attenuates the increase in extracellular adenosine induced by A1 receptor antagonists. Finally, this study shows that the effects of A1receptor antagonists on extracellular adenosine levels develop with a time lag of several hours.. Our working hypothesis is that high-affinity A1receptors detect elevated levels of adenosine in the biophase of the cell surface and engage a signal transduction process that ultimately decreases ...

TY - JOUR. T1 - Chronic exposure to adenosine receptor agonists and antagonists reciprocally regulates the A1 adenosine receptor-adenylyl cyclase system in cerebellar granule cells. AU - Hettinger-Smith, Barbara D.. AU - Leid, Mark. AU - Murray, Thomas F.. PY - 1996/11. Y1 - 1996/11. N2 - Chronic treatment with the adenosine receptor antagonist caffeine evokes an up-regulation of A1 adenosine receptors and increased coupling of the receptor to G proteins in rat brain membranes. However, chronic agonist exposure has not been explored. Primary cultures of cerebellar granule cells were exposed chronically to A1 adenosine receptor agonists and antagonists. Exposure to the A1 adenosine receptor agonist N6-cyclopentyladenosine resulted in (1) a time- and concentration-dependent reduction in the density of receptors labeled by 1,3[3H]dipropyl-8-cyclopentylxanthine, (2) an enhanced ability of guanyl nucleotides to decrease the fraction of A1 adenosine receptor sites displaying high affinity for ...

Background Adenosine is generated in response to cellular stress and damage and is elevated in the lungs of patients with chronic lung disease. Adenosine signaling through its cell surface receptors serves as an amplifier of chronic lung disorders, suggesting adenosine-based therapeutics may be beneficial in the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Previous studies in mouse models of chronic lung disease demonstrate that the key components of adenosine metabolism and signaling are altered. Changes include an up-regulation of CD73, the major enzyme of adenosine production and down-regulation of adenosine deaminase (ADA), the major enzyme for adenosine metabolism. In addition, adenosine receptors are elevated. Methodology/Principal Findings The focus of this study was to utilize tissues from patients with COPD or IPF to examine whether changes in purinergic metabolism and signaling occur in human disease. Results

Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower Km and Vmax than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. While extracellular adenosine is primarily cleared by cellular uptake with a ...

Adenosine is a candidate sleep substance. It can be both a distress signal of importance in pathology and a physiological regulator. Key factors in determining which of these possibilities pertain are: (i) the number of receptors expressed, and (ii) the mechanisms that establish extracellular adenosine levels. The roles of adenosine are studied by means of antagonists and/or animals (mostly mice) with targeted deletions of receptors or enzymes involved in adenosine metabolism. Whereas adaptive changes in the genetically modified mice can occur for the physiologically important effects, such adaptive changes are less likely to occur in situations where adenosine acts as a distress signal. The relevance to sleep will be covered only in general terms in this review and will be covered in other contributions to this volume.

Adenosine is a nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. For instance, adenosine plays an important role in energy transfer - as adenosine triphosphate (ATP) and adenosine diphosphate (ADP). It also plays a role in signal transduction as cyclic adenosine monophosphate, cAMP. Adenosine itself is both a neurotransmitter and potent vasodilator. When administered intravenously, adenosine causes transient heart block in the AV node. Because of the effects of adenosine on AV node-dependent supraventricular tachycardia, adenosine is considered a class V antiarrhythmic agent ...

Having the ability to modulate lymphocyte entry into the central nervous system (CNS) would benefit patients with neuroinflammatory diseases. We have previously shown that extracellular adenosine regulates CNS entry of lymphocytes during experimental autoimmune encephalomyelitis (EAE), the animal model for the CNS inflammatory disease multiple sclerosis. For instance, while extracellular adenosine levels are vastly increased following inflammatory cellular damage (from the hydrolysis of released cytoplasimic ATP by CD39 and CD73), mice lacking CD73 or given adenosine receptor (AR) antagonists have significantly reduced CNS lymphocyte entry during EAE. We now show through detailed genetic studies that AR signaling regulates lymphocyte migration into the CNS though induction of CX3CL1, a specialized chemokine that acts as both an adhesion molecule and chemoattractant for lymphocytes, monocytes, and NK cells. We show that AR signaling is necessary and sufficient to induce CNS expression of CX3CL1 ...

Vasodilator stress with adenosine or dipyridamole is an alternative to exercise stress with myocardial perfusion imaging for the detection of coronary artery disease. Although the safety of adenosine and dipyridamole has been well established, undesirable side effects including chest pain, headache, dyspnea, and atrioventricular conduction abnormalities do occur in a majority of patients.1-4 In addition, both adenosine and dipyridamole produce severe bronchoconstriction when given to asthmatics. Because of its ultrashort half-life, adenosine must be administered by a constant IV infusion.. Whereas adenosine-induced coronary vasodilatation is mediated primarily by stimulation of the A2A receptor subtype on vascular smooth muscle, the side effects described above are believed to be caused by stimulation of 1 or more of the other 3 adenosine receptor subtypes, A1, A2B, and A3.5 The discovery of highly selective and relatively short-acting adenosine receptor A2A agonists6-9 has opened the ...

A concise synthesis of a series of N6-substituted adenosines with bicyclo[3.2.1]octan-6-yl and polycyclic N6-substituents has been developed. The adenosine A1 receptor (A1R) affinity and potency of these compounds was initially assessed using competitive binding assays and cyclic adenosine monophosphate (cAMP) accumulation assays in DDT1 MF-2 cells. The potency and receptor subtype selectivity of selected examples was further evaluated by measuring their effects on cAMP accumulation at all human adenosine receptor subtypes expressed in CHO cells. The results of these assays indicated that all of the synthesised N6-substituted adenosines are full agonists at A1R and activate this receptor selectively over the other adenosine receptor subtypes. The two standout compounds in terms of potency were N6-(3-thiabicyclo[3.2.1]octan-6-yl)adenosine and N6-(cubanylmethyl)adenosine with EC50 values at human A1R of 2.3 nM and 1.1 nM, respectively. The cubanylmethyl derivative in particular proved to be highly ...

We examined how the endogenous anticonvulsant adenosine might influence gamma-aminobutyric acid type A (GABA(A)) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 microM), GABA(A) receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABA(A)-current (I(GABA)) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/ml), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced I(GABA) run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated I(GABA) run-down in approximately 40% and approximately 20% of tested oocytes, respectively. The ...

Introduction: Prior studies demonstrate that ischemic preconditioning (IP) alters adenosine metabolism. The significance of this effect is not fully understood, but evidence suggests that reduction in extracellular adenosine may represent use as an alternative fuel. Transformation into AMP/ADP may also replenish intracellular total adenine nucleotides (TAN), improving the potential high-energy phosphate bonds available in cells facing ischemia. In both cases, adenosine supports cell energy requirements and may be a key component of IPs protective mechanisms. There are no previous studies of brain adenosine in human patients undergoing remote IP.. Methods: In adults with aneurysmal subarachnoid hemorrhage (SAH), 3-4 remote IP sessions were conducted on non-consecutive days, 4-12 days after hemorrhage. Each session consisted of 4 5-min cycles of lower extremity blood pressure cuff inflation to 30mmHg above systolic blood pressure, followed by 5-min reperfusion. Patients had microdialysis (MD) ...

To the Editor: Recently, Jeremias et al1 reported their studies comparing the vasodilator action of intracoronary injected adenosine with ATP in 6 healthy mongrel dogs. On the basis of a dose-response curve ranging from 10 to 100 μg, the authors conclude that adenosine and ATP are approximately equipotent vasodilators. Neither substance could induce maximal vasodilation, as assessed with postischemic hyperemia. Similar results were obtained by Kato et al2 in the human coronary vasculature using a single dose of adenosine and ATP (20 μg), without comparison with postischemic hyperemia. Both groups conclude that adenosine and ATP are equipotent coronary vasodilators and suggest that the ATP-induced vasodilation is caused by its degradation to AMP and adenosine, with subsequent stimulation of adenosine A2 receptors. We disagree their conclusions for the following 2 reasons:. 1. Equimolar doses of ATP and adenosine should be compared. The molecular weight of ATP is roughly twice that of adenosine ...

