IPSIndian Journal of Pharmacology
Home  IPS  Feedback Subscribe Top cited articles Login 
Users Online : 3488 
Small font sizeDefault font sizeIncrease font size
Navigate Here
 » Next article
 » Previous article 
 » Table of Contents
Resource Links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (291 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)

In This Article
 »  Abstract
 »  Introduction
 »  Refractory prima...
 »  Conclusions
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    PDF Downloaded1553    
    Comments [Add]    
    Cited by others 15    

Recommend this journal


Year : 2009  |  Volume : 41  |  Issue : 3  |  Page : 97-105

Adenosine and adenosine receptors: Newer therapeutic perspective

Department of Pharmacology, M.R. Medical College, Sedam Road, Gulbarga-585 105, India

Date of Submission10-Mar-2009
Date of Decision31-Mar-2009
Date of Acceptance08-Jun-2009
Date of Web Publication28-Aug-2009

Correspondence Address:
S Manjunath
Department of Pharmacology, M.R. Medical College, Sedam Road, Gulbarga-585 105
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0253-7613.55202

Rights and Permissions

 » Abstract 

Adenosine, a purine nucleoside has been described as a 'retaliatory metabolite' by virtue of its ability to function in an autocrine manner and to modify the activity of a range of cell types, following its extracellular accumulation during cell stress or injury. These effects are largely protective and are triggered by binding of adenosine to any of the four adenosine receptor subtypes namely A1, A2a, A2b, A3, which have been cloned in humans, and are expressed in most of the organs. Each is encoded by a separate gene and has different functions, although overlapping. For instance, both A1 and A2a receptors play a role in regulating myocardial oxygen consumption and coronary blood flow. It is a proven fact that adenosine plays pivotal role in different physiological functions, such as induction of sleep, neuroprotection and protection against oxidative stress. Until now adenosine was used for certain conditions like paroxysmal supraventricular tachycardia (PSVT) and Wolff Parkinson White (WPW) syndrome. Now there is a growing evidence that adenosine receptors could be promising therapeutic targets in a wide range of conditions including cardiac, pulmonary, immunological and inflammatory disorders. After more than three decades of research in medicinal chemistry, a 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. So this review focuses mainly on the newer potential role of adenosine and its receptors in different clinical conditions.

Keywords: Anaesthesia and critical care, asthma, epilepsy, inflammatory bowel diseases, ischaemia/reperfusion injury, Parkinson′s disease, refractory primary pulmonary hypertension

How to cite this article:
Manjunath S, Sakhare PM. Adenosine and adenosine receptors: Newer therapeutic perspective. Indian J Pharmacol 2009;41:97-105

How to cite this URL:
Manjunath S, Sakhare PM. Adenosine and adenosine receptors: Newer therapeutic perspective. Indian J Pharmacol [serial online] 2009 [cited 2022 Jun 25];41:97-105. Available from: https://www.ijp-online.com/text.asp?2009/41/3/97/55202

 » Introduction Top

Adenosine is a metabolite of adenosine triphosphate (ATP), having a very short half-life (1.5 s) due to its rapid metabolism [Figure 1]. It accumulates in the area where ATP is utilised but not reformed, for example during ischaemia and possibly during sepsis. Unlike ATP, adenosine exists free in cytosol of all cells and is transported in and out of the cell by a membrane transporter. It is not a conventional transmitter but a sort of local hormone or better say 'homeostatic modulator'.

Adenosine is an endogenous purine nucleoside that mediates a wide variety of physiological functions by interacting with four cell surface receptors namely A1, A2a, A2b and A3 [Table 1]. Adenosine is an intermediate metabolite in many important biochemical pathways and has been shown to play a role in the regulation of coronary and systemic vascular tone, platelet function and lipolysis in adipocytes. [1],[2] In addition, it mediates important functions like induction of sleep, antioxidant and, antiseizure effects, neuroprotection etc. Until now adenosine was mainly used for terminating paroxysmal supraventricular tachycardia (PSVT) and Wolff Parkinson White (WPW) syndrome. Now, with advances in understanding of adenosine receptors and development of agonists and antagonists [Table 2], adenosine receptors have emerged as potential newer therapeutic targets. Mainly, A2a receptor plays an important role in mediating inflammatory and immune responses. [3] Its actions through the various adenosine receptor subtypes, bring about a decrease in energy demand and an increase in energy supply and thus are protective. [4] Similar to endocannabinoid, the neuromodular adenosine plays a very important integrative role in striatal function. [5] Adenosine and dopamine receptor interactions, also have integrative mechanism in basal ganglia. [6] In addition, several drugs act through modulation of adenosine effect like methylxanthine, dipyridamole, ketamine, beta blockers, calcium channel blockers, dopamine, cannabinoids etc. Adenosine also plays an important role in renal function. Renal tubular sodium transport is the principal consumer of ATP. [7] Sodium transport is influenced by changes in glomerular filtration rate (GFR) and by primary changes in tubular transport. Intrarenal adenosine released by cleavage of ATP, maintains the balance between energy supply and demand by affecting both of these processes. In the renal microcirculation, adenosine receptors exert control over renal blood flow, GFR, renin release and tubuloglomerular feedback. [8]

There is a growing interest in elucidating the mechanisms by which adenosine inhibits inflammation. Hence, these inhibitory adenosine receptors (Gi-A1 and A3) and their downstream signaling pathways are promising targets for newer antiinflammatory therapies. By signalling through the A 2 a adenosine receptors, adenosine suppresses the release of inflammatory mediators, [3] primarily by inhibiting lymphoid or myeloid cells including neutrophils, macrophages, lymphocytes , and platelets.

Newer potential therapeutic role of adenosine and its receptors

Bronchial asthma: Adenosine, a primordial signalling molecule, produces a number of physiological and pathophysiological effects in the human body. It has been shown that stable form of adenosine, i.e. the nucleotide adenosine monophosphate (AMP) induces bronchoconstriction in asthma, but not in normal airways. Following facts convince that adenosine plays a key role in pathophysiology of asthma and has an important function in acute bronchoconstrictor [Figure 2] and airway inflammatory responses in humans.

