Evidence that adenosine receptors in the dog left atrium are not of the typical A1 or A2 adenosine receptor subtypes

Adenosine receptors are a subfamily of highly-conserved G-protein coupled receptors. They are found in the membranes of various human cells and play many physiological functions. Blood platelets express two (A2A and A2B) of the four known adenosine receptor subtypes (A1, A2A, A2B, and A3). Agonization of these receptors results in an enhanced intracellular cAMP and the inhibition of platelet activation and aggregation. Therefore, adenosine receptors A2A and A2B could be targets for anti-platelet therapy, especially under circumstances when classic therapy based on antagonizing the purinergic receptor P2Y12 is insufficient or problematic. Apart from adenosine, there is a group of synthetic, selective, longer-lasting agonists of A2A and A2B receptors reported in the literature. This group includes agonists with good selectivity for A2A or A2B receptors, as well as non-selective compounds that activate more than one type of adenosine receptor. Chemically, most A2A and A2B adenosine receptor agonists are adenosine analogues, with either adenine or ribose substituted by single or multiple foreign substituents. However, a group of non-adenosine derivative agonists has also been described. This review aims to systematically describe known agonists of A2A and A2B receptors and review the available literature data on their effects on platelet function.

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Adenosine Receptors as Targets for Therapeutic Intervention

Kathmandu University Medical Journal ◽

10.3126/kumj.v11i1.11054 ◽

2014 ◽

Vol 11 (1) ◽

pp. 96-101 ◽

Cited By ~ 1

Author(s):

B Suvarna

Keyword(s):

Medical Journal ◽

Adenosine Receptor ◽

Adenosine Receptors ◽

Receptor Subtypes ◽

Therapeutic Application ◽

Chemistry Research ◽

Wide Range ◽

The World ◽

Selective Agonists ◽

Receptor Modulators

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 selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer. DOI: http://dx.doi.org/10.3126/kumj.v11i1.11054 Kathmandu University Medical Journal Vol.11(1) 2013: 96-101

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Regulation of Adenosine Receptor Subtypes during Cultivation of Human Monocytes: Role of Receptors in Preventing Lipopolysaccharide-Triggered Respiratory Burst

Infection and Immunity ◽

10.1128/iai.72.3.1349-1357.2004 ◽

2004 ◽

Vol 72 (3) ◽

pp. 1349-1357 ◽

Cited By ~ 34

Author(s):

Andrea Thiele ◽

Romy Kronstein ◽

Anne Wetzel ◽

Anja Gerth ◽

Karen Nieber ◽

...

Keyword(s):

Receptor Antagonist ◽

Adenosine Receptor ◽

Adenosine Receptors ◽

Receptor Agonist ◽

Inhibitory Action ◽

Suppressive Effect ◽

Receptor Subtypes ◽

Human Monocytes ◽

Oxygen Intermediates ◽

Adenosine Concentration

ABSTRACT Adenosine is a potent anti-inflammatory agent that modulates the function of cells involved in the inflammatory response. Here we show that it inhibits lipopolysaccharide (LPS)-induced formation of reactive oxygen intermediates (ROI) in both freshly isolated and cultured human monocytes. Blocking of adenosine uptake and inactivation of the adenosine-degrading enzyme adenosine deaminase enhanced the inhibitory action of adenosine, indicating that both pathways regulate the extracellular adenosine concentration. Adenosine-mediated inhibition could be reversed by XAC (xanthine amine congener), an antagonist of the adenosine receptor A2A, and MRS 1220 {N-9-chloro-2-(2-furanyl)[1, 2, 4]-triazolo[1,5-c]quinazolin-5-benzeneacetamide}, an A3 receptor antagonist, in both cell populations, while DPCPX (1,3-dipropyl-8-cyclopentylxanthine), an A1 receptor antagonist, had no effect. Similar to what was seen with adenosine, CGS 21680, an A2A and A3 receptor agonist, and IB-MECA, a nonselective A1 and A3 receptor agonist, dose dependently prevented ROI formation, indicating the involvement of A3 and probably also A2A in the suppressive effect of adenosine. Pretreatment of monocytes with adenosine did not lead to changes in the LPS-induced increase in intracellular calcium levels ([Ca2+]i). Thus, participation of [Ca2+]i in the action of adenosine seems unlikely. The adenosine-mediated suppression of ROI production was found to be more pronounced when monocytes were cultured for 18 h, a time point at which changes in the mRNA expression of adenosine receptors were observed. Most prominent was the increase in the A2A receptor mRNA. These data demonstrate that cultivation of monocytes is accompanied by changes in the inhibitory action of adenosine mediated by A3 and probably also the A2A receptor and that regulation of adenosine receptors is an integral part of the monocyte differentiation program.