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 A 3Rs - 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

TY - JOUR. T1 - Desensitization of A1 adenosine receptors in rat cerebral cortex. AU - Park, K. S.. AU - Yang, W. S.. AU - Kim, K. H.. PY - 1996. Y1 - 1996. N2 - Following the subcutaneous administration of R(-)N6-(2-phenylisopropyl)adenosine (600 nmol/kg/hr) to rats for 1 week using Alzet® mini-osmotic pumps, A1 adenosine receptor functions were determined using [3H]DPCPX binding, [365]GTP(γ)S binding, and adenylyl cyclase assays. A1 adenosine receptor binding and the inhibition of adenylyl cyclase activity by PIA was not altered in cerebrocortical membranes prepared from PIA-treated rats. However, there was a significant decrease in the A1 adenosine receptor-mediated stimulation of [35S]GTP(γ)S binding to cerebrocortical membranes prepared from PIA-treated rats (22.0% decrease in basal activity; 19.7% decrease in maximal activity). These results suggest that the desensitization of A1 adenosine receptors following chronic administration involves agonist-induced uncoupling of the receptors ...

Adenosine is an important mediator of the endogenous defense against ischemia-induced injury in the heart. Adenosine can achieve cardioprotection by mediating the effect of ischemic preconditioning and by protecting against myocyte injury when it is present during the infarct-producing ischemia. A novel adenosine A3 receptor can mediate this protective function. One approach to achieve cardioprotection is to enhance myocardial sensitivity to the endogenous adenosine by increasing the number of adenosine receptors instead of administering an adenosine receptor agonist. The objective of the present study was to investigate whether genetic manipulation of the cardiac myocyte, achieved by gene transfer and overexpression of the human A3 receptor cDNA, renders the myocytes resistant to the deleterious effect of ischemia. Prolonged hypoxia with glucose deprivation, causing myocyte injury and adenosine release, was used to simulate ischemia in cultured chick embryo ventricular myocytes. During simulated

In the heart, endogenous adenosine attenuates the beta-adrenergic-elicited increase in contractile performance via activation of adenosine A1 receptors. It has been recently reported that this function of adenosine becomes more pronounced with myocardial maturation. The purpose of the present study was to determine whether mature hearts possess a greater sensitivity than immature hearts to this antiadrenergic effect of adenosine. Isolated perfused hearts or atria from immature (ca. 23 days) and mature (ca. 80 days) rats were stimulated with isoproterenol (Iso), a beta-adrenergic agonist, at 10(-8) M and concomitantly exposed to increasing concentrations of 2-chloro-N6-cyclopentyladenosine (CCPA), a highly selective and potent adenosine A1-receptor agonist, from 10(-12) to 10(-6) M. CCPA at 10(-10)-10(-6) M dose dependently reduced the Iso-elicited contractile response more in immature than in mature hearts or atria. At 10(-6) M, CCPA reduced the Iso-elicited contractile response by 103% in immature

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We have demonstrated previously that both acute and chronic oral administration of adenosine have novel functions such as anti-hypertensive effects and improved hyperlipidaemia in stroke-prone spontaneously hypertensive rats (SHRSP) fed a normal diet. The purpose of the present study was to investigate the effect of adenosine administration on metabolic syndrome-related parameters in SHRSP fed a high-fat diet. Six-week-old rats were divided into three groups, and were administered either water (control) or adenosine (10 or 100 mg/l) for 8 weeks. During this period, the rats had free access to a high-fat diet based on AIN-93M. The results showed that hypertension, plasma lipid, NO, insulin, glucose and urinary 8-hydroxy-2-deoxyguanosine levels improved significantly in both adenosine groups. The mRNA expression levels of genes involved in anti-oxidative activity and adenosine receptors were also altered in the adenosine groups. Administration of adenosine also increased plasma adiponectin ...

Cyclic 3, 5-[14C]AMP was measured in platelets that had first been incubated with [14C]adenine. Maximum increases of 2-4-fold were observed 0.5 min after addition of 10-40 µM adenosine. Smaller increases were obtained with higher concentrations of adenosine. In 0.5-min incubations 2-chloroadenosine was less effective than adenosine at concentrations below 20 µM and more effective at concentrations above 100 µM. Incorporation of 1-10 µM adenosine into platelets was inhibited at least 96% by p-nitrobenzylthioguanosine without any effect on the increase in cyclic [14C]AMP caused by these concentrations of adenosine, suggesting that adenosine acts at an extracellular site. With higher adenosine concentrations, p-nitrobenzylthioguanosine was less effective in inhibiting incorporation of adenosine but blocked the decline in cyclic [14C]AMP levels observed on increasing the adenosine concentration above 40 µM. This inhibitory effect of high adenosine concentrations on the accumulation of cyclic ...

Each type of adenosine receptor has different functions, although with some overlap.[3] For instance, both A1 receptors and A2A play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow, while the A2A receptor also has broader anti-inflammatory effects throughout the body.[4] These two receptors also have important roles in the brain,[5] regulating the release of other neurotransmitters such as dopamine and glutamate,[6][7][8] while the A2B and A3 receptors are located mainly peripherally and are involved in processes such as inflammation and immune responses. Most older compounds acting on adenosine receptors are nonselective, with the endogenous agonist adenosine being used in hospitals as treatment for severe tachycardia (rapid heart beat),[9] and acting directly to slow the heart through action on all four adenosine receptors in heart tissue,[10] as well as producing a sedative effect through action on A1 and A2A receptors in the brain. Xanthine derivatives ...

TY - ABST. T1 - Dose-dependent effect of caffeine on adenosine-induced myocardial stress perfusion in Rubidium-82 PET/CT. T2 - no influence of one cup of coffee on myocardial flow reserve. AU - Byrne, C.. AU - Kjaer, A.. AU - Wissenberg, M.. AU - Hurry, P. K.. AU - Schmedes, A. V.. AU - Forman, J. L.. AU - Hasbak, P.. PY - 2018. Y1 - 2018. U2 - 10.1093/eurheartj/ehy563.3007. DO - 10.1093/eurheartj/ehy563.3007. M3 - Conference abstract in journal. VL - 39. SP - 628. EP - 629. JO - European Heart Journal. JF - European Heart Journal. SN - 0195-668X. IS - suppl. 1. ER - ...

TY - JOUR. T1 - Silk polymer-based adenosine release. T2 - Therapeutic potential for epilepsy. AU - Wilz, Andrew. AU - Pritchard, Eleanor M.. AU - Li, Tianfu. AU - Lan, Jing Quan. AU - Kaplan, David L.. AU - Boison, Detlev. N1 - Funding Information: This project was supported by grant R01NS058780 from the National Institute of Neurological Disorders and Stroke and by the Epilepsy Research Foundation through the generous support of the Arlene and Arnold Goldstein Family Foundation.. PY - 2008/9. Y1 - 2008/9. N2 - Adenosine augmentation therapies (AAT) make rational use of the brains own adenosine-based seizure control system and hold promise for the therapy of refractory epilepsy. In an effort to develop an AAT compatible with future clinical application, we developed a novel silk protein-based release system for adenosine. Adenosine releasing brain implants with target release doses of 0, 40, 200, and 1000 ng adenosine per day were prepared by embedding adenosine containing microspheres into ...

