Biological Implications of Extracellular Adenosine in Hepatic Ischemia and Reperfusion Injury
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Adenosine A3 receptor
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Adenosine receptors are present on most cells and organs, yet, although the physiological effects of adenosine were first described over 60 years ago, the potential therapeutic uses of adenosine have only been recognized and realized recently. A decade ago the potent anti-inflammatory effects of adenosine were first described; adenosine, acting at specific A2 receptors, inhibits some, but not all, neutrophil functions. Adenosine inhibits phagocytosis, generation of toxic oxygen metabolites, and adhesion (to some surfaces and to endothelial cells) but does not inhibit degranulation or chemotaxis. Occupancy of adenosine A2 receptors modulates leukocyte function by a novel mechanism. Although adenosine A2 receptors are classically linked to heterotrimeric GS signaling proteins and stimulation of adenylate cyclase, adenosine 3',5'-cyclic monophosphate does not act as the second messenger for inhibition of leukocyte function. By a mechanism that still remains obscure, occupancy of adenosine A2 receptors on neutrophils "uncouples" chemoattractant receptors from their stimulus-transduction proteins. The concentrations of adenosine that inhibit inflammatory cell function are similar to those observed in vivo and suggest a role for adenosine in the modulation of inflammation in vivo. Indeed, recent studies indicate that nonmetabolized adenosine receptor agonists are potent anti-inflammatory agents, and other studies indicate that methotrexate, a commonly used anti-inflammatory agent, diminishes inflammation by increasing adenosine release at inflamed sites. The observations reviewed here suggest that adenosine and agents that act through adenosine are excellent candidates for development as anti-inflammatory agents.
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This review focuses on the potential role of site- and event-selective adenosinergic drugs in the treatment of cardiovascular diseases. Adenosine is released from the myocardium and vessels in response to various forms of stress and acts on four receptor subtypes (A1, A2A, A2B and A3). Adenosine is an important endogenous substance with important homeostatic activity in the regulation of cardiac function and circulation. Adenosine receptors are also involved in the modulation of various cellular events playing crucial role in physiological and pathological processes of the cardiovascular system. These actions are associated to activation of distinct adenosine receptor subtypes, therefore drugs targeting specific adenosine receptors might be promising therapeutic tools in treatment of several disorders including various forms of cardiac arrhythmia, myocardial ischemia-reperfusion injury, angina pectoris, chronic heart failure, etc. Recently, in addition to subtype-specific adenosine receptor agonists and antagonists, a number of substances that enhance adenosine receptor activation locally at the site where the release of endogenous adenosine is the most intensive have been developed. Thus global actions of adenosine receptor agonists and antagonists, as well as desensitization or down-regulation following chronic administration of these orthosteric compounds can possibly be avoided. We discuss the chemical, pharmacological and clinical features of these compounds: (1) inhibitors of membrane adenosine transporters (NBTI, dipyridamole), (2) inhibitors of adenosine deaminase (coformycin, EHNA), (3) inhibitors of adenosine kinase (tubercidin, aristeromycin), (4) inhibitors of AMP deaminase (GP3269), (5) activators of 5'- nucleotidase (methotrexate), (6) adenosine regulators (acadesine) and (7) allosteric adenosine receptor modulators (PD81723, LUF6000). The development of this type of substances might offer a novel therapeutic approach for treating cardiovascular diseases in the near future. Keywords: Site and event specific action, adenosinergic drugs, membrane adenosine transport, adenosine deaminase, adenosine kinase, AMP deaminase, 5'-nucleotidase, adenosine regulators, allosteric receptor modulators, Cardiovascular Disorders
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Adenosine, an endogenous nucleoside, has a plethora of biological actions on a large variety of cells and can modulate the various functions of cells involved in inflammatory responses. On the other hand, production of extracellular matrices is one of the critical functions of fibroblasts. Among various extracellular matrices, hyaluronate (HA) plays important roles in migration, growth and differentiation of a variety of cells during the course of inflammatory reactions and process of wound healing.In this study, we investigated the expression of adenosine receptor subtypes in human gingival fibroblasts (HGF) and examined the effects of adenosine on the HA production of HGF by utilizing various agonists specific for adenosine receptor subtypes.Concerning the expression of adenosine receptors, RT-PCR analysis revealed that HGF expressed adenosine receptor A1, A2 a, and A2 b, but not A3 mRNA. Ligation of adenosine receptors by adenosine or adenosine analogue, 2-chlor-oadenosine (2 CADO) and N6-cyclopentyladenosine (CPA; A1 adenosine receptor agonist) but not CGS-21680 (A2 a adenosine receptor agonist) induced the expression of HA synthase mRNA, which is responsible for HA production in HGF. These results suggest that intracellular signal (s) via A1 adenosine receptor may play a central role for the upregulation of HA production by activated HGF in inflamed periodontal lesions.These results provide new evidence for the possible involvement of adenosine in the regulation of extracellular matrix production during the course of inflammatory responses in periodontal tissues.