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Discovery of benzothiazolylquinoline conjugates as novel human A 3 receptor antagonists: biological evaluations and molecular docking studies

Royal Society Open Science ◽

10.1098/rsos.171622 ◽

2018 ◽

Vol 5 (2) ◽

pp. 171622 ◽

Cited By ~ 3

Author(s):

Bidisha Sarkar ◽

Santanu Maiti ◽

Gajanan Raosaheb Jadhav ◽

Priyankar Paira

Keyword(s):

Molecular Docking ◽

Cell Lines ◽

Adenosine Receptor ◽

Adenosine Receptors ◽

Radioligand Binding ◽

Physiological Responses ◽

Docking Studies ◽

Receptor Subtypes ◽

Binding Data ◽

Major Interest

Adenosine is known as an endogenous purine nucleoside and it modulates a wide variety of physiological responses by interacting with adenosine receptors. Among the four adenosine receptor subtypes, the A 3 receptor is of major interest in this study as it is overexpressed in some cancer cell lines. Herein, we have highlighted the strategy of designing the h A 3 receptor targeted novel benzothiazolylquinoline scaffolds. The radioligand binding data of the reported compounds are rationalized with the molecular docking results. Compound 6a showed best potency and selectivity at h A 3 among other adenosine receptors.

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Effects of targeted deletion of A1 adenosine receptors on postischemic cardiac function and expression of adenosine receptor subtypes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00158.2005 ◽

2006 ◽

Vol 291 (4) ◽

pp. H1875-H1882 ◽

Cited By ~ 41

Author(s):

R. Ray Morrison ◽

Bunyen Teng ◽

Peter J. Oldenburg ◽

Laxmansa C. Katwa ◽

Jurgen B. Schnermann ◽

...

Keyword(s):

Real Time ◽

Adenosine Receptor ◽

Adenosine Receptors ◽

Diastolic Pressure ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Receptor Subtypes ◽

Rt Pcr ◽

Targeted Deletion ◽

Developed Pressure

To examine ischemic tolerance in the absence of A1 adenosine receptors (A1ARs), isolated wild-type (WT) and A1AR knockout (A1KO) murine hearts underwent global ischemia-reperfusion, and injury was measured in terms of functional recovery and efflux of lactate dehydrogenase (LDH). Hearts were analyzed by real-time RT-PCR both at baseline and at intervals during ischemia-reperfusion to determine whether compensatory expression of other adenosine receptor subtypes occurs with either A1AR deletion and/or ischemia-reperfusion. A1KO hearts had higher baseline coronary flow (CF) and left ventricular developed pressure (LVDP) than WT hearts, whereas heart rate was unchanged by A1AR deletion. After 20 min of ischemia, CF was attenuated in A1KO compared with WT hearts, and this reduction persisted throughout reperfusion. Final recovery of LVDP was decreased in A1KO hearts (54.4 ± 5.1 vs. WT 81.1 ± 3.4% preischemic baseline) and correlated with higher diastolic pressure during reperfusion. Postischemic efflux of LDH was greater in A1KO compared with WT hearts. Real-time RT-PCR demonstrated the absence of A1AR transcript in A1KO hearts, and the message for A2A, A2B, and A3 adenosine receptors was similar in uninstrumented A1KO and WT hearts. Ischemia-reperfusion increased A2B mRNA expression 2.5-fold in both WT and A1KO hearts without changing A1 or A3 expression. In WT hearts, ischemia transiently doubled A2A mRNA, which returned to preischemic level upon reperfusion, a pattern not observed in A1KO hearts. Together, these data affirm the cardioprotective role of A1ARs and suggest that induced expression of other adenosine receptor subtypes may participate in the response to ischemia-reperfusion in isolated murine hearts.

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Molecular probes for the human adenosine receptors

Purinergic Signalling ◽

10.1007/s11302-020-09753-8 ◽

2020 ◽

Author(s):

Xue Yang ◽

Laura H. Heitman ◽

Adriaan P. IJzerman ◽

Daan van der Es

Keyword(s):

Adenosine Receptor ◽

Adenosine Receptors ◽

Molecular Probes ◽

G Protein Coupled Receptors ◽

Receptor Subtypes ◽

The Past ◽

New Chemical Entities ◽

And Function ◽

Receptor Modulators ◽

G Protein Coupled

AbstractAdenosine receptors, G protein–coupled receptors (GPCRs) that are activated by the endogenous ligand adenosine, have been considered potential therapeutic targets in several disorders. To date however, only very few adenosine receptor modulators have made it to the market. Increased understanding of these receptors is required to improve the success rate of adenosine receptor drug discovery. To improve our understanding of receptor structure and function, over the past decades, a diverse array of molecular probes has been developed and applied. These probes, including radioactive or fluorescent moieties, have proven invaluable in GPCR research in general. Specifically for adenosine receptors, the development and application of covalent or reversible probes, whether radiolabeled or fluorescent, have been instrumental in the discovery of new chemical entities, the characterization and interrogation of adenosine receptor subtypes, and the study of adenosine receptor behavior in physiological and pathophysiological conditions. This review summarizes these applications, and also serves as an invitation to walk another mile to further improve probe characteristics and develop additional tags that allow the investigation of adenosine receptors and other GPCRs in even finer detail.