Regadenoson produced higher stress MBF than dipyridamole and adenosine (3.58 ± 0.58 vs. 2.81 ± 0.67 vs. 2.78 ± 0.61 ml/min/g, p = 0.0009 and p = 0.0008 respectively). Regadenoson had a much higher heart rate response than adenosine and dipyridamole respectively (95 ± 11 vs. 76 ± 13 vs. 86 ± 12 beats/ minute) When stress MBF was adjusted for heart rate, there were no differences between regadenoson and adenosine (37.8 ± 6 vs. 36.6 ± 4 μl/sec/g, p = NS), but differences between regadenoson and dipyridamole persisted (37.8 ± 6 vs. 32.6 ± 5 μl/sec/g, p = 0.03). The unadjusted MPR was higher with regadenoson (3.11 ± 0.63) when compared with adenosine (2.7 ± 0.61, p = 0.02) and when compared with dipyridamole (2.61 ± 0.57, p = 0.04). Similar to stress MBF, these differences in MPR between regadenoson and adenosine were abolished when adjusted for heart rate (2.04 ± 0.34 vs. 2.12 ± 0.27, p = NS), but persisted between regadenoson and dipyridamole (2.04 ± 0.34 vs. 1.77 ± 0.33, p = ...

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In the central nervous system, the nucleoside adenosine regulates neuronal activity by modulating the actions of other neurotransmitter systems, thereby influencing many different physiological processes and behaviors. Adenosinergic mechanisms are especially important in fine-tuning glutamatergic neurotransmission. Astrocytic release of adenosine triphosphate and its subsequent extracellular breakdown provides adenosine to drive homeostatic sleep. Acute ethanol (alcohol) exposure increases extracellular adenosine, which mediates the ataxic and hypnotic/sedative effects of alcohol, while chronic ethanol exposure leads to downregulated adenosine signaling that underlies insomnia, a major predictor of relapse. Adenosine gates glutamatergic input to the circadian clock located in the suprachiasmatic nucleus of the hypothalamus, modulating both photic (light-induced) and nonphotic (behaviorally-induced) synchronization of circadian activity rhythms. A recent study using mice lacking the equilibrative ...

Adenosine mediates many physiological functions via activation of extracellular receptors. The modulation of cell growth by adenosine was found to be receptor-mediated. In A431 cells adenosine evoked a biphasic response in which a low concentration (~10 μM) produced inhibition of colony formation but at higher concentrations (up to 100 μM) this inhibition was progressively reversed. Evidence for the involvement of A1 (inhibitory) and A2 (stimulatory) adenosine receptors in regulating cell growth of these tumor cells was obtained through plating efficiency studies based on the relative potency of adenosine agonists and antagonists. When both A1 and A2 receptors were blocked, colony formation or growth was not inhibited at low concentrations of adenosine but was inhibited at high adenosine concentrations ...

Objective. Adenosine infusion causes selective pulmonary vasodilation in fetal and neonatal lambs with pulmonary hypertension. We investigated the effects of a continuous infusion of adenosine on oxygenation in term infants with persistent pulmonary hypertension of newborn (PPHN).. Design. A randomized, placebo-controlled, masked trial comparing the efficacy of intravenous infusion of adenosine to normal saline infusion over a 24-hour period.. Setting. Inborn and outborn level III neonatal intensive care units at a university medical center.. Participants. Eighteen term infants with PPHN and arterial postductal Po2 of 60 to 100 Torr on inspired O2 concentration of 100% and optimal hyperventilation (PaCo2 ,30 Torr) were enrolled into the study. Study infants were randomly assigned to receive a placebo infusion of normal saline, or adenosine infusion in doses of 25 to 50 µg/kg/min over a 24-hour period.. Results. Nine infants each received adenosine or placebo. The two groups did not differ in ...

The initial studies to test the hypothesis that adenosine release mediates the anti-inflammatory effects of methotrexate were performed in vitro. In these studies, methotrexate treatment increased adenosine release from cultured endothelial cells and fibroblasts and the adenosine released diminished stimulated neutrophil adhesion to the monolayers of cultured cells (Cronstein et al., 1991). Subsequent in vivo studies confirmed the hypothesis that adenosine mediates the anti-inflammatory effects of methotrexate; pharmacologically relevant doses of methotrexate induce intracellular AICAR accumulation in splenocytes, increase adenosine concentrations in inflammatory exudates, and diminish leukocyte accumulation at an inflamed site (Cronstein et al., 1993). Moreover, the increase in exudate adenosine concentration was responsible for the anti-inflammatory effects of the drug since adenosine receptor antagonists or adenosine deaminase, an enzyme which converts adenosine to the receptor-inactive ...

Our work demonstrates that human endothelial cells of disparate origin are characterized by differential expression of adenosine receptor subtypes. HUVECs express mRNA for A2A and A2B receptors at a ratio of 10:1, and this preferential gene expression agrees well with the typical pharmacological phenotype of A2A receptor-mediated simulation of adenylate cyclase by adenosine analogs. Using complementary techniques, RT-PCR, and gene expression array, we found that A1 and A3 adenosine receptors are not expressed in HUVECs. Previous studies in HUVECs have suggested a potential role of A1 receptor in maintaining endothelial barrier function4 and of A1 and A3 receptors in modulation of tissue factors expression.6 The apparent contradiction between these results and ours can be explained by the use of nonselective concentrations of adenosine receptor ligands in previous studies.. HMEC-1 also express only A2A and A2B mRNA, but in contrast to HUVECs, they express predominantly A2B receptor mRNA, with a ...

Adenosine receptors (AR) belong to the G-protein coupled receptor family. There are four receptor subtypes: A1, A2A, A2B e A3. Adenosine receptor subtypes show a different distribution in the organism and are implicated in several physiopathological processes. In particular, antagonists towards A1AR are promising in the treatment of cognitive disorders. A2A antagonists seem to be involved in decrease the neurological impairment observed in Parkinson’s disease. A2B antagonists are potential therapeutic agents in asthma and diabetes. Finally, antagonists at the A3AR could be implicated in tumor growth inhibition and in glaucoma treatment. The crystallographic structure acquisition of the human A2A receptor allowed the design of new AR antagonists by the help of computational techniques. Our group is focused on the synthesis of new adenosine receptor antagonists (particularly towards A2A and A3) for their potential therapeutic use, but also as tools for pharmacological investigations on ...

Summary 1. The effect of the adenosine A2 receptor (AdoA2R) agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA) on adenosine A1 receptor (AdoA1R)-mediated negative inotropic responses was investigated in rat heart. 2. Hearts from male Wistar rats (250-350 g) were perfused with Krebs-Henseleit solution at constant flow in non-recirculating Langendorff mode. Hearts were paced at 5 Hz (5 ms duration, supramaximal voltage) via ventricular electrodes. After 30 min equilibration, (R)-N6-phenylisopropyl adenosine (R-PIA) concentration-response curves were constructed in the absence or presence of DPMA. 3. In paced hearts, R-PIA induced concentration-dependent decreases in triple product (heart rate נpeak systolic developed pressure נdP?/?dtmax), which were significantly attenuated by 1 nmol?/?L DPMA with a shift in pEC50 from 8.0 ᠰ.5 (n = 9) in control hearts to 6.63 ᠱ.03 (n = 5) in treated tissues (P , 0.05). The AdoA2AR antagonist 8-(3-chlorostyryl)caffeine (1 ...

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TY - JOUR. T1 - Modulating P1 Adenosine Receptors in Disease Progression of SOD1G93A Mutant Mice. AU - Armida, Monica. AU - Matteucci, Alessandra. AU - Pèzzola, Antonella. AU - Baqi, Younis. AU - Müller, Christa E. AU - Popoli, Patrizia. AU - Potenza, Rosa Luisa. PY - 2019/5. Y1 - 2019/5. N2 - Amyotrophic lateral sclerosis (ALS) is a fatal progressing neurodegenerative disease; to date, despite the intense research effort, only two therapeutic options, with very limited effects, are available. The purinergic system has been indicated as a possible new therapeutic target for ALS, but the results are often contradictory and generally confused. The present study was designed to determine whether P1 adenosine receptor ligands affected disease progression in a transgenic model of ALS. SOD1G93A mice were chronically treated, from presymptomatic stage, with a selective adenosine A2A receptor agonist (CGS21680), antagonist (KW6002) or the A1 receptor antagonist DPCPX. Body weight, motor performance ...