  • Adenosine levels are increased in broncho-alveolar-lavage fluid [9] and exhaled breath condensate of patients with allergic asthma [10] and in the plasma of patients with exercise-induced asthma. [11]
  • The sensitivity of airways to adenosine and adenosine monophosphate (AMP), which is metabolized locally by the 5' nucleotidase to adenosine, more closely reflects an inflammatory process and the phenotype for allergic asthma.[12],[13]
  • Adenosine induces hyperresponsiveness in the airways of asthmatics, in vivo following inhalation and in vitro in small airways. [14],[15]
  • At therapeutic plasma levels, less than those required to inhibit phospho-diesterase enzyme both theophylline, a non-selective adenosine receptor antagonist and bamiphylline, a selective A1 adenosine receptor antagonist (which does not bind to human A 2 b and A 3 receptors), improve lung function and symptoms in humans with asthma. [16],[17]
  • Adenosine elicits hyperreactive airway response in humans with allergic asthma by acting on its receptors. All the four adenosine receptors, which have been cloned in humans, are expressed in lung and all are targets for drug development for human asthma. [18]

 » Refractory primary pulmonary hypertension (RPPH) Top

Primary pulmonary hypertension of the newborn (PPHN) is a serious disease in which the pulmonary vascular resistance remains elevated during the neonatal period. It is a clinical syndrome that may occur in association with diverse neonatal cardiorespiratory disorders, such as meconium aspiration, sepsis, pneumonia, acute respiratory distress syndrome, asphyxia, congenital diaphragmatic hernia or lung hypoplasia. As a matter of fact, it is often difficult to rapidly make the correct diagnosis since it may share common pathophysiologic and clinical features with other diseases. Primary pulmonary hypertension of the newborn contributes to neonatal hypoxemia, which is often refractory and remains a major clinical problem, significantly contributing to morbidity and mortality in term and preterm neonates. Indeed, this condition is traditionally treated by correcting the primary and triggering factors, whenever possible and by using conventional protocols including recent ventilation strategies (high-frequency oscillatory ventilation), maintenance of a reasonable electrolytic and acid-base balance, nutritional support and the use of non-specific agents like alkali infusion, magnesium sulphate, prostacyclin, tolazoline and more specific pulmonary vasodilator agents like nitric oxide. [19],[20]

Recent reports recommend the use of adenosine infusion for PPHN, alone or associated with other strategies, for refractory scenarios. The pathophysiologic hypothesis is supported by the fact that pulmonary vasodilation is achieved by two known pathways. Nitric oxide acts by elevating intracellular cyclic guanosine monophosphate levels resulting in smooth muscle relaxation with a specific potent vasodilator effect. [21] On the other hand, adenosine causes potent selective pulmonary vasodilation by acting at adenosine receptors (A2) on vascular smooth muscle to increase intracellular cyclic adenosine 3'5' monophosphate (AMP), [22] resulting in smooth muscle relaxation and improvement in systemic and myocardial oxygen delivery. Adenosine may also stimulate K + ATP channels, resulting in hyperpolarization of smooth muscle. The rationale behind its use is more consistent with the fact that patients with pulmonary hypertension have low adenosine levels.

Inflammatory bowel diseases (IBDs): Traditional medical treatments for inflammatory bowel diseases have focused on nonspecific suppression of immune reaction and inflammation with limited efficacy and safety. However, recent advances in the knowledge of enteric immunopathogenesis have paved the way to targeted therapies, allowing a selective blockade of the inflammatory cascade and modulation of key cytokines. In the search for novel therapeutic options, increasing attention is being paid to the adenosine system and its involvement in the pathophysiology of IBDs. The potential therapeutic applications resulting from its pharmacological modulation have been recognized in recent years. The expression of adenosine receptor subtypes in the gastrointestinal tract has been investigated in humans and evidence has been obtained for their localization, both in small and large bowel.

Once released at sites of inflammation, adenosine plays prominent roles in maintaining tissue integrity by modulation of immune functions, down-regulation of phlogistic reactions, interference with the biosynthesis of proinflammatory cytokines and inhibition of neutrophil adhesion, degranulation and anti-oxidant activity. [23] In these settings, the concentrations of adenosine closely reflect the metabolic status of the tissue, and it has been proposed that the purinergic system may act as a sensor apparatus, which provides the immune system with essential information about tissue health, thus contributing to the resolution of inflammation. In gastrointestinal tract, adenosine also contributes to the control of enteric neurotransmission and smooth muscle contractility, thus participating in physiological regulation of gut motor functions. Under physiological conditions, adenosine is mainly formed at the intracellular level from S-adenosylhomocysteine hydrolase. However, in the presence of adverse situations such as hypoxia or inflammation, adenosine production occurs both intracellularly and extracellularly by dephosphorylation of ATP via 5'-nucleotidase enzymes accompanied by suppression of adenosine kinase activity [Figure 3].