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Adenosine, a purine nucleoside catabolite of ATP, regulates numerous effects in mammalian organ systems. The discovery by Drury and Szent-Gyorgy (1929) that adenosine can affect several bodily functions inspired much research interest. Regulatory functions of adenosine are especially important when cellular energy supply fails to meet the demand. Adenosine is omnipresent; it is released by nearly all cells and is continuously formed intracellularly as well as extracellularly. The intracellular production is mediated by an intracellular 50-nucleotidase, which dephosphorylates AMP (Schubert et al. 1979; Zimmermann et al. 1998), or by hydrolysis of S-adenosylhomocysteine (Broch and Ueland 1980). It is estimated that the levels of adenosine in interstitial fluid are within the 30–300 nM range (Winn et al. 1981; Delaney et al. 1998; Delaney and Geiger 1998; Zetterstrom et al. 1982; Porkka-Heiskanen et al. 1997). Adenosine generated intracellularly is transported into extracellular space via specific bidirectional transporters. Adenosine is generated in the extracellular space through ATP breakdown by series of ectoenzymes (50-nucleotidase and apyrase) (Zimmermann 2000). When the levels of adenosine in extracellular space are high, adenosine is transported into the cells and then inside the cells is phosphorylated to AMP by adenosine kinase or degraded to inosine by adenosine deaminase (Arch and Newsholme 1978; Lloyd and Fredholm 1995). The levels of adenosine increase, up to 100-fold, as a result of oxidative stress and ischemia (Rudolphi et al. 1992a; Latini et al 1999). Adenosine mediates its effects by activation of family of four G protein-coupled receptors: the A1, A2A, A2B, and A3 adenosine receptors. All four adenosine receptors have been cloned from different species. There is a close similarity between receptors of the same subtype, at least among mammals, with exception for A3 receptor for which there is almost 30 % difference at the amino acid level between human and rat (Fredholm et al. 2000, 2001; Klotz 2000; Zhou et al. 1992). Activation of adenosine A1 and A3 receptors results in decreased adenylate cyclase activity through activation of proteins of Gi/Go family. (VanCalker et al. 1978; Londos et al. 1980; Palmer and Stiles 1995; Borea et al. 2015). The adenosine A2A and A2B receptors are coupled to Gs-proteins, and activation of both types A2 receptors increases adenylate cyclase activity (Palmer and Stiles 1995; Brackett and Daly 1994; Peakman and Hill 1994; Fredholm et al. 2001, 2011; Sattin and Rall 1970; VanCalker et al. 1978). Recently, evidence was presented that A2A receptor may be coupled to different G proteins in different areas (Kull et al. 2000a, b), and adenosine A2B receptors may also activate phospholipase C in human mast cells (Feoktistov and Biaggioni 1995). Besides the “canonical” signaling pathways of adenosine receptors, numbers of “noncanonical” pathways for each receptor’s types have been described (Kull et al. 2000a; Schulte and Fredholm 2000; de Lera Ruiz et al. 2014; Chen et al. 2014).
Adenosine A2B receptor
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In the past decades, increased concentrations of the signaling molecule adenosine have been shown to play an important role in the prevention of tissue damage evoked by several stressful circumstances. During systemic inflammation, the circulating adenosine concentration increases rapidly, even up to 10-fold in septic shock patients. By binding to specific adenosine receptor subtypes, designated A1, A2a, A2b, and A3, adenosine exerts a wide variety of immunomodulating and (cyto)protective effects. Only recently, several specific adenosine receptor agonists and other drugs that modulate adenosine metabolism have been developed for human use. Importantly, correct interpretation of the effects of adenosine is highly related to the model of inflammation used, e.g., administration of endotoxin or live bacteria. This review will discuss the potential role for adenosine as an immunomodulating and cytoprotective signaling molecule and will discuss its potential role in the treatment of the patient suffering from sepsis.
Adenosine kinase
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