2 Biologic Description. Side effects requiring immediate medical attention. Adverse reactions to Adenosine of any severity reported in less than 1% of patients include: back discomfort, lower extremity discomfort, weakness, myocardial infarction, ventricular arrhythmia, third-degree AV block, bradycardia, palpitation, sinus exit block, sinus pause, T-wave changes, hypertension (systolic blood pressure > 200 mm Hg), drowsiness, emotional instability, tremors, blurred vision, dry mouth, ear discomfort, metallic taste, nasal congestion, scotomas, tongue discomfort. 1. Since Adenosine significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Adenosine causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after Adenosine between areas served by normal and areas served by stenotic vessels than is seen prior to Adenosine. Do not use in patients with ...

Adenosine is one of the bodys more powerful molecules and is linked to the digestion process. During digestion, the glucose in the foods we eat breaks down into glycolysis. This breaks down further into Adenosine Tri-Phosphate (ATP). This is responsible for energy transference between cells. After ATP is used up, it decomposes yet again into adenosine. As adenosine builds up in the bloodstream, it interacts with specific cell receptors, inhibiting neural activity and causing drowsiness.. What does this actually mean? Well, when the body runs out of fuel in the form of easily digestible sugars from the food we eat, adenosine signals the body to become drowsy. This essentially tells us to sleep and rebuild our energy reserves. Its a critical chain reaction that initiates the early stages of non-REM sleep and is essential to the natural sleep cycle.. ...

P>Adenosine is a well-described anti-inflammatory modulator of immune responses within peripheral tissues. Extracellular adenosine accumulates in inflamed and damaged tissues and inhibits the effector functions of various immune cell populations, including CD8 T cells. However, it remains unclear whether extracellular adenosine also regulates the initial activation of naive CD8 T cells by professional and semi-professional antigen-presenting cells, which determines their differentiation into effector or tolerant CD8 T cells, respectively. We show that adenosine inhibited the initial activation of murine naive CD8 T cells after alpha CD3/CD28-mediated stimulation. Adenosine caused inhibition of activation, cytokine production, metabolic activity, proliferation and ultimately effector differentiation of naive CD8 T cells. Remarkably, adenosine interfered efficiently with CD8 T-cell priming by professional antigen-presenting cells (dendritic cells) and semi-professional antigen-presenting cells ...

The review summarizes data evaluating the role of adenosine receptor signaling in murine hematopoietic functions. The studies carried out utilized either non-selective activation of adenosine receptors induced by elevation of extracellular adenosine or by administration of synthetic adenosine analogs having various proportions of selectivity for a particular receptor. Numerous studies have described stimulatory effects of non-selective activation of adenosine receptors, manifested as enhancement of proliferation of cells at various levels of the hematopoietic hierarchy. Subsequent experimental approaches, considering the hematopoiesis-modulating action of adenosine receptor agonists with a high level of selectivity to individual adenosine receptor subtypes, have revealed differential effects of various adenosine analogs. Whereas selective activation of A(1) receptors has resulted in suppression of proliferation of hematopoietic progenitor and precursor cells, that of A(3) receptors has led to ...

The effects of adenosine on inhibitory synaptic transmission in area CA1 were examined using the rat hippocampal slice preparation and intracellular recording. Adenosine did not change fast inhibitory synaptic potentials (IPSPs) but depressed late IPSPs evoked by direct activation of interneurons in the presence of 6,7-dinitroquinoxaline-2,3-dione (DNQX) and D,L-2-amino-5-phosphonovalerate (APV). Directly activated IPSPs were unchanged by the selective adenosine A1 receptor antagonist 8-cyclopentyltheophylline (CPT), but CPT reversed hyperpolarization and depression of late IPSPs produced by adenosine. These results indicate that adenosine depresses disynaptic IPSPs in area CA1 by decreasing synaptic activation of inhibitory neurons ...

Recent evidence suggests that ethanol initially causes an increase in receptor-dependent cAMP levels, followed by heterologous desensitization of receptors coupled to GS after chronic exposure. Here we investigated the role of adenosine in mediating these responses. We found that ethanol caused accumulation of extracellular adenosine in NG108-15 and S49 lymphoma cells. This adenosine activated adenosine receptors to increase intracellular cAMP levels. The addition of adenosine deaminase, to degrade accumulated extracellular adenosine, or isobutyl-methylxanthine, an adenosine receptor antagonist, completely blocked ethanol-induced increases in cAMP levels in NG108-15 cells. Chronic exposure of NG108-15 and S49 wild type cells to ethanol resulted in heterologous desensitization of adenosine receptor- and prostaglandin E1 receptor-dependent cAMP signal transduction. Coincubation of NG108-15 and S49 wild type cells with adenosine deaminase and ethanol for 48 hr prevented heterologous ...

Treatment with an adenosine uptake inhibitor attenuates glomerulonephritis in mice.: This study evaluated the effects of KF24345 (3-[1-(6,7-diethoxy-2-morpholin

Activation of protein kinase C (PKC) via adenosine receptors is known to be involved in the cardioprotection of ischemic preconditioning (IPC). Specifically, activation of PKCε is critical for cardioprotection. There is ample evidence that PKCε resides in cardiac mitochondria. However, the signals that promote translocation of PKCε are largely unknown. The present study was designed to determine whether and how adenosine receptor activation induces translocation of PKCε to mitochondria. Freshly isolated adult rat cardiac myocytes and rat heart-derived H9c2 were used in the study. Immunofluorescence imaging of isolated mitochondria showed that PKCε but not PKCδ was localized in mitochondria and this mitochondrial localization of PKCε was significantly increased by adenosine treatment. The adenosine-induced increase in PKCε-positive mitochondria was largely prevented not only by PKC inhibitor chelerythrine, but also by the HSP90 inhibitor geldanamycin and by siRNA targeting HSP90. ...

The adenosine A3 receptor, also known as ADORA3, is an adenosine receptor, but also denotes the human gene encoding it. Adenosine A3 receptors are G protein-coupled receptors that couple to Gi/Gq and are involved in a variety of intracellular signaling pathways and physiological functions. It mediates a sustained cardioprotective function during cardiac ischemia, it is involved in the inhibition of neutrophil degranulation in neutrophil-mediated tissue injury, it has been implicated in both neuroprotective and neurodegenerative effects, and it may also mediate both cell proliferation and cell death[citation needed]. Recent publications demonstrate that adenosine A3 receptor antagonists (SSR161421) could have therapeutic potential in bronchial asthma (17,18). Multiple transcript variants encoding different isoforms have been found for this gene. An adenosine A3 receptor agonist (CF-101) is in clinical trials for the treatment of rheumatoid arthritis. In a mouse model of infarction the A3 ...

In the current study, the combination of T62 and clonidine produced a synergistic interaction in rats with incisional pain. Synergy usually indicates that the two drugs have different final pathways to produce their effect, although other levels of interaction, such as altered drug disposition, can also be responsible. We did not measure tissue concentrations of drugs, so we cannot exclude a pharmacokinetic mechanism of synergy in the current study. Nonetheless, the observation of synergy is somewhat surprising if, as indicated by studies with spinal nerve ligation, the effect of T62 relies entirely on stimulating spinal norepinephrine release, which acts on α2adrenoceptors. One would in that case expect an additive interaction, and intrathecal adenosine and clonidine do interact additively in spinal-ligated rats. 14 In contrast, a synthetic adenosine agonist interacts synergistically with clonidine in acute thermal nociception tests in normal rats. 20 In addition, idazoxan only partially ...

