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Adenosine A2 Receptor

Gemma Vilahur, Manuel Gutierrez, Laura Casani, Lourdes Varela, Antoni Capdevila, Guillem Pons-Lladó, Francesc Carreras, Leif Carlsson, Alberto Hidalgo, Lina Badimon
BACKGROUND: -The P2Y12 receptor antagonist ticagrelor has shown to be clinically superior to clopidogrel. Although the underlying mechanisms remain elusive, ticagrelor may exert off-target effects through adenosine-related mechanisms. We sought to investigate whether ticagrelor reduces myocardial injury to a greater extent than clopidogrel after myocardial infarction (MI) at similar level of platelet inhibition and determine the mechanisms behind. METHODS: -Pigs received prior to MI-induction: I) placebo-control; II) a loading dose (LD) of clopidogrel (600mg); III) a LD of ticagrelor (180mg); or IV) a LD of ticagrelor followed by an adenosine A1/A2-receptor antagonist (8-p-sulfophenyl-theophylline; 8SPT, 4mg/kg intravenous) to determine the potential contribution of adenosine in ticagrelor-related cardioprotection...
October 27, 2016: Circulation
Dmitry Mayorov, Sergey Kasparov, Julian Paton
OBJECTIVE: Functional defects in purinergic neurotransmission, and specifically adenosine A1 receptor, have been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Here, we examined the role of adenosine receptors in regulating cerebrovascular function in pre-hypertensive SHR. DESIGN AND METHOD: Changes in the diameter of pial arterioles (20-100 μm) in response to adenosine A1 and A2 receptor agonists were assessed after pre-constriction with the thromboxane agonist U46619 in slices from the brainstem and cortex of 4-6 week-old Wistar and SHR...
September 2016: Journal of Hypertension
Dmitry Mayorov, Sergey Kasparov, Julian Paton
OBJECTIVE: Functional defects in purinergic neurotransmission, and specifically adenosine A1 receptor, have been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Here, we examined the role of adenosine receptors in regulating cerebrovascular function in pre-hypertensive SHR. DESIGN AND METHOD: Changes in the diameter of pial arterioles (20-100 μm) in response to adenosine A1 and A2 receptor agonists were assessed after pre-constriction with the thromboxane agonist U46619 in slices from the brainstem and cortex of 4-6 week-old Wistar and SHR...
September 2016: Journal of Hypertension
In Seok Jeong, Hwa Jin Cho, Jeong Gwan Cho, Sang Hyung Kim, Kook Joo Na, Jong-Keun Kim
BACKGROUND AND OBJECTIVES: Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels play an important role in myocardial protection. We examined the effects of thromboxane A2 on the regulation of KATP channel activity in single ventricular myocytes. SUBJECTS AND METHODS: Single ventricular myocytes were isolated from the hearts of adult Institute of Cancer Research (ICR) mice by enzymatic digestion. Single channel activity was recorded by excised inside-out and cell-attached patch clamp configurations at -60 mV holding potential during the perfusion of an ATP-free K-5 solution...
July 2016: Korean Circulation Journal
Byron Carpenter, Rony Nehmé, Tony Warne, Andrew G W Leslie, Christopher G Tate
G-protein-coupled receptors (GPCRs) are essential components of the signalling network throughout the body. To understand the molecular mechanism of G-protein-mediated signalling, solved structures of receptors in inactive conformations and in the active conformation coupled to a G protein are necessary. Here we present the structure of the adenosine A(2A) receptor (A(2A)R) bound to an engineered G protein, mini-Gs, at 3.4 Å resolution. Mini-Gs binds to A(2A)R through an extensive interface (1,048 Å2) that is similar, but not identical, to the interface between Gs and the β2-adrenergic receptor...
August 4, 2016: Nature
Rodrigo A Cunha
The adenosine modulation system mostly operates through inhibitory A1 (A1 R) and facilitatory A2A receptors (A2A R) in the brain. The activity-dependent release of adenosine acts as a brake of excitatory transmission through A1 R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: high-frequency stimulation triggers ATP release in the 'activated' synapse, which is locally converted by ecto-nucleotidases into adenosine to selectively activate A2A R; A2A R switch off A1 R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the 'activated' synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change...
December 2016: Journal of Neurochemistry
Markus Bender, David Stegner, Bernhard Nieswandt
Platelet adhesion and aggregation at sites of vascular injury are crucial for hemostasis; however, under pathological conditions, they can cause myocardial infarction and stroke. Platelet adhesion is mediated by binding of the glycoprotein (GP)Ib-V-IX complex to immobilized von Willebrand factor (vWF), thereby enabling the interaction of GPVI with exposed collagen and subsequent platelet activation. This process is reinforced by locally produced thrombin and platelet-derived adenosine diphosphate (ADP) and thromboxane A2 (TxA2), leading to a conformational change of integrins from a low- to a high-affinity state, which allows firm platelet adhesion and aggregation...