As discussed above, adenosine can exert antiinflammatory actions in a variety of systems, including the gastrointestinal tract. The involvement of the adenosine system in the antiinflammatory action has been recognized since the early 1990s. In recent years, increasing interest is being focused on the search for drugs that act via a direct stimulation of adenosine receptor subtypes, in particular A2a and A3 or through an increase in local adenosine concentration and could offer novel therapeutic options for treatment of IBDs. The large body of evidence supporting the prominent role played by A2a receptors in the antiinflammatory actions of adenosine has prompted the synthesis of drugs acting as selective agonists of this receptor subtype and their testing in models of intestinal inflammation. In a study by Odashima et al ., [24] the potential antiinflammatory effect of ATL-146e, a selective A2a receptor agonist, was investigated on the acute and chronic model of colitis evoked by formalin-immune complex in rabbits, as well as in a model of spontaneous ileitis in SAMP1/YitFc mice. The stimulation of A2a receptors was associated with a significant amelioration of inflammation in the intestinal mucosa, with a reduction of leucocyte infiltration and inhibition of proinflammatory cytokine levels (TNF-α, IFN-γ and IL-4). However, it has been recently observed that the selective A2a receptor agonist CGS21680 was ineffective in ameliorating various inflammatory parameters of colitis induced by dextran sodium sulphate (DSS) in mice. Overall, the actual significance of A2a receptors in the pathophysiology of intestinal inflammation remains undetermined, and further investigations are required to establish the therapeutic relevance of A2a agonists in IBD. Adenosine A3 receptors are also emerging as possible targets for treatment of bowel inflammation. [25] IB-MECA, an A3 receptor agonist, exerted significant ameliorative effects, both in DSS-induced intestinal inflammation and spontaneous colitis in IL-10 deficient mice. In particular, this drug markedly reduced the colonic levels of the proinflammatory cytokines IL-1, IL-6 and IL-12 and decreased the local production of MIP-1a (Macrophage Inflammatory Protein-1alpha), and MIP-2, with a powerful downregulation of leucocyte trafficking in both models of bowel inflammation. Treatment with IB-MECA prevented the induction of various cytokine/chemokine/inflammatory genes, together with a marked suppression of ROS (Reactive Oxygen Species) production and a significant amelioration of intestinal damage. As an alternative strategy to the direct pharmacological modulation of adenosine receptors, it has been proposed that the elevation of endogenous adenosine concentrations, through the blockade of pivotal catabolic enzymes, might exert a beneficial influence on enteric inflammation. Various authors have reported a significant increase in adenosine-deaminase expression and activity in inflamed tissues, including intestinal ones and the association of a defective adenosine production, with chronicization of the phlogistic conditions. [26] In a model of experimental colitis induced by dinitrobenzene sulphonic acid (DNBS), the results indicated that the blockade of adenosine conversion into inosine, promoted by inhibition of adenosine deaminase, was able to protect the colonic tissues from inflammatory injury. This effect was associated with a significant reduction of TNF-α release, neutrophil infiltration and ROS production. [27] Cellular adenosine uptake is another key event regulating extracellular adenosine concentrations, and therefore the inhibition of nucleoside transporters could represent a further approach to enhance the antiinflammatory actions of this nucleoside. In this regard, a recent in vitro study compared the immunomodulatory effects of dipyridamole (a non-selective inhibitor of adenosine uptake) with that of methotrexate, evaluating the effects of these drugs on TNF-α and IL-10 release from intestinal mononuclear cells obtained either from patients with Crohn's disease or healthy controls and stimulated with LPS (lipopolysaccharide) and phytohemagglutinin. The results showed a significant suppression of TNF-α levels in cells treated with both drugs whereas dipyridamole was more effective than methotrexate in increasing IL-10 levels. [28] Thus with development of these adenosine receptor modulators, new door for the treatment of IBD has opened.

Anaesthesia and intensive care medicine: Extracellular adenosine and adenosine triphosphate (ATP) are involved in biological processes including neurotransmission, muscle contraction, vasodilatation, signal transduction and secretion in a variety of cell types. [29] Recently established and potential clinical applications of adenosine, ATP in general and ATP-MgCl2 in intensive care medicine have been well documented.

Several double-blind, placebo-controlled, cross-over studies in healthy human subjects, have shown pain-reducing effects of intravenous adenosine infusion at doses of 50-70 mg/kg/min. [30] In addition, the effectiveness of adenosine in reducing ischaemic pain (70 mg/kg/min IV for 30 min) is comparable to morphine (20 mg/kg/min IV for 5 min) or ketamine (20 mg/kg/min IV for 5 min). Furthermore, adenosine given in combination with morphine or ketamine has an additive effect on pain reduction. [31] A recent study [32] suggested that, adenosine infusion during general anaesthesia for surgery provided good recovery from anaesthesia, associated with pronounced and sustained postoperative pain relief. In this study, adenosine (50-500 mg/kg/min), during surgery-induced pain relief, reduced opioid requirements and attenuated side-effects, such as protracted sedation, cardiorespiratory instability, nausea and vomiting, during the postoperative recovery period. Adenosine was superior to remifentanil (0.05-0.5 mg/kg/min) in all these aspects.

These results suggest that adenosine could be very useful in anaesthesia and intensive care medicine, where it acts by inhibiting nociceptive transmission.

Epilepsy: Current therapies of epilepsy largely rely on the suppression of spontaneous seizures by pharmacotherapy or surgical intervention; however, till date no effective prophylaxis or true pharmacotherapeutic cure is available. Epileptogenesis i.e. the process that leads to epilepsy and spontaneous seizures is thought to be triggered by an initial acute brain injury, e.g. status epilepticus, followed by progressive neuronal cell loss, mossy fibre sprouting and formation of an astrogliotic scar.[33] However, it is presently unclear why some brain injuries evolve into epilepsy while others do not. Therefore, the identification of diagnostic markers to predict epileptogenesis is of utmost importance. The identification of astrogliosis as a hallmark in brain of epileptics, and the identification of astrocytes as important modulators of neuronal activity imply that dysfunction of astrocytes might play a key role in the pathogenesis of epilepsy. [34] Animal models of epileptogenesis have been developed that closely mimic the pathogenesis of human mesial temporal lobe epilepsy, a form of human focal epilepsy that is frequently associated with progression to chronic intractable epilepsy. These models rely on the intrahippocampal, [35] intraamygdaloid or intracerebroventricular administration of small doses of kainic acid (KA). As a primary consequence of KA injection, status epilepticus is elicited, which in turn leads to a characteristic pattern of hippocampal cell death, mossy fibre sprouting, astrogliosis and spontaneous recurrent seizures [35] during a span of several weeks.

Adenosine is an inhibitory modulator of brain activity. By acting on its receptors, mainly by activation of A1 receptors in hippocampus, it exerts predominant inhibitory effects. [36] These inhibitory actions of adenosine can be used therapeutically to suppress seizures [37] and are considered important for maintaining postictal depression [38] and for restoring the metabolic equilibrium following seizures. [39] However, despite more than 20 years of research on the role of adenosine in experimentally induced seizures and the identification of adenosine as endogenous anticonvulsant of the brain, [40] the pathogenic role of the adenosine system in epileptogenesis remains understudied.