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DESCRIPTION: (Adapted from the Investigators Abstract): Adenosine administered as an aerosol to asthmatics causes bronchoconstriction, while in non-asthmatics adenosine causes bronchodilation. This occurs because the activation of A2B adenosine receptors on sensitized mast cells triggers degranulation, releasing histamine, leukotrienes, and other allergic mediators. A2B adenosine receptors are blocked by theophylline, a xanthine that is effective in treating asthma. However, theophylline is a non-selective antagonist of all four adenosine receptor subtypes and produces side effects due primarily to A1 receptor blockade, including insomnia and diuresis. The incidence of asthma is increasing and current treatment options are limited. New drugs that are potent and selective antagonists of A2B adenosine receptors have great potential for the treatment of asthma and other allergic diseases. Adenosine Therapeutics, LLC owns the first potent and selective A2B antagonists. The purpose of this phase I ...

Objectives:. The overall goal of this proposal is to develop methods to achieve heart and vascular protection from ischemia and thus improve soldiers performance in adverse environment. The major hypothesis is that new approach and method can be developed to enhance resistance to stress-induced circulatory insufficiency and myocardial ischemia. The goals here are to determine whether a decreased adenosine transporter function is associated with a reduced physiological responsiveness to the vasculo-protective drug persantine using two in vitro endpoints: the ability of persantine 1) to inhibit platelet aggregation and 2) to inhibit [3H] uridine uptake. Both are endpoints that indicate physiological responsiveness. Both relate directly to the cardiovascular protective effects of , that is, persantine the availability of extracellular adenosine level and the anti-platelet property. Specifically, the relationship between circulating adenosine increase to persantine in vivo and blockade of ...

TY - JOUR. T1 - Attenuation of chronic pulmonary inflammation in A2B adenosine receptor knockout mice. AU - Zaynagetdinov, Rinat. AU - Ryzhov, Sergey. AU - Goldstein, Anna E.. AU - Yin, Huiyong. AU - Novitskiy, Sergey V.. AU - Goleniewska, Kasia. AU - Polosukhin, Vasiliy V.. AU - Newcomb, Dawn C.. AU - Mitchell, Daphne. AU - Morschl, Eva. AU - Zhou, Yang. AU - Blackburn, Michael R.. AU - Peebles, R. Stokes. AU - Biaggioni, Italo. AU - Feoktistov, Igor. PY - 2010/5/1. Y1 - 2010/5/1. N2 - Pharmacologic evidence suggests that activation of A2B adenosine receptors results in proinflammatory effects relevant to the progression of asthma, a chronic lung disease associated with elevated interstitial adenosine concentrations in the lung. This concept has been challenged by the finding that genetic removal of A2B receptors leads to exaggerated responses in models of acute inflammation. Therefore, the goal of our study was to determine the effects of A2B receptor gene ablation in the context of ...

Previous in vitro studies have shown biphasic effects of adenosine on mast cell activity; however, the receptor subtypes that mediate the inhibitory effects of adenosine are still controversial (Peachell et al., 1991; Yip et al., 2009). Mast cells express two distinct Gs-coupled adenosine receptors; their biologic roles have not been comprehensively defined, especially in vivo. Since activation of Gs-coupled adenosine receptors increases intracellular cAMP, we hypothesized that the inhibitory effects of adenosine on mast cells are mediated by the Gs-coupled adenosine receptors. In this study, we used both genetically modified animal models and mast cell cultures to comprehensively investigate the role of Gs-coupled adenosine receptors on mast cells both in vitro and in vivo. First, our data demonstrate a potent inhibitory effect of the nonhydrolyzable adenosine analog NECA on IgE-induced mast cell degranulation; this inhibitory effect of NECA was abolished by the genetic deletion of the A2B but ...

BACKGROUND: Increased sympathetic activity contributes to the progression of heart failure. Adenosine counteracts sympathetic activity by inhibition of presynaptic norepinephrine release and attenuation of the metabolic and contractile responses to beta-adrenergic stimulation. In this study, we tested the hypothesis that the adenosinergic effects (uptake blockade) of dipyridamole may retard the progression of pressure overload hypertrophy in the rat. METHODS AND RESULTS: To verify that the administration of dipyridamole increases myocardial adenosine levels in the rat, epicardial adenosine concentrations were measured from 12 isolated, perfused rat hearts exposed to 10(-7) and 10(-6) mol/l dipyridamole. Adenosine concentrations were increased with both doses of dipyridamole. Also, 9 weeks of dipyridamole treatment resulted in decreased sensitivity to the adenosine A1-receptor agonist, 2-chloro-N6-cyclopentyl adenosine, suggesting that dipyridamole increases adenosine levels in the intact rat. In ...

Adenosine is the first drug of choice in the treatment of supraventricular arrhythmias. While the effects of adenosine on sympathetic nerve activity (SNA) have been investigated, no information is available on the effects on cardiac vagal nerve activity (VNA). We assessed in rats the responses of cardiac VNA, SNA and cardiovascular variables to intravenous bolus administration of adenosine. in 34 urethane-anaesthetized rats, cardiac VNA or cervical preganglionic sympathetic fibres were recorded together with ECG, arterial pressure and ventilation, before and after administration of three doses of adenosine (100, 500 and 1000 mu g kg-1). the effects of adenosine were also assessed in isolated perfused hearts (n= 5). Adenosine induced marked bradycardia and hypotension, associated with a significant dose-dependent increase in VNA (+204 +/- 56%, P , 0.01; +275 +/- 120%, P , 0.01; and +372 +/- 78%, P , 0.01, for the three doses, respectively; n= 7). Muscarinic blockade by atropine (5 mg kg-1, i.v.) ...

TY - JOUR. T1 - Determination of adenosine effects and adenosine receptors in murine corpus cavernosum. AU - Tostes, Rita C.. AU - Giachini, Fernanda R.C.. AU - Carneiro, Fernando S.. AU - Leite, Romulo. AU - Inscho, Edward W.. AU - Webb, R. Clinton. PY - 2007/8. Y1 - 2007/8. N2 - This study tested the hypothesis that adenosine, in murine corpora cavernosa, produces direct relaxation of smooth muscle cells and inhibition of contractile responses mediated by sympathetic nerve stimulation. Penes were excised from anesthetized male C57BL/6 mice, dissected, and cavernosal strips were mounted to record isometric force. Adenosine, 2-chloroadenosine (stable analog of adenosine), and 2-phenylaminoadenosine (CV1808) (A2 A/A2B agonist) produced concentration-dependent relaxations of phenylephrine-contracted tissues. Relaxation to 2-chloroadenosine was inhibited, in a concentration-dependent manner, by 2-(2-furanyl)-7-(2- phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (SCH58261; A2A ...

A review. The low affinity A2B adenosine receptor, like any other adenosine receptor subtype, belongs to the super-family of seven transmembrane domain G protein-coupled receptors (7TMs GPCR) and is classified by the GPCR database in the family of rhodopsin like receptors (Class A of GPCR). It has been cloned from various species, including rat and human, and its sequences are highly similar across species, ranging from 85% identity between human and mouse and 95% identity between rat and mouse. The A2B receptors show a ubiquitous distribution, the highest levels are present in cecum, colon and bladder, followed by blood vessels, lung, eye and mast cells. Through A2B receptors adenosine seems to cause mast cells degranulation, vasodilation, cardiac fibroblast proliferation, inhibition of Tumor Necrosis Factor (TNF-α), increased synthesis of interleukin-6 (IL-6), stimulation of Cl- secretion in intestinal epithelia and hepatic glucose prodn. Hence, A2B adenosine receptor agonists could be useful ...