June 23, 2016: Platelets
Karen P Briski, Prem K Shrestha
Hindbrain dorsal vagal complex A2 noradrenergic signaling represses the pre-ovulatory luteinizing hormone (LH) surge in response to energy deficiency. Insulin-induced hypoglycemia augments A2 neuron adenosine 5'-monophosphate-activated protein kinase (AMPK) activity and estrogen receptor-beta (ERβ) expression, coincident with LH surge suppression. We hypothesized that ERβ is critical for hypoglycemia-associated patterns of LH secretion and norepinephrine (NE) activity in key reproduction-relevant forebrain structures...
September 7, 2016: Neuroscience
Baoman Li, Shuang Qi, Guangfeng Sun, Li Yang, Jidong Han, Yue Zhu, Maosheng Xia
Spinal cord injury (SCI) causes long-term disability and has no clinically effective treatment. After SCI, adenosine triphosphate (ATP) may be released from neuronal cells and astrocytes in large amounts. Our previous studies have shown that the extracellular release of ATP increases the phosphorylation of cytosolic phospholipase A2 (cPLA2 ) and triggers the rapid release of arachidonic acid (AA) and prostaglandin E2 (PGE2) via the stimulation of epidermal growth factor receptor (EGFR) and the downstream phosphorylation of extracellular-regulated protein kinases 1 and 2...
October 2016: Journal of Neuroscience Research
Endre Pongrácz, Katalin Schweitzer, József Furész, János Fent, Attila Tordai, Zoltán Nagy
Platelet hyperaggregation in ischaemic stroke patients is a proven finding, and associated with increased expression of the platelet surface GPIIb/IIIa receptor. The polymorphism occurs at nucleotide position 1565 of the GPIIIa gene resulting a 33Leu-Pro change. Data are conflicting regarding the abnormal function of the PlA1/A2 receptor in stroke. The aim of the study was to address the difference of platelet receptor function in ischemic stroke patients with the wild PlA1/A1 and heterozygous PlA1/A2 genotype...
December 5, 2007: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
K V Sivak, A V Vasin, V V Egorov, V B Tsevtkov, N N Kuzmich, V A Savina, O I Kiselev
Sepsis is a generalized infection accompanied by response of the body that manifests in a clinical and laboratory syndrome, namely, in the systemic inflammatory response syndrome (SIRS) from the organism to the infection. Although sepsis is a widespread and life-threatening disease, the assortment of drugs for its treatment is mostly limited by antibiotics. Therefore, the search for new cellular targets for drug therapy of sepsis is an urgent task of modern medicine and pharmacology. One of the most promising targets is the adenosine A(2A) receptor (A(2A)AR)...
March 2016: Molekuliarnaia Biologiia
Mahreen Pakzad, Youko Ikeda, Carly McCarthy, Darryl G Kitney, Rita I Jabr, Christopher H Fry
To measure the relative transcription of adenosine receptor subtypes and the contractile effects of adenosine and selective receptor-subtype ligands on detrusor smooth muscle from patients with neuropathic overactive (NDO) and stable bladders and also from guinea-pigs. Contractile function was measured at 37°C in vitro from detrusor smooth muscle strips. Contractions were elicited by superfusate agonists or by electrical field stimulation. Adenosine-receptor (A1, A2A, A2B, A3) transcription was measured by RT-PCR...
August 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
Chang-Chieh Wu, Fu-Ming Tsai, Mao-Liang Chen, Semon Wu, Ming-Cheng Lee, Tzung-Chieh Tsai, Lu-Kai Wang, Chun-Hua Wang
Antipsychotic drugs (APDs) used to treat clinical psychotic syndromes cause a variety of blood dyscrasias. APDs suppress the aggregation of platelets; however, the underlying mechanism remains unknown. We first analyzed platelet aggregation and clot formation in platelets treated with APDs, risperidone, clozapine, or haloperidol, using an aggregometer and rotational thromboelastometry (ROTEM). Our data indicated that platelet aggregation was inhibited, that clot formation time was increased, and that clot firmness was decreased in platelets pretreated with APDs...
2016: BioMed Research International
Laurie Bruzzese, Emmanuel Fenouillet, Julien Fromonot, Josée-Martine Durand-Gorde, Jocelyne Condo, Nathalie Kipson, Giovanna Mottola, Pierre Deharo, Régis Guieu, Jean Ruf
High homocysteine (HCy) levels are associated with lymphocyte-mediated inflammatory responses that are sometimes in turn related to hypoxia. Because adenosine is a potent lymphocyte suppressor produced in hypoxic conditions and shares metabolic pathways with HCy, we addressed the influence of high HCy levels on the hypoxia-induced, adenosine-mediated, alteration of lymphocyte viability. We treated mitogen-stimulated human lymphocytes isolated from healthy individuals and the human lymphoma T-cell line CEM with cobalt chloride (CoCl2 )to reproduce hypoxia...