Ambient concentrations of adenosine are largely regulated by the activity of its major metabolic enzyme adenosine kinase (ADK), [41] which in the adult brain is predominantly expressed in astrocytes. Consequently, astrogliosis in epilepsy is associated with upregulation of ADK. [42] Transgenic upregulation of ADK in brain leads to a reduction in the tone of ambient adenosine and therefore is associated with increased susceptibility to seizures [43] and ischaemic cell death. These findings provide a neurochemical rationale for therapeutic intervention. [44] Consequently, cultured cells engineered to release adenosine by disrupting their Adk gene were tested as therapeutic brain implants in the rat kindling model. These studies have provided the proof-of-concept that focal augmentation of adenosine by cellular brain implants can reduce induced (kindled) seizures and the progression of kindled seizure severity. [45] Hence, adenosine kinase inhibitor like GP515 has been discovered.

However, it remains to be demonstrated whether focal augmentation of adenosine can prevent the development of spontaneous seizures, i.e. true epileptogenesis.

Ischaemia/reperfusion (I/R) Injury: Ischaemic preconditioning (IPC) refers to the mechanism whereby brief periods of ischaemia/reperfusion render a tissue relatively resistant to the harmful effects of subsequent prolonged periods of ischaemia/reperfusion. First described in canine hearts in 1986, IPC has been shown to occur in most species and tissues.[46] The exact mechanism of IPC may vary in different tissues and species where adenosine has an important role. [47],[48],[49] This 'adenosine theory' is supported by three facts:

  • Interstitial adenosine concentration doubles after 5 min of cardiac ischaemia. [50]
  • Adenosine antagonists reduce the effect of cardiac IPC. [47],[48]
  • Adenoreceptor stimulation reduces myocardial damage following ischaemia/reperfusion [51] and during cardiopulmonary bypass. [52]
Adenosine may attenuate ischaemia/reperfusion injury by a number of possible mechanisms, [53] including purine salvaging, improved tissue perfusion, antiinflammatory action and a direct intracellular initiator/effector mechanism.

Purine salvaging: In this process, adenosine acts as a substrate for ATP production. This appears unlikely, as studies have failed to show an improvement in the replenishment of the adenine nucleotide pool. [54]

Improved tissue perfusion: Administration of high doses of adenosine have shown to increase tissue perfusion. [55] Adenosine infusion significantly reduces capillary hyperpermeability, leucocyte adherence and leucocyte extravasation. [56]

Antiinflammatory action: Certain in vitro experiments on ischaemia/reperfusion [55] have demonstrated a maximum reduction in granulocyte respiratory burst activity of 20%, using an adenosine concentration of 1 µM. However, the remaining 80% of activity (37 nmol O2/min per million neutrophils) is toxic to cultured endothelial cells. [57] It was concluded that the protective effect observed in the in vivo study was due to the 65% decrease in leucocyte extravasation during reperfusion, rather than due to a 20% reduction in respiratory burst activity.[55]

Direct intracellular initiator/effector mechanism: A direct intracellular effect of IPC [53] has been proposed to include all of the preceding observations, while explaining the role of other mediators and the delayed (days or weeks) protective effect of IPC.

By all the above-mentioned mechanisms, adenosine could be very useful in handling the ischaemia/reperfusion injury.

Sepsis: Thiel and colleagues [58] investigated pretreatment of porcine endotoxaemia (  Salmonella More Details abortus equi endotoxin 5 µg/kg/h IV injection) with adenosine (150mg/kg/hr intravenous injection started before endotoxin infusion). Adenosine had no effect on endotoxin-induced neutropenia, neutrophil binding/phagocytosis of complement-opsonized zymosan or luminal-enhanced neutrophil chemiluminescence, in response to complement-opsonized zymosan. It did, however, strongly inhibit extracellular superoxide anion release, as measured by lucigenin-enhanced neutrophil chemiluminescence, in response to complement-opsonized zymosan.

Following a soft tissue injury and the induction of hemorrhagic shock, [59] mongrel pigs were resuscitated with Ringer lactate solution (control) or Ringer lactate solution plus acadesine, an adenosine precursor in the dose of (1 or 10 mg bolus intravenously every 12 h, with an initial IV injection of 0.5 mg/kg/min for 30 min). Seventy-two hours later, the animals received  Escherichia More Details coli 0111:B4 endotoxin (0.5 µg/kg over 30 min). The higher dose acadesine treatment had the following effects:

  • Reduced the endotoxin-induced increase in alveolar protein extravasation, systemic oxygen consumption and cardiac index.
  • Reduced the endotoxin-induced hypoxia and early transient pulmonary hypertension.
  • Reduced the fluid requirement necessary to maintain systemic hemodynamics.
  • Reduced mortality and prolonged survival time.
It had no effect on endotoxin-induced leucopoenia or tumour-necrosis factor production. In this study, acadesine may have been acting as an adenosine precursor but also could have been acting as a free radical scavenger, [60] which can be a potential therapeutic tool for treatment of sepsis.

Parkinson's disease: Although current medication treatment of Parkinson's disease (PD) provides good benefit for number of years, long-term treatment remains inadequate. The underlying neuronal degeneration continues to progress and many patients develop long-term complications of the dopamine replacement therapy. Continued neuronal degeneration can lead to the emergence of dementia or imbalance, problems that can cause substantial disability and that are poorly responsive to symptomatic treatment.