In the present study, we have made some progress in understanding the extracellular adenosine involved in the LFS-induced depotentiation at Schaffer collateral-CA1 synapses. There are four principal observations emerged from this work. First, the time-dependent reversal of LTP by LFS was mimicked by extracellular application of adenosine and was blocked by A1 adenosine receptor antagonist DPCPX but not by A2 receptor antagonist DMPX. Although transient extracellular application of 5-HT1A receptor agonist buspirone after LTP induction could also effectively reverse previously established LTP, 5-HT1A receptor antagonist NAN-190 did not affect the LFS-induced depotentiation. Second, the source of extracellular adenosine during LFS to exert depotentiation appeared to be attributable to the efflux of cAMP that is subsequently converted into adenosine by ecto-5′-nucleotidase. However, the extracellular conversion of ATP is not the major source of adenosine underlying the LFS-induced depotentiation. ...

Uncoupling between ATP overflow and extracellular adenosine formation shifts purinergic signaling in post-inflammatory ileitis. small amounts of adenosine discovered in TNBS-treated arrangements, since blockade of Cav3 (T-type) stations existing in ICCs with mibefradil (3 M) or inhibition from the equilibrative nucleoside transporter 1 with dipyridamole (0.5 M), both reduced extracellular adenosine. Data suggest that post-inflammatory ileitis operates a change on purinergic neuromodulation reflecting the upregulation of ATP-releasing enteric glial cells as well as the depletion of ICCs accounting for buy UNC 0224 reduced adenosine overflow via equilibrative nucleoside transporters. = 6) and 0.80 0.09 (= 6) in charge and TNBS-treated samples, respectively (see Number ?Figure5A5A). Negative and positive ideals represent facilitation and inhibition of evoked [3H]ACh launch, respectively. None from the medicines considerably ( 0.05) changed the basal tritium outflow. Open up in another window Number ...

We performed experiments to test the hypothesis that endogenous adenosine acts as an essential cofactor required for eliciting angiotensin II (Ang II)-induced afferent and/or efferent arteriolar vasoconstriction. Enalaprilat (2 mg IV) was administered to anesthetized rats to reduce endogenous Ang II levels. Kidneys and blood were harvested from these animals and used for study of renal microvascular function using the in vitro blood-perfused juxtamedullary nephron technique. Arteriolar inside diameter was monitored videomicroscopically in (1) normal kidneys, (2) kidneys subjected to adenosine receptor blockade (100 mumol/L 1,3-dipropyl-8-p-sulfophenylxanthine), and (3) kidneys continuously exposed to 1 mumol/L adenosine. Under resting conditions, arteriolar diameters were similar in all three groups of kidneys, averaging 24.8 +/- 1.0 microns (n = 23) in afferent arterioles and 24.0 +/- 0.9 microns (n = 16) in efferent arterioles. In normal kidneys, adenosine (10 mumol/L) decreased both afferent ...

The effect of (-)-N6-phenylisopropyl adenosine (PIA), a metabolically stable P1-receptor agonist, was investigated on guinea-pig isolated trachea. PIA showed two opposite effects: contraction, evident at low concentrations (10(-7) to 2-5 X 10(-6) M), and relaxation at higher doses. Relaxation by PIA was antagonized in an apparently competitive manner by two antagonists of extracellular (P1) adenosine receptors: theophylline (Theo) and 8-phenyltheophylline (PT). Contraction by PIA was not inhibited by methylxanthines and was not mediated by stimulation of cholinergic or histaminergic systems. Inhibitors of arachidonic acid cascade acting at different levels, i.e. indomethacin, nordihydroguaiaretic acid (NDGA) and BW755C, all inhibited the contraction by PIA, while they potentiated the relaxation in a concentration-dependent manner. Mepacrine, an inhibitor of phospholipase A2, inhibited the contraction by PIA, but did not affect the relaxation. These results indicate that the contractile effect induced by

Preeclampsia is a prevalent pregnancy hypertensive disease with both maternal and fetal morbidity and mortality. Emerging evidence indicates that global placental DNA hypomethylation is observed in patients with preeclampsia and is linked to altered gene expression and disease development. However, the molecular basis underlying placental epigenetic changes in preeclampsia remains unclear. Using 2 independent experimental models of preeclampsia, adenosine deaminase-deficient mice and a pathogenic autoantibody-induced mouse model of preeclampsia, we demonstrate that elevated placental adenosine not only induces hallmark features of preeclampsia but also causes placental DNA hypomethylation. The use of genetic approaches to express an adenosine deaminase minigene specifically in placentas, or adenosine deaminase enzyme replacement therapy, restored placental adenosine to normal levels, attenuated preeclampsia features, and abolished placental DNA hypomethylation in adenosine deaminase-deficient ...

Pharmacologic stress with dipyridamole has provided useful diagnostic, as well as prognostic, information in patients undergoing thallium-201 myocardial perfusion imaging. With its ultrashort half-life and a potent and consistent vasodilator effect, adenosine may be the coronary vasodilator of choice with myocardial perfusion imaging.. Fifty-one healthy subjects and 93 patients with suspected coronary artery disease constituted the study group. In this multicenter study the comparative safety and diagnostic efficacy of single-photon emission computed tomography (SPECT) thallium imaging during adenosine-induced coronary hyperemia was compared with exercise treadmill stress. There was a mean increase in heart rate of 37% and a mean decrease in diastolic blood pressure of 5% during the adenosine infusion of 140 μg/kg per min for 6 min. Adenosine infusion was well tolerated in 95% of the subjects. Side effects requiring intervention occurred in seven subjects (5%). None of the subjects experienced ...

Efflux transport of adenosine across the choroid plexus (CP) epithelium might contribute to the homeostasis of this neuromodulator in the extracellular fluids of the brain. The aim of this study was to explore adenosine transport across sheep CP epithelial cell monolayers in primary culture. To explore transport of adenosine across the CP epithelium, we have developed a method for primary culture of the sheep choroid plexus epithelial cells (CPEC) on plastic permeable supports and analysed [14C] adenosine transport across this cellular layer, [14C] adenosine metabolism inside the cells, and cellular uptake of [14C] adenosine from either of the chambers. The primary cell culture consisted of an enriched epithelial cell fraction from the sheep fourth ventricle CP and was grown on laminin-precoated filter inserts. CPEC grew as monolayers forming typical polygonal islands, reaching optical confluence on the third day after the seeding. Transepithelial electrical resistance increased over the time after

1. Human leucocytes whose adenine nucleotide pool was prelabelled with [3H]adenine were investigated for their capacity to release adenosine and its metabolites and histamine when activated with the calcium ionophore A23187, antiimmunoglobulin E and the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (f-MLP).. 2. Sixty-nine per cent of the 3H-label assimilated by the cells was incorporated into their adenine nucleotide pool in the ratio adenosine 5′-phosphate (AMP):adenosine 5′-pyrophosphate (ADP):adenosine 5′-triphosphate (ATP), 3:1:1. Spontaneous release of label from leucocytes plateaued at 5 min at 22.1 ± 4.2% of the total radiolabel incorporated and mainly consisted of hypoxanthine, inosine and adenosine.. 3. Activation of cells with the calcium ionophore A23187 (1.0 μmol/l) caused a net increase in [3H]purine release above baseline of 27.9 ± 4.6% accompanied by a net basophil histamine release of 46.6 ± 9.4%. A23187 (1.0-3.0 μmol/l) caused a parallel ...

A vasoconstrictory response to adenosine has been reported in coronary rings from fish. Since the reactivity of the large coronary arteries and the microcirculation may differ, the present study was undertaken to determine the role of adenosine in the intact coronary system of trout under constant pressure or flow using an isolated and non-working heart preparation. The involvement of nitric oxide (NO) and the interaction with noradrenaline were also studied. At 10(-9) to 10(-8 )mol l-1, adenosine caused a vasoconstrictory response, whereas between 10(-7) and 10(-5 )mol l-1 the response was predominantly vasodilative. Theophylline abolished both these responses to adenosine. The vasodilation induced by adenosine (at 10(-5 )mol l-1) was significantly reduced when the preparation was perfused under constant-flow than rather under constant-pressure conditions. The nitric oxide synthase inhibitor N-nitro-l-arginine (l-NA, 10(-4 )mol l-1) partially reduced the vasodilation induced by adenosine (at ...

