Adenosine & adenosine receptors :
Newer therapeutic perspective
Dr Suyash Bharat Sharma
PG JR 3rd Pharmacology
• Adenosine is a metabolite of adenosine
• It accumulates in the area where ATP is utilised
but not reformed, eg- ischemia
• Exists free in cytosol
• ‘Homeostatic modulator’
• Endogenous purine nucleoside
• 4 cell surface receptors namely A1, A2a, A2b
• Until now adenosine was mainly used for
terminating paroxysmal supraventricular
tachycardia (PSVT) and Wolff Parkinson White
• Advances in understanding of adenosine
receptors development of agonists and
(Very high affinity)
Isoforms have distinct, but
overlapping, cellular distribution
and are widely expressed in
of the body.
Adenosine Receptors: Signal
Newer potential therapeutic role of
adenosine and its receptors
1. Bronchial asthma:
• AMP induces bronchoconstriction in asthmatic pts (only)
• Adenosine levels are increased in BAL fluid ,exhaled breath
• Adenosine induces hyperresponsiveness in the airways of
asthmatics, in vivo following inhalation and in vitro in small
• At therapeutic plasma levels, less than those required to
inhibit phosphodiesterase enzyme,Theophylline, a
nonselective adenosine receptor antagonist & Bamiphylline, a
selective A1 adenosine receptor antagonist improve lung
function and symptoms in humans with asthma.
• All the 4 adenosine receptors, are targets for drug
development for human asthma.
Refractory primary pulmonary
• PPHN is a serious disease in which the pulmonary
vascular resistance remains elevated during the
• Occurs in association with diverse neonatal
cardiorespiratory disorders(meconium aspiration,
sepsis, pneumonia, acute respiratory distress
syndrome, asphyxia, CDH or lung hypoplasia)
• PPHN of the newborn contributes to neonatal
hypoxemia, which is often refractory morbidity
and mortality in term and preterm neonates.
• treated by correcting the primary and triggering factors
• Ventilation strategies / electrolytic and acid base balance/
nutritional support /nonspecific agents ( alkali infusion,
magnesium sulphate, prostacyclin, tolazoline ) &
pulmonary vasodilator agents (nitric oxide.)
• Adenosine infusion for PPHN, alone or associated with
other strategies (refractory cases)
• The pathophysiologic hypothesis pulmonary
vasodilation is achieved by two known pathways.
1. Nitric oxide elevating intracellular cGMP levels Smt
muscle relaxation vasodilator effect.
2. Adenosine selective pulmonary vasodilation by acting
at A2 receptors on vascular smooth muscle to increase
intracellular cyclic AMP smt muscle relaxation &
improvement in systemic & myocardial O2 delivery.
Adenosine may also stimulate K+ ATP channels, resulting
in hyperpolarization of smooth muscle.
Inflammatory bowel diseases (IBDs)
• Traditional treatments nonspecific suppression of
immune reaction and inflammation
• Enteric immunopathogenesis targeted therapies
• Adenosine system and its involvement in the
pathophysiology of IBDs.
• Once released at sites of inflammation, adenosine
plays prominent roles in maintaining tissue integrity -
1. By modulation of immune functions
2. Downregulation of phlogistic reactions
3. Interference with the biosynthesis of
proinflammatory cytokines and inhibition of
neutrophil adhesion, degranulation.
4. Antioxidant activity.
• Concentrations of adenosine closely reflect the
metabolic status of the tissue
• Been proposed that The Purinergic System act as a
sensor apparatus, which provides immune system
information about tissue health
• GIT tract, adenosine control of ENS & smt muscle
• Under physiological conditions, adenosine is mainly
formed at the intracellular level from S-adenosyl
• In cases of hypoxia or inflammation, adenosine
production occurs both intracellularly and
extracellularly by dephosphorylation of ATP via
5'nucleotidase enzymes + by suppression of
adenosine kinase activity
• Direct stimulation of adenosine receptor subtypes
A2a & A3 treatment of IBDs.