Due to these limitations of current therapy, an intense search for new medications to treat PD is ongoing. There is a need for medications that can slow the underlying progression of degeneration, improve PD symptoms in early disease without inducing dyskinesia and improve motor fluctuations and 'off' time in advanced disease without worsening dyskinesia. Much interest has focused on non-dopaminergic therapies, especially adenosine A2a receptor antagonists. Istradefylline (KW-6002) is an adenosine A2a receptor antagonist that is now in phase III clinical trials for PD. [61]

Although the anatomy of the A2a receptor distinguishes it from other non-dopaminergic targets in the quest for improved anti-Parkinsonian therapy, it is the behavioural pharmacology of A2a receptor antagonists that has provided the central rationale for their development as anti-Parkinsonian agents. Relatively specific A2a receptor antagonists consistently reverse motor deficits or enhance dopaminergic treatments in animal models of PD. For example, in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the dopaminergic pathway, A2a receptor antagonists including KF17837, KW-6002 and MSX-3 potentiated the contralateral turning behaviour induced by levodopa or a dopamine agonist. [62] In addition, motor stimulation by an A2a receptor antagonist in this model showed no tolerance after repeated treatment. Furthermore, the case for developing adenosine A2a receptor antagonists as anti-Parkinsonian therapy has been built on a solid foundation of preclinical evidence. [63]

As hypolipidaemic agent: Coronary artery disease (CAD) is the leading cause of death in the industrialized nations, accounting for 42% of all deaths and for 50% of the total cardiovascular healthcare expenditure. [64] Despite efforts to treat dyslipidaemia with proper diet and drug treatment, CAD remains one of the most common cause of death. Many risk factors (e.g., older age, male gender, hypertension, diabetes, smoking, etc.) are associated with the development and progression of CAD and among them are the serum lipid abnormalities or dyslipidaemias. High total and low density lipoprotein (LDL) cholesterol levels are strongly related to CAD risk, and reductions in LDL levels are associated with reduced coronary disease risk. The importance of elevated triglycerides (TGs) as an independent risk factor of CAD has been controversial. Recently, a metaanalysis of 17 prospective studies of TG levels and cardiovascular disease showed that elevated TG levels can be an independent risk factor for CAD. [65] RPR749 (molecular formula C22H26F3N7O3, molecular weight 493.49) is a potent and selective adenosine A1 agonist targeted for the management of hypertriglyceridaemia [66] to reduce/normalize TG levels, leading to a reduction in death and morbidity from CAD with little effect on other receptors. The methylated metabolite of RPR749 shows similar pharmacological properties. In the animal models of hypertriglyceridaemia, RPR749 also appears to lower free fatty acid (FFA) and insulin levels and may have additional lipid-modifying effects.

As stated above there is a clear need for developing drugs that can reduce TG levels. The current therapy includes statins, fibrates and niacinic acid. Fibrates (gemfibrozil, fenofibrate and bezafibrate) reduce TGs by approximately 35% and lower LDL at doses of approximately 600 mg/d administered twice daily, but are associated with gallstones and gastrointestinal disorders. Nicotinic acid can also lower TGs by approximately 35% and decrease LDL at doses of 3 g/d given three times daily but is associated with an extremely poor side effect profile and is contraindicated in patients with diabetes. Statins (lovastatin, pravastatin, simvastatin, atorvastatin and cerivastatin) at dose of 20-80 mg/d lower TG levels by approximately 25% and can decrease LDL but may be associated with myopathy. The target was to achieve at least 35% or more lowering of TG levels by RPR749 based on the efficacy of other available therapies. RPR749 (0.1-30 mg/kg) has been shown to reduce TG levels from 20 to 70% [67] and thus could be important tool in treating coronary artery disease.

 » Conclusions Top

Adenosine is very useful therapeutic tool in handling a variety of clinical conditions like ischaemia/reperfusion injury and refractory primary pulmonary hypertension. In addition, it has created its own place in the field of anaesthesia and critical medicine. Alternatives to adenosine administration include modulation of its metabolism and administration of specific agonists/antagonists like:

  1. Adenosine precursors (e.g. acadesine).
  2. Adenosine analogues-A1 antagonists and A2 agonists both of which are antiinflammatory.
  3. Adenosine metabolism inhibitors that increase the concentration of endogenous adenosine. These are:

    • Adenosine deaminase inhibitors (e.g. pentostatin)
    • Adenosine kinase inhibitors (e.g. GP515)
    • Nucleoside transport inhibitors (e.g. R75231). By preventing the uptake of extracellular adenosine into cells, endogenous adenosine is protected from metabolism by adenosine deaminase.
These modulators of adenosine metabolism and specific agonists/antagonists could be very useful in treating certain conditions like bronchial asthma, inflammatory bowel disorders, epilepsy, sepsis etc. Almost all these modulators and agonists/antagonists of adenosine are under clinical trial, but could be potential therapeutic tools.