Rat islets were used to compare the mechanisms whereby adenosine and adrenaline inhibit insulin release. Adenosine (1 microM-2.5 mM) and its analogue N6(-)-phenylisopropyladenosine (L-PIA) (1 nM-10 microM) caused a concentration-dependent but incomplete (45-60%) inhibition of glucose-stimulated release. L-PIA was more potent than D-PIA [the N6(+) analogue], but much less than adrenaline, which caused nearly complete inhibition (85% at 0.1 microM). 8-Phenyltheophylline prevented the inhibitory effect of L-PIA and 50 microM-adenosine, but not that of 500 microM-adenosine or of adrenaline. In contrast, yohimbine selectively prevented the inhibition by adrenaline. Adenosine and L-PIA thus appear to exert their effects by activating membrane A1 receptors, whereas adrenaline acts on alpha 2-adrenergic receptors. Adenosine, L-PIA and adrenaline slightly inhibited 45Ca2+ efflux, 86Rb+ efflux and 45Ca2+ influx in glucose-stimulated islets. The inhibition of insulin release by adenosine or L-PIA was ...

Adenosine was coupled to human serum albumin by two different procedures that preserved the purine and ribose rings. The conjugates were evaluated for antigenicity in rabbits and guinea pigs. A conjugate containing 2′(3′)-O-succinoyladenosine failed to elicit antibodies, whereas one containing laevulinic acid (O2′, 3′-adenosine-acetal) elicited antibodies in all animals injected. The affinity and specificity of binding of adenosine to three selected antisera were evaluated. Dissociation constants of 31-187 nM were observed. Displacement of adenosine binding to all antisera by adenine 5′-nucleotides, adenine, inosine and hypoxanthine required more than 1000-fold higher concentrations than of adenosine itself. Similar affinities for adenosine and 2′-deoxyadenosine were observed. By exploiting the high specificity of the antisera, a radioimmunoassay method was established that was capable of detecting down to 1 pmol of adenosine (20 nM) in unfractionated heart perfusates and cell ...

Adenosine is a multi-functional physiological molecule found abundantly in the body. It is one of the important components of ATP cellular energy metabolism. Adenosine has diverse actions as a ligand on many different types of cells and tissues acting via specific receptors. Currently, four subtypes of adenosine receptors are described, namely, the A1, A2A, A2B and A3 receptors. Neuroblastoma, mostly found in young children, is a malignant tumor derived from peripheral neurons in the body. Several different types of neuroblastoma cell lines of human origin have been established and contributed to the studies of neuroblastoma itself, neuronal differentiation, neurotransmitters, alcoholism, Alzheimers disease and other neuronal diseases and disorders. In 1987, it was shown by Abbracchio et al. that a human neuroblastoma cell line, IMR32, could be induced to differentiate into cells that have a more neuronal morphology, with long neurites, by an adenosine receptor agonist ...

August 20, 2007 By Grendel Burrell, M.D. [1] Preliminary results of the Phase 2, 50-patient, of BG9928 (ADENTRI®), an A1 adenosine receptor antagonist in stable patients with heart failure were reported in 2003 at the American Heart Associations annual scientific session. Dr. Barry Greenberg, professor of medicine and director of the Advanced Heart Failure Program at University of California, San Diego Medical Center, and colleagues reported the results in the August 14, 2007, issue of the Journal of the American College of Cardiology, in an article titled Effects of Multiple Oral Doses of an A1 Adenosine Antagonist, BG9928, in Patients With Heart Failure: Results of a Placebo-Controlled, Dose-Escalation Study (J Am Coll Cardiol, 2007; 50:600-606, doi:10.1016/j.jacc.2007.03.059 (Published online 29 July 2007)). BG9928 is a selective inhibitor of the A1 adenosine receptor. The objective of the study was to assess the pharmacokinetics and pharmacologic effects of BG9928 (ADENTRI®) in heart ...

TY - JOUR. T1 - Evidence for increased dorsal hippocampal adenosine release and metabolism during pharmacologically induced seizures in rats. AU - Berman, Robert F. AU - Fredholm, Bertil B.. AU - Aden, Ulrika. AU - OConnor, William T.. PY - 2000/7/28. Y1 - 2000/7/28. N2 - There is growing pharmacological evidence from several animal models of seizure disorder that adenosine possesses endogenous anticonvulsant activity. In order to further evaluate the role of adenosine in seizure activity, we monitored adenosine and its major biochemical metabolites inosine, xanthine, and hypoxanthine in the dorsal hippocampus by in vivo microdialysis before and during the induction of generalized seizures. Seizures were induced pharmacologically in groups of urethane-anesthetized rats by the administration of bicuculline (0.5 mg/kg, i.v.), kainic acid (12.0 mg/kg, i.v.) or pentylenetetrazol (100-250 mg/kg, i.p). Seizure activity was monitored electrophysiologically from the dorsal hippocampus. Dialysate ...

Disclosed are processes for the synthesis of novel compounds that are A.sub.2B adenosine receptor antagonists, having the structure of Formula I or Formula II: ##STR00001## by cyclizing a compound of the formula (3): ##STR00002##

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The actions of adenosine on histamine release of human lung fragments were investigated. Histamine release was stimulated either with the calcium ionophore A 23187 orwith concanavalin A. Adenosine and its analogue 5-N-ethylcarboxamidoadenosine alone had no significant effect on basal release or on the release elicited by A 23187 or concanavalin A. However, in the presence of the adenosine receptor antagonist 8-[4-[[[[(2-aminoethyl)amino]-carbonyl] methyloxy]-phenyl]-1,3-dipropylaxanthine (XAC), which itself did not affect the release, adenosine increased the stimulated histamine release. On the other hand, in the presence of the nucleoside transport inhibitor S-(p-nitrobenzyl)-6-thioninosine (NBTI), adenosine caused a reduction in stimulated histamine release. NBTI itself caused a stimulation of release. Thus, a stimulatory effect of adenosine was seen in the presence ofXAC, whereas an inhibitory effect was unmasked by NBTI. From these data it is concluded that adenosine exerts two opposing ...

The actions of adenosine on histamine release of human lung fragments were investigated. Histamine release was stimulated either with the calcium ionophore A 23187 orwith concanavalin A. Adenosine and its analogue 5-N-ethylcarboxamidoadenosine alone had no significant effect on basal release or on the release elicited by A 23187 or concanavalin A. However, in the presence of the adenosine receptor antagonist 8-[4-[[[[(2-aminoethyl)amino]-carbonyl] methyloxy]-phenyl]-1,3-dipropylaxanthine (XAC), which itself did not affect the release, adenosine increased the stimulated histamine release. On the other hand, in the presence of the nucleoside transport inhibitor S-(p-nitrobenzyl)-6-thioninosine (NBTI), adenosine caused a reduction in stimulated histamine release. NBTI itself caused a stimulation of release. Thus, a stimulatory effect of adenosine was seen in the presence ofXAC, whereas an inhibitory effect was unmasked by NBTI. From these data it is concluded that adenosine exerts two opposing ...

TY - JOUR. T1 - A1 adenosine receptors potently regulate heart rate in mammalian embryos. AU - Hofman, Paul L.. AU - Hiatt, Kelly. AU - Yoder, Mervin. AU - Rivkees, Scott A.. PY - 1997. Y1 - 1997. N2 - A1 adenosine receptors (A1ARs) have been recently shown to be expressed in rodent embryonic hearts at very early stages of development. To determine the functional significance of fetal cardiac A1AR expression during embryogenesis, murine fetal heart preparations were studied between postconceptual days 9 and 12. Dose-response curves generated using a variety of adenosine agonists revealed that A1AR activation potently regulated fetal heart rates. The A1AR agonist, N6-cyclopentyladenosine, inhibited heart rates in a dose-dependent manner (half-maximal effective concentration = 3.6 x 10-8M) and stopped fetal cardiac contractions in 63% of preparations. In contrast, A2a and A2b receptor activation did not alter heart rates, and activation of A3 receptors produced modest declines in heart rates. ...