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Expression of adenosine receptors in the preglomerular microcirculation

AJP Renal Physiology ◽

10.1152/ajprenal.00232.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. F41-F51 ◽

Cited By ~ 69

Author(s):

Edwin K. Jackson ◽

Chongxue Zhu ◽

Stevan P. Tofovic

Keyword(s):

Iron Oxide ◽

Adenosine Receptor ◽

Adenosine Receptors ◽

Renal Cortex ◽

Renal Medulla ◽

Northern Blotting ◽

Receptor Protein ◽

Receptor Subtypes ◽

Rt Pcr ◽

Mesenteric Microvessels

The purpose of this study was to systematically investigate the abundance of each of the adenosine receptor subtypes in the preglomerular microcirculation vs. other vascular segments and vs. the renal cortex and medulla. Rat preglomerular microvessels (PGMVs) were isolated by iron oxide loading followed by magnetic separation. For comparison, mesenteric microvessels, segments of the aorta (thoracic, middle abdominal, and lower abdominal), renal cortex, and renal medulla were obtained by dissection. Adenosine receptor protein and mRNA expression were examined by Western blotting, Northern blotting, and RT-PCR. Our results indicate that compared with other vascular segments and renal tissues, A1 and A2B receptor protein and mRNA are abundantly expressed in the preglomerular microcirculation, whereas A2A and A3 receptor protein and mRNA are barely detectable or undetectable in PGMVs. We conclude that, relative to other vascular and renal tissues, A1 and A2Breceptors are well expressed in PGMVs, whereas A2A and A3 receptors are notably deficient. Thus A1 and A2B receptors, but not A2A or A3receptors, may importantly regulate the preglomerular microcirculation.

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Effects of Shenfu injection on myocardial adenosine receptors in rats with myocardial ischemia-reperfusion postconditioning

Human & Experimental Toxicology ◽

10.1177/09603271211041668 ◽

2021 ◽

pp. 096032712110416

Author(s):

Jie Wang ◽

Xiaohuan Wang ◽

Weiping Wan ◽

Yuanying Guo ◽

Yanfang Cui ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Ischemia ◽

Adenosine Receptor ◽

Adenosine Receptors ◽

Sham Group ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Receptor Subtypes ◽

Shenfu Injection ◽

Myocardial Ischemia Reperfusion

Objective Shenfu injection (SFI) has been reported to have a protection against myocardial ischemia-reperfusion (MI/R) injury. However, the changes of adenosine receptors in MI/R postconditioning when pretreated with SFI are unclear. Methods Forty-five rats were randomly divided into sham group (sham), MI/R postconditioning group (MI/R-post), low-dose SFI group (1 mL/kg), middle-dose SFI group (2.5 mL/kg), and high-dose SFI group (5 mL/kg). In SFI groups, SFI was intravenously injected before reperfusion, and rats were treated with ischemic postconditioning after ischemia for 30 min. After 24 h of reperfusion, the levels of Ca2+ and cAMP in blood platelets were analyzed. Myocardial infarct volume and myocardial pathology were observed. The levels of adenosine receptor subtypes A1, A2b, and A3 in myocardium were analyzed using immunohistochemistry and Western blot. The oxidative stress–related indicators were also observed. Results Compared with the MI/R-post group, SFI ameliorated the MI/R injury by decreasing the myocardial infarct area, oxidative stress, and concentration of Ca2+ and cAMP ( p < 0.01). Pretreatment with SFI enhanced the expression of adenosine receptors A1 and A2b in a dose manner compared with the MI/R-post group. In contrast, the levels of adenosine receptor A3 were increased after MI/R postconditioning compared with the sham group, and its expression continued to increase with the increase of SFI. Furthermore, the oxidative stress reduced with the concentrations of SFI. Conclusion These results demonstrated that pretreatment with SFI might regulate the expression of adenosine receptors to improve the MI/R postconditioning.

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Adenosine Can Mediate its Actions through Generation of Reactive Oxygen Species

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.70 ◽

2010 ◽

Vol 30 (10) ◽

pp. 1777-1790 ◽

Cited By ~ 21

Author(s):

Debebe Gebremedhin ◽

Brian Weinberger ◽

David Lourim ◽

David R Harder

Keyword(s):

Nadph Oxidase ◽

Adenosine Receptor ◽

Adenosine Receptors ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Receptor Subtypes ◽

Adenosine Receptor Antagonist ◽

Cgs 21680 ◽

Mediating Mechanisms ◽

Arterial Tone ◽

Stimulation Of

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.

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