 » References Top

1.Arch JR, Newsholme EA. The control of the metabolism and the hormonal role of adenosine. Essays Biochem 1978;14:82- 123.  Back to cited text no. 1  [PUBMED]  
2.Berne RM, Winn HR, Knabb RM, Ely SW, Rubio R. Blood flow regulation by adenosine in heart, brain and skeletal muscle. In: Berne RM, Rall TW, Rubio R, editors: Regulatory function of adenosine. Boston: Martinus Nijhoff Publishers; 1983. p. 293.   Back to cited text no. 2    
3.Palmer TM, Trevethick MA. Suppression of inflammatory and immune responses by A2a adenosine receptor: an introduction. Br J Pharmacol 2008;153:527-34.   Back to cited text no. 3    
4.Burns RF. Adenosine receptors: Roles and pharmacology. Ann Ny Acad Sci 1990;603:211-25.   Back to cited text no. 4    
5.Ferres, Borycz J, Goldbreg SR, Hope BT, Morales M, Lluis C, et al. Role of adenosine in control of homosynaptic plasticity in striatal excitatory synapses. Neurosci J Integr 1995;4:445-64.   Back to cited text no. 5    
6.Ferre S, Fedholm BB, Morelli M, Popoli P, Fuxe K. Adenosine - dopoamine receptor - receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci 1997;20:482-7.   Back to cited text no. 6    
7.Kiil F, Sejersted OM, Steen PA. Energetics and specificity of transcellular NACL transport in the dog kidney. Int J Biochem 1980;12:245-50.   Back to cited text no. 7  [PUBMED]  
8.Vallon V, Muhlbauer B, Osswald H. Adenosine and kidney function. Physiol Rev 2006;86:901-40.   Back to cited text no. 8    
9.Driver AG, Kukoly CA, Ali S, Mustafa SJ. Adenosine in bronchoalveolar lavage fluid in asthma. Am Rv Dis 1993;148:91-7.   Back to cited text no. 9    
10.Huszar E, Vass G, Vizi E, Csoma Z, Barat E, Molnar VG, et al. Adenosine in exhaled breath condensate in healthy volunteers and in patients with Asthma. Eur Respir J 2002;20:1393-8.   Back to cited text no. 10    
11.Vizi E, Huzzar E, Csoma Z, Boszormenyi-Nagy G, Barat E, Horrath I, et al. Plasma adenosine concentration increases during exercise: A possible contributing factor in exercise - induced bronchoconstriction in Asthma. J Allergy Clin Immunol 2002;109:446-8.   Back to cited text no. 11    
12.Holgate ST. Adenosine provocation: a new test for allergic airway inflammation. Am J Respir Crit Care Med 2002;165:317-9.   Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Spicuzza L, Bonfiglio C, Polosa R. Research applications and implications of adenosine in diseases of airways. Trends in Phamacol Sciences 2003;24:409-13.   Back to cited text no. 13    
14.Dahlen SE, Hansson G, Hedqvist P, Bjorck T, Granstrom E, Dahlen B. Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4 and E4. Proc Natl Acad Sci USA 1983;80:1712-6.   Back to cited text no. 14    
15.Bjorck T, Gustafsson LE, Dahlen SE. Isolated bronchi from asthamtics are hyper- responsive to adenosine, which apparently act indirectly by liberation of leutotrienes and histamine. Am Rev Respir Dis 1992;145:1087-91.   Back to cited text no. 15    
16.Catena E, Gunella G, Monici PPA, Oliani C.Evaluation of the risk / benefit ratio of bamiphylline in the treatment of chronic obstructive lung disease. Italian J Chest Dis 1988;42:419-26.   Back to cited text no. 16    
17.Crescioli S, Spinazzi A, Plebani M, Pozzani M, Mapp CE, Boschetto P, et al. Theophylline inhibits early and late asthmatic reactions induced by allergens in asthmatic subjects. Ann Allergy1991;66:245-51.   Back to cited text no. 17  [PUBMED]  
18.Rorke S, Holgate ST. Targeting adenosine receptors: novel therapeutic targets in asthma and chronic obstructive pulmonary disease. Am J Respir Med 2002;1:99-105.   Back to cited text no. 18  [PUBMED]  
19.Oishi P, Fineman JR. Pharmacological therapy for persistent pulmonary hypertension of the newborn: As "poly" as the disease itself. Pediatr Crit Care Med 2004;5:94-5.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Patole S, Lee J, Buetner P. Improved oxygenation following adenosine infusion in persistent pulmonary hypertension of the newborn. Biol Neonate 1998;74:345-50.  Back to cited text no. 20    
21.Roberts JD, Polaner DM, Lang P. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:818-9.  Back to cited text no. 21    
22.Fullerton DA, Agrafojo J, McIntyre RC Jr. Pulmonary vascular smooth muscle relaxation by cAMP-mediated pathways. J Surg Res 1996;61:444-8.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Hasko G, Cronstein BN. Adenosine: an endogenous regulator of innate immunity. Trends Immunol 2004;25:33-9.  Back to cited text no. 23    
24.Odashima M, Bamias G, Rivera-Nieves J. Activation of A2a adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. Gastroenterology. 2005;129:26-33.  Back to cited text no. 24    
25.Rybaczyk L, Wunderlich JE, Needleman B. Differential dysregulation of ADORA3, ADORA2A, ADORA2B, and P2RY14 expression profiles from 34 purine genes in mucosal biopsies and peripheral blood mononuclear cells in inflammatory bowel diseases. Gastroenterology 2007;132:A-246.  Back to cited text no. 25    
26.Frode TS, Medeiros YS. Myeloperoxidase and adenosine-deaminase levels in the pleural fluid leakage induced by carrageenan in the mouse model of pleurisy. Mediators Inflamm 2001;10:223-7.  Back to cited text no. 26    
27.Antonioli L, Fornai M, Colucci R. Inhibition of adenosine deaminase attenuates inflammation in experimental colitis. J Pharmacol Exp Ther 2007;322:435-42.  Back to cited text no. 27    
28.Poturoglu S, Kaymakoglu S, Gurel Polat N, Ibrisim D, Ahishali E, Akyuz F, et al. A new agent for tumour necrosis factor-a inhibition: in vitro effects of dipyridamole in Crohn's disease. Scand J Clin Lab Invest 2009 May 18:1-7. [in press].   Back to cited text no. 28    
29.Gordon JL. Extracellular ATP: effects, sources and fate. Biochem J 1986;233:309-19.  Back to cited text no. 29  [PUBMED]  [FULLTEXT]
30.Segerdahl M, Irestedt L, Sollevi A. Antinociceptive effect of perioperative adenosine infusion in abdominal hysterectomy. Acta Anaesthesiol Scand 1997;41:473-9.  Back to cited text no. 30  [PUBMED]  
31.Segerdahl M, Persson E, Ekblom A, Sollevi A. Peroperative adenosine infusion reduces isoflurane concentrations during general anesthesia for shoulder surgery. Acta Anaesthesiol Scand 1996;40:792-7.  Back to cited text no. 31  [PUBMED]  
32.Fukunaga AF, Alexander GE, Stark CW. Characterization of the analgesic actions of adenosine: comparison of adenosine and remifentanil infusions in patients undergoing major surgical procedures. Pain 2003;101:129-38.  Back to cited text no. 32  [PUBMED]  [FULLTEXT]
33.Pitkanen A, Sutula TP. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol 2002;1:173-81.  Back to cited text no. 33    