Title:Adenosine Receptors as Novel Targets for the Treatment of Various Cancers. VOLUME: 25 ISSUE: 26. Author(s):Bapi Gorain, Hira Choudhury*, Gan Sook Yee and Subrat Kumar Bhattamisra*. Affiliation:School of Pharmacy, Faculty of Health and Medical Science, Taylors University, Subang Jaya, Selangor, Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur. Keywords:Adenosine, adenosine receptors, receptor modulators, cancer, signalling pathways, tumour cell.. Abstract:Adenosine is a ubiquitous signaling nucleoside molecule, released from different cells within the body to act on vasculature and immunoescape. The physiological action on the proliferation of tumour cell has been reported by the ...

The ontogenesis of rat forebrain adenosine uptake sites labelled by [3H]nitrobenzylthioinosine ([3H]NBI) was determined and compared to that of rat forebrain adenosine receptors labelled by N6-cyclohexyl[3H]adenosine ([3H]-CHA). [3H]NBI binding is highly invariant with similar levels of [3H]NBI binding sites from embryonic day 19 to day 30 postpartum. Scatchard and Hill analyses reveal the binding of [3H]NBI in 6-day-old tissue to be indistinguishable from such binding in 30-day-old tissue. In contrast, [3H]-CHA binding is highly variant. [3H]CHA binding develops slowly but steadily from about embryonic day 19, with adult binding levels being achieved at around 25 days postpartum. The ontogenetic profile of [3H]CHA appears to coincide with synaptogenesis whereas that of [3H]NBI does not.

We prospectively recruited from 1230 consecutive patients undergoing CMRP. First pass CMRP was performed on a Philips Achieva CV 1.5 T MR scanner (Philips, The Netherlands), with standardised acquisition protocol with standard dose adenosine (SDA) at 140 µg/kg/min for 3 minutes. 3 short axis slices of 10 mm thickness were acquired per cardiac cycle using a single shot prospectively gated balanced TFE sequence (TR 2.5 ms, TE 1.3 ms, Flip angle 50° and voxel size 2.8 × 2.8 mm2) after the administration of a 0.1 mmol/Kg bolus of intravenous Gadolinium. Heart rate (HR) and blood pressure (BP) were recorded at baseline and during stress. Non responders were defined as those patients with a normal CMRP scan and blunted haemodynamic response (maximum HR increase ,10 beats per minute and fall in systolic BP (SBP) ,10 mmHg). CMRP in this group was then repeated with high dose adenosine (HDA) at 175 µg/kg/min for 3 minutes. CMRP images were interpreted by 2 independent experienced observers. Coronary ...

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TY - JOUR. T1 - Contribution of Adenosine A2A and A2B Receptors to Ischemic Coronary Dilation. T2 - Role of KV and KATP Channels. AU - Berwick, Zachary C.. AU - Payne, Gregory A.. AU - Lynch, Brandon. AU - Dick, Gregory M.. AU - Sturek, Michael. AU - Tune, Johnathan D.. PY - 2010/11/1. Y1 - 2010/11/1. N2 - This study was designed to elucidate the contribution of adenosine A2A and A2B receptors to coronary reactive hyperemia and downstream K+ channels involved. Coronary blood flow was measured in open-chest anesthetized dogs. Adenosine dose-dependently increased coronary flow from 0.72 ± 0.1 to 2.6 ± 0.5 mL/minute/g under control conditions. Inhibition of A2A receptors with SCH58261 (1 μm) attenuated adenosine-induced dilation by ~50%, while combined administration with the A2B receptor antagonist alloxazine (3 μm) produced no additional effect. SCH58261 significantly reduced reactive hyperemia in response to a transient 15 second occlusion; debt/repayment ratio decreased from 343 ± 63 to ...

Definition of adenosine diphosphate in the Financial Dictionary - by Free online English dictionary and encyclopedia. What is adenosine diphosphate? Meaning of adenosine diphosphate as a finance term. What does adenosine diphosphate mean in finance?

Adenosine is a purine nucleoside released locally in BAT when noradrenaline and ATP are released from sympathetic nerves. Recently it was found that adenosine activates murine and human brown adipocytes, and recruits beiging of white fat via adenosine A2A receptors (A2AR). Furthermore, studies with mice have shown improvements in glucose homeostasis after administration of A2AR agonists.. In this study the investigators use the PET radiotracer [15O]-H2O to quantify perfusion of BAT, white adipose tissue (WAT) and muscle in three conditions: room temperature, cold exposure and intravenous infusion of adenosine. Another PET radiotracer [11C]TMSX is used to quantify adenosine A2A receptor density of BAT, WAT and muscle in room temperature and during cold exposure. ...

Permanent functional deficits following spinal cord injury (SCI) arise both from mechanical injury and from secondary tissue reactions involving inflammation. Enhanced release of adenosine and glutamate soon after SCI represents a component in the sequelae that may be responsible for resulting functional deficits. The role of adenosine A2A receptor in central ischemia/trauma is still to be elucidated. In our previous studies we have demonstrated that the adenosine A2A receptor-selective agonist CGS21680, systemically administered after SCI, protects from tissue damage, locomotor dysfunction and different inflammatory readouts. In this work we studied the effect of the adenosine A2A receptor antagonist SCH58261, systemically administered after SCI, on the same parameters. We investigated the hypothesis that the main action mechanism of agonists and antagonists is at peripheral or central sites. Spinal trauma was induced by extradural compression of SC exposed via a four-level T5-T8 laminectomy in mouse.

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Although dipyridamole produces coronary vasodilation, most reports on dipyridamole effects in animals have failed to show a change in CBF after intravenous infusion of dipyridamole.16 17 18 19 To our knowledge, this is the first study to quantitatively estimate the change in CBF in response to intravenous dipyridamole in humans. We found CBF values for the dipyridamole stress to be lower than those at rest (Table 2⇑ and Figure 2⇑). Dipyridamole stress also caused a significant reduction in Paco2 (Table 1⇑), and the vascular response to Paco2 change caused by the dipyridamole infusion closely followed the response due to hypocapnia (Table 2⇑ and Figure 1⇑). Thus, the decrease in CBF during dipyridamole stress can be explained by the decrease in Paco2 rather than the direct action of dipyridamole on CBF. The decrease in Paco2 during dipyridamole stress is most likely due to the hyperventilation side effect of adenosine.29 It has been reported that large doses of intravenous adenosine and ...

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The role of adenosine and ATP in the regulation of hepatic arterial blood flow in the buffer response was studied in vitro and in a new in vivo model in the rabbit. The model achieves portal-systemic diversion by insertion of a silicone rubber prosthesis between the portal vein and inferior vena cava and avoids alterations in systemic haemodynamics. Hepatic arterial (HA) blood flow increased in response to reduced portal venous (PV) blood flow, the buffer response, from 19.4 (3.3) ml min-1 100 g-1 to 25.6 (4.3) ml min-1 100 g-1 (mean (SE), p | 0.05, Students paired t-test). This represented a buffering capacity of 18.7 (5.2) %. Intra-portal injections of ATP or adenosine (1 micrograms kg-1-0.5 mg kg-1) elicited immediate increases in HA blood flow to give -log ED50 values of 2.0 and 1.7 mg kg-1 for ATP and adenosine respectively. Injection of ATP and adenosine had no measurable effect on PV flow. In vitro, using an isolated dual-perfused rabbit liver preparation, the addition of 8