• ATL146e, a selective A2a receptor agonist,
acute / chronic model of colitis(formalin immune
complex in rabbits) & spontaneous ileitis in
SAMP1/YitFc mice anti inflamatory axn
• Stimulation of A2a receptors significant
decrease in inflammation in the intestinal
mucosa, with a reduction of leucocyte infiltration
& inhibition of proinflammatory cytokine levels
(TNFα, IFNγ and IL4).
• A3 receptor agonist significant ameliorative
effects, both in DSS induced intestinal
inflammation and spontaneous colitis in IL10
Anaesthesia and intensive care
• Pain reducing effects of intravenous adenosine
infusion (50–70 mg/kg/min.)
• Effectiveness of adenosine in reducing ischaemic
pain is comparable to morphine or ketamine
• Adenosine given in combination with morphine or
ketamine additive effect on pain reduction
• Adenosine infusion during GA for surgery provided
good recovery from anaesthesia, associated with
pronounced and sustained postoperative pain
• Acts by inhibiting nociceptive transmission.
• Adenosine is an inhibitory modulator of brain
• By activation of A1 receptors in hippocampus
predominant inhibitory effects can
suppress seizures and maintaining postictal
depression and restore metabolic equilibrium
• Pathogenic role of the adenosine system in
epileptogenesis remains understudied.
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.
‘Adenosine Theory’ supported by three facts:
1. Interstitial adenosine concentration doubles
after 5 min of cardiac ischaemia.
2. Adenosine antagonists reduce the effect of
3. Adenoreceptor stimulation reduces myocardial
damage following ischaemia / reperfusion &
during cardiopulmonary bypass
• Conversion of reversibly injured endothelial and
myocardial cells to irreversibly injured cells
• Prolonged left ventricular dysfunction of reversibly
Potential Sequelae of Reperfusion on Ischemic
Conversion of reversibly injured endothelial and
myocardial cells to irreversibly injured cells
during the peri-reperfusion period.
Not synonymous with entity of acceleration of
necrosis of cells that are already irreversibly
Myocardial Reperfusion Injury
Mechanisms of Myocardial Reperfusion Injury
and Effects of Adenosine
Ang II, NE, ET-1
Transverse Myocardial Slice in
Adenosine and Control Animal
• Adenosine may attenuate ischaemia /
reperfusion injury by a number of possible
1. purine salvaging
2. Improved Tissue Perfusion At high doses
adenosine + reduces capillary
hyperpermeability + leucocyte adherence +
3. antiinflammatory action reduction in
granulocyte respiratory burst activity
4. direct intracellular initiator/effector
• Strongly inhibit extracellular superoxide anion
• 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 .
• Istradefylline (KW6002) is an adenosine A2a
receptor antagonist that is now in phase III
clinical trials for PD.
• Relatively specific A2a receptor antagonists
consistently reverse motor deficits or enhance
dopaminergic treatments in animal models.
• RPR749 is a potent and selective adenosine A1
agonist hypertriglyceridaemia CAD pts.
• RPR749 (0.1–30 mg/kg) has been shown to
reduce TG levels from 20 to 70%
• Very useful therapeutic tool
• Alternatives to adenosine administration include
modulation of its metabolism and administration of specific
1. Adenosine precursors (e.g. acadesine).
2. Adenosine analogues—A1 antagonists and A2 agonists
both of which are anti-inflammatory.
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
• S. Manjunath and Pranavkumar M. Sakhare.Adenosine and
adenosine receptors: Newer therapeutic perspective.
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• Purinergic Signaling, American Society for Neurochemistry.
Published by Elsevier . 2012
• Mervyn B. Forman, Role of Adenosine in Acute Myocardial
• Arch JR, Newsholme EA. The control of the metabolism and
the hormonal role of adenosine. Essays Biochem.
• Peralta C, Hotter G, Closa D. Protective effect of
preconditioning on the injury associated to hepatic
ischaemiareperfusion in the rat: Role of nitric oxide and
adenosine. Hepatology. 1997;25:934–37.