34.Tian GF, Azmi H, Takano T, Xu Q, Peng W, Lin J, et al. An astrocytic basis of epilepsy. Nat Med 2005;11:973-81.  Back to cited text no. 34  [PUBMED]  [FULLTEXT]
35.Arabadzisz D, Antal K, Parpan F, Emri Z, Fritschy JM. Epileptogenesis and chronic seizures in a mouse model of temporal lobe epilepsy are associated with distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampus. Exp Neurol 2005;194:76-90.  Back to cited text no. 35  [PUBMED]  [FULLTEXT]
36.Johansson B. Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor. Proc Natl Acad Sci U. S. A. 2001;98:9407-12.  Back to cited text no. 36    
37.Huber A. Grafts of adenosine-releasing cells suppress seizures in kindling epilepsy. Proc Natl Acad Sci U. S. A. 2001;98:7611-16.  Back to cited text no. 37    
38.Etherington LA, Frenguelli BG. Endogenous adenosine modulates epileptiform activity in rat hippocampus in a receptor subtype-dependent manner. Eur J Neurosci 2004;19:2539-50.  Back to cited text no. 38  [PUBMED]  [FULLTEXT]
39.Dunwiddie TV. Adenosine and suppression of seizures. Adv Neurol 1999;79:1001-10.  Back to cited text no. 39  [PUBMED]  
40.Dragunow M, Goddard GV, Laverty R. Is adenosine an endogenous anticonvulsant? Epilepsia 1985;26:480-7.  Back to cited text no. 40  [PUBMED]  
41.Boison D. Adenosine kinase, epilepsy and stroke: mechanisms and therapies. Trends Pharmacol Sci 2006;27:652-8.  Back to cited text no. 41  [PUBMED]  [FULLTEXT]
42.Gouder N, Scheurer L, Fritschy JM, Boison D. Overexpression of adenosine kinase in epileptic hippocampus contributes to epileptogenesis. J Neurosci 2004;24:692-701.  Back to cited text no. 42  [PUBMED]  [FULLTEXT]
43.Fedele DE. Astrogliosis in epilepsy leads to overexpression of adenosine kinase resulting in seizure aggravation. Brain 2005;128:2383-95.  Back to cited text no. 43    
44.Boison D. Adenosine and epilepsy: from therapeutic rationale to new therapeutic strategies. Neuroscientist 2005;11:25-36.  Back to cited text no. 44  [PUBMED]  [FULLTEXT]
45.Li T. Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants. Brain 2007;130:1276-88.  Back to cited text no. 45    
46.Peralta C, Hotter G, Closa D. Protective effect of preconditioning on the injury associated to hepatic ischaemia-reperfusion in the rat: Role of nitric oxide and adenosine. Hepatology 1997;25:934-37.  Back to cited text no. 46    
47.Miura T, Iimura O. Infarct size limitation by preconditioning: Its phenomenological features and the key role of adenosine. Cardiovasc Res 1993;27:36-42.  Back to cited text no. 47  [PUBMED]  [FULLTEXT]
48.Miura T, Ogawa T, Iwamoto T. Dipyridamole potentiates the myocardial infarct size-limiting effect of ischemic preconditioning. Circulation 1992;86:979-85.  Back to cited text no. 48    
49.Thornton JD, Liu GS, Olsson RA. Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction. Circulation 1992;85:659-65.  Back to cited text no. 49    
50.Dorheim TA, Wang T, Mentzer RM Jr. Interstitial purine metabolites during regional myocardial ischemia. J Surg Res 1990;48:491-7.  Back to cited text no. 50    
51.Jordan JE, Zhao ZQ, Sato H. Adenosine A2 receptor activation attenuates reperfusion injury by inhibiting neutrophil accumulation, superoxide generation and coronary endothelial adherence. J Pharmacol Exp Ther 1997;280:301-9.  Back to cited text no. 51    
52.Mathew JP, Rinder CS, Tracey JB.Acadesine inhibits neutrophil CD11b upregulation in vitro and during in vivo cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995;109:448-56.  Back to cited text no. 52    
53.Bouma MG, van den Wildenberg FA, Buurman WA. The anti-inflammatory potential of adenosine in ischaemia-reperfusion injury: Established and putative beneficial actions of a retaliatory metabolite. Shock 1997;8: 313-20.  Back to cited text no. 53  [PUBMED]  
54.Galinanes M, Qiu Y, Van Belle H. Metabolic and functional effects of the nucleoside transport inhibitor R75231 in the ischaemic and blood reperfused rabbit heart. Cardiovasc Res 1993;27:90-5.  Back to cited text no. 54    
55.Elias AN, Wesley RC, Gordon IL. Effects of adenosine infusion on renal function, plasma ANP and ADH concentrations and central hemodynamics in anesthetized pigs. Gen Pharmacol 1997;28:429-33.  Back to cited text no. 55    
56.Grisham MB, Hernandez LA, Granger DN. Adenosine inhibits ischemia-reperfusion induced leukocyte adherence and extravasation. Am J Physiol 1989;257:H1334-9.  Back to cited text no. 56  [PUBMED]  [FULLTEXT]
57.Bishop CT, Mirza Z, Crapo JD. Free radical damage to cultured porcine aortic endothelial cells and lung fibroblasts: Modulation by culture conditions. In vitro Cell Dev Biol 1985;21:229-36.  Back to cited text no. 57    
58.Thiel M, Holzer K, Kreimeier U. Effects of adenosine on the functions of circulating polymorphonuclear leukocytes during hyperdynamic endotoxemia. Infect Immun 1997; 65:2136-44.  Back to cited text no. 58    
59.Fabian TC, Fabian MJ, Yockey JM. Acadesine and lipopolysaccharide-evoked pulmonary dysfunction after resuscitation from traumatic shock. Surgery 1996;119:302-15.  Back to cited text no. 59    
60.Bullough DA, Potter S, Fox MH. Acadesine prevents oxidant-induced damage in the isolated guinea pig heart. J Pharmacol Exp Ther 1993;266:666-7.  Back to cited text no. 60    
61.Hauser RA, Schwarzschild MA. Adenosine A2a Receptor Antagonists for Parkinson's Disease-Rationale, Therapeutic potential and Clinical Experience. Drugs Aging 2005:22:471-82.  Back to cited text no. 61    
62.Koga K, Kurokawa M, Ochi M, Nakamura J, Kuwana Y. Adenosine A2a receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-Parkinsonian rats. Eur J Pharmacol 2000;408:249-55.  Back to cited text no. 62  [PUBMED]  [FULLTEXT]
63.Xu K, Bastia E, Schwarzschild M. Therapeutic potential of adenosine A2a receptor antagonists in Parkinson's disease. Pharmacol Ther 2005;105:267-310.  Back to cited text no. 63  [PUBMED]  [FULLTEXT]
64.Harwood HJ, Hamanaka BS. Modulators of dislipidemia. Emerg Drugs 1998;3:147-72.  Back to cited text no. 64    
65.Grundy SM. Consensus statement: role of therapy with "statin" in patients with hypertriglyceridemia. Am J Cardiol 1998;81:1B-6B.  Back to cited text no. 65  [PUBMED]  
66.Shah B, Rohatagi S, Natarajan C, Kirkesseli S, Baybutt R, Jensen BK. Pharmacokinetics, Pharmacodynamics and Safety of a Lipid-Lowering Adenosine A1 Agonist RPR749, in healthy subjects. Am J Ther 2004;11:175-89.  Back to cited text no. 66  [PUBMED]  [FULLTEXT]
67.Zannikos PN, Rohatagi S, Jensen BK. Pharmacokineticpharmacodynamic modeling of the antilipolytic effects of an adenosine receptor agonist. J Clin Pharmacol 2001;41:61-9.  Back to cited text no. 67  [PUBMED]  [FULLTEXT]


