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Adenosine and adenosine receptors

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it gives you a brief review about Adenosine and its receptors.

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Adenosine and adenosine receptors

  1. 1. Adenosine & adenosine receptors : Newer therapeutic perspective Dr Suyash Bharat Sharma PG JR 3rd Pharmacology
  2. 2. Introduction • Adenosine is a metabolite of adenosine triphosphate (ATP) • It accumulates in the area where ATP is utilised but not reformed, eg- ischemia • Exists free in cytosol • ‘Homeostatic modulator’ • Endogenous purine nucleoside
  3. 3. Very short halflife (1.5 s) rapid metabolism
  4. 4. • 4 cell surface receptors namely A1, A2a, A2b and A3 • Until now adenosine was mainly used for terminating paroxysmal supraventricular tachycardia (PSVT) and Wolff Parkinson White (WPW) syndrome. • Advances in understanding of adenosine receptors  development of agonists and antagonists
  5. 5. Adenosine Receptors
  6. 6. A3 A2A A2B A1 (Very high affinity) (High affinity) (Low affinity) (Low affinity) Gi Gs ACKATPPLC Ca2+PLA2 Isoforms have distinct, but overlapping, cellular distribution and are widely expressed in most cells/tissues/organs of the body. Adenosine Receptors: Signal Transduction Mechanisms
  7. 7. 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 condensate. • Adenosine induces hyperresponsiveness in the airways of asthmatics, in vivo following inhalation and in vitro in small airways. • 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.
  8. 8. Refractory primary pulmonary hypertension (RPPH) • PPHN is a serious disease in which the pulmonary vascular resistance remains elevated during the neonatal period. • 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.
  9. 9. • 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.
  10. 10. 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.
  11. 11. • 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 contractility • Under physiological conditions, adenosine is mainly formed at the intracellular level from S-adenosyl homocysteine hydrolase. • 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
  12. 12. • 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 deficient mice.
  13. 13. Anaesthesia and intensive care medicine • 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 relief. • Acts by inhibiting nociceptive transmission.
  14. 14. Epilepsy • Adenosine is an inhibitory modulator of brain activity. • By activation of A1 receptors in hippocampus  predominant inhibitory effects can suppress seizures and maintaining postictal depression and restore metabolic equilibrium following seizures • Pathogenic role of the adenosine system in epileptogenesis remains understudied.
  15. 15. 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 cardiac IPC. 3. Adenoreceptor stimulation reduces myocardial damage following ischaemia / reperfusion & during cardiopulmonary bypass
  16. 16. Reperfusion Injury • Conversion of reversibly injured endothelial and myocardial cells to irreversibly injured cells Myocardial Stunning • Prolonged left ventricular dysfunction of reversibly injured myocytes Reperfusion Arrhythmias Potential Sequelae of Reperfusion on Ischemic Myocardium
  17. 17. • Definition: 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 injured. Myocardial Reperfusion Injury
  18. 18. Effects of Adenosine A1 SA NODE AV NODE VENTRICLE MYOCYTE BLOOD VESSELS Θ Θ Θ  Θ CHRONOTROPIC EFFECT DROMOTROPIC EFFECT INOTROPIC EFFECT PRE- & POST- CONDITIONING NEURO- TRANSMITTER RELEASE A1
  19. 19. Effects of Adenosine A2A/A2B VESSELS PLATELETS NEUTROPHILS VSMC’S & CARDIAC FIBROBLASTS ENDOTHELIAL CELL  Θ Θ Θ  DILATATION AGGREGATION TxB2 RELEASE ADHERANCE TO EC’s & FREE RADICAL RELEASE PROLIFERATION & MIGRATION AND ECM PRODUCTION ANGIO- & VASCULO- GENESIS A2A/A2B
  20. 20. Effects of Adenosine A3 MYOCYTE ENDOTHELIAL VSM CELLS   PRE-CONDITIONING, ↑ANTI-OXIDANT ENZYMES ↑ANTI-OXIDANT ENZYMES A3
  21. 21. Reperfusion Mechanisms of Myocardial Reperfusion Injury and Effects of Adenosine LeukocytesTxA2, PAF, Ang II, NE, ET-1 Calcium OxygenPlatelets A2A/2B Angiogenesis Vasculogenesis MPO Proteases Cellular Calcium Overload Platelet Aggregation Vasoconstriction Oxygen Free Radicals No Reflow Vascular Plugging Cell Death A2A A2A A2A A1 A3 ADENOSINE
  22. 22. Transverse Myocardial Slice in Adenosine and Control Animal
  23. 23. • Adenosine may attenuate ischaemia / reperfusion injury by a number of possible mechanisms- 1. purine salvaging 2. Improved Tissue Perfusion At high doses adenosine + reduces capillary hyperpermeability + leucocyte adherence + leucocyte extravasation 3. antiinflammatory action  reduction in granulocyte respiratory burst activity 4. direct intracellular initiator/effector mechanism.
  24. 24. Sepsis: • Strongly inhibit extracellular superoxide anion release. • 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 .
  25. 25. Parkinson's disease • 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.
  26. 26. Hypolipidaemic agent • 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%
  27. 27. Conclusions • Very useful therapeutic tool • 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 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 adenosine deaminase.
  28. 28. Reference • S. Manjunath and Pranavkumar M. Sakhare.Adenosine and adenosine receptors: Newer therapeutic perspective. Indian J Pharmacol. 2009 Jun; 41(3): 97–105. • Purinergic Signaling, American Society for Neurochemistry. Published by Elsevier . 2012 • Mervyn B. Forman, Role of Adenosine in Acute Myocardial Infarction.(ppt online) • Arch JR, Newsholme EA. The control of the metabolism and the hormonal role of adenosine. Essays Biochem. 1978;14:82–123. • 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.
  29. 29. Thank you

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