August 2016: Journal of Cellular and Molecular Medicine
Callum N Watson, Steven W Kerrigan, Dermot Cox, Ian R Henderson, Steve P Watson, Mònica Arman
Gram-negative Escherichia coli cause diseases such as sepsis and hemolytic uremic syndrome in which thrombotic disorders can be found. Direct platelet-bacterium interactions might contribute to some of these conditions; however, mechanisms of human platelet activation by E. coli leading to thrombus formation are poorly understood. While the IgG receptor FcγRIIA has a key role in platelet response to various Gram-positive species, its role in activation to Gram-negative bacteria is poorly defined. This study aimed to investigate the molecular mechanisms of human platelet activation by E...
September 2016: Platelets
César Quiroz, Marco Orrú, William Rea, Andrés Ciudad-Roberts, Gabriel Yepes, Jonathan P Britt, Sergi Ferré
It is generally assumed that infralimbic cortex (ILC) and prelimbic cortex, two adjacent areas of the medial prefrontal cortex (mPFC) in rodents, provide selective excitatory glutamatergic inputs to the nucleus accumbens (NAc) shell and core, respectively. It is also generally believed that mPFC influences the extracellular levels of dopamine in the NAc primarily by an excitatory collateral to the ventral tegmental area (VTA). In the present study, we first established the existence of a selective functional connection between ILC and the posteromedial portions of the VTA (pmVTA) and the mNAc shell (pmNAc shell), by measuring striatal neuronal activation (immunohistochemical analysis of ERK1/2 phosphorylation) and glutamate release (in vivo microdialysis) upon ILC electrical stimulation...
January 20, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Michelle Lam, Retsu Mitsui, Hikaru Hashitani
Prostatic smooth muscle develops spontaneous myogenic tone which is modulated by autonomic neuromuscular transmission. This study aimed to investigate the role of purinergic transmission in regulating electrical activity of prostate smooth muscle and whether its contribution may be altered with age. Intracellular recordings were simultaneously made with isometric tension recordings in smooth muscle preparations of the guinea-pig prostate. Immunostaining for P2X1 receptors on whole mount preparations was also performed...
January 2016: Autonomic Neuroscience: Basic & Clinical
Stevan P Tofovic, Eman M Salah, Glenn J Smits, Eric T Whalley, Barry Ticho, Aaron Deykin, Edwin K Jackson
Heart failure with preserved ejection fraction (HFpEF) is prevalent and often accompanied by metabolic syndrome. Current treatment options are limited. Here, we test the hypothesis that combined A1/A2B adenosine receptor blockade is beneficial in obese ZSF1 rats, an animal model of HFpEF with metabolic syndrome. The combined A1/A2B receptor antagonist 3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)-1-bicyclo[2.2.2]octanyl]propanoic acid (BG9928) was administered orally (10 mg/kg/day) to obese ZSF1 rats (n = 10) for 24 weeks (from 20 to 44 weeks of age)...
February 2016: Journal of Pharmacology and Experimental Therapeutics
Henrique Camara, Juliano Quintella Dantas Rodrigues, Gabriel Andrade Alves, Edilson Dantas da Silva Junior, Afonso Caricati-Neto, Antônio G Garcia, Aron Jurkiewicz
Autonomic nerves release ATP, which is processed into adenosine in the synaptic cleft. Adenosine and ATP exert a negative chronotropic effect in the heart. This study aims to evaluate adenosine and P2 receptors and cellular signalling in cardiac arrest produced by purines in the heart. Right atria of adult Wistar rats were used to evaluate the effects of adenosine, ATP and CPA (an adenosine A1 receptor agonist), in the presence and absence of DPCPX, an adenosine A1 receptor antagonist. Effects of adenosine A2 and A3 receptors agonists and antagonists were also investigated...
December 5, 2015: European Journal of Pharmacology
Valentina Chiodi, Antonella Ferrante, Luca Ferraro, Rosa Luisa Potenza, Monica Armida, Sarah Beggiato, Antonella Pèzzola, Michael Bader, Kjell Fuxe, Patrizia Popoli, Maria Rosaria Domenici
Adenosine A2A receptors (A2 A Rs) and cannabinoid CB1 receptors (CB1 Rs) are highly expressed in the striatum, where they functionally interact and form A2A /CB1 heteroreceptor complexes. We investigated the effects of CB1 R stimulation in a transgenic rat strain over-expressing A2 A Rs under the control of the neural-specific enolase promoter (NSEA2A rats) and in age-matched wild-type (WT) animals. The effects of the CB1 R agonist WIN 55,212-2 (WIN) were significantly lower in NSEA2A rats than in WT animals, as demonstrated by i) electrophysiological recordings of synaptic transmission in corticostriatal slices; ii) the measurement of glutamate outflow from striatal synaptosomes and iii) in vivo experiments on locomotor activity...
March 2016: Journal of Neurochemistry
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