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]

This article has been cited by
1 ?Searching for novel antagonists of adenosine A1 receptors among azolo[1,5-a]pyrimidine nitro derivatives
Dmitry S. Yakovlev, Pavel M. Vassiliev, Yana V. Agatsarskaya, Anastasia A. Brigadirova, Kira T. Sultanova, Maria O. Skripka, Alexander A. Spasov, Konstantin V. Savateev, Vladimir L. Rusinov, Dmitriy V. Maltsev
Research Results in Pharmacology. 2022; 8(2): 69
[Pubmed] | [DOI]
2 Antioxidant and Neuroprotective Effects of Caffeine against Alzheimer’s and Parkinson’s Disease: Insight into the Role of Nrf-2 and A2AR Signaling
Muhammad Ikram, Tae Ju Park, Tahir Ali, Myeong Ok Kim
Antioxidants. 2020; 9(9): 902
[Pubmed] | [DOI]
3 A1 adenosine receptor-stimulated exocytosis in bladder umbrella cells requires phosphorylation of ADAM17 Ser-811 and EGF receptor transactivation
H. S. Prakasam,L. I. Gallo,H. Li,W. G. Ruiz,K. R. Hallows,G. Apodaca
Molecular Biology of the Cell. 2014; 25(23): 3798
[Pubmed] | [DOI]
4 Ketamine and Peripheral Inflammation
Marc De Kock,Sebastien Loix,Patricia Lavandæhomme
CNS Neuroscience & Therapeutics. 2013; 19(6): 403
[Pubmed] | [DOI]
5 The interaction of adenosine and morphine on pentylenetetrazole-induced seizure threshold in mice
Leila Moezi,Reyhane Akbarian,Hossein Niknahad,Hamed Shafaroodi
Neuropharmacology. 2013; 72: 1
[Pubmed] | [DOI]
6 Ligand-Specific Binding and Activation of the Human Adenosine A2BReceptor
Dominik Thimm,Anke C. Schiedel,Farag F. Sherbiny,Sonja Hinz,Katharina Hochheiser,Daniela C. G. Bertarelli,Astrid Maaß,Christa E. Müller
Biochemistry. 2013; 52(4): 726
[Pubmed] | [DOI]
7 Involvement of adenosine and standardization of aqueous extract of garlic (Allium sativum Linn.) on cardioprotective and cardiodepressant properties in ischemic preconditioning and myocardial ischemia-reperfusion induced cardiac injury
Journal of Biomedical Research. 2012; 26(1): 24
[VIEW] | [DOI]
8 Accidental intra-arterial injection of adenosine in a patient with supraventricular tachycardia
Janna M. A. ter Schure, Tjalling W. de Vries
Cardiology in the Young. 2011; : 1
[VIEW] | [DOI]
9 Computational Study of the Binding Modes of Caffeine to the Adenosine A<sub>2A</sub> Receptor
Yuli Liu, Steven K. Burger, Paul W. Ayers, Esteban Vöhringer-Martinez
The Journal of Physical Chemistry B. 2011; 115(47): 13880
[VIEW] | [DOI]
10 Development of asystole requiring cardiac resuscitation after the administration of regadenoson in a patient with pulmonary fibrosis receiving n-acetylcysteine
Grady, E.C., Barron, J.T., Wagner, R.H.
Journal of Nuclear Cardiology. 2011; 18(3): 521-525
11 Adenosine inhibits the release of arachidonic acid in activated human peripheral mononuclear cells. A proposed model for physiologic and pathologic regulation in systemic lupus erythematosus
Sipka, S.
TheScientificWorldJournal. 2011; 11: 972-980
12 A facile microwave-assisted synthesis of 8,9-cycloalkathieno[3,2-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones
Kaur, R., Kishore, D.P., Narayana, B.L., Rao, K.V., Balakumar, C., Rajkumar, V., Raoa, A.R.
Journal of Chemical Sciences. 2011; 123(1): 69-73
13 A facile microwave-assisted synthesis of 8,9-cycloalkathieno[3,2-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones
Journal of Chemical Sciences. 2011; 123(1): 69
[Pubmed] | [DOI]
14 Development of asystole requiring cardiac resuscitation after the administration of regadenoson in a patient with pulmonary fibrosis receiving n-acetylcysteine
Erin C. Grady,John T. Barron,Robert H. Wagner
Journal of Nuclear Cardiology. 2011; 18(3): 521
[Pubmed] | [DOI]
15 Adenosine 2A receptor: a crucial neuromodulator with bidirectional effect in neuroinflammation and brain injury
Shuang-Shuang Dai, Yuan-Guo Zhou
Reviews in the Neurosciences. 2011; 22(2): 231
[VIEW] | [DOI]


Print this article  Email this article


Site Map | Home | Contact Us | Feedback | Copyright and Disclaimer | Privacy Notice
Online since 20th July '04
Published by Wolters Kluwer - Medknow