Review Article Adenosine and adenosine receptors: Newer therapeutic perspective S. Manjunath, Pranavkumar M. Sakhare 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 Department of Pharmacology, M.R. receptor subtypes namely A1, A2a, A2b, A3, which have been cloned in humans, and Medical College, Sedam Road, are expressed in most of the organs. Each is encoded by a separate gene and has different Gulbarga-585 105, India 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 RReceived:eceived: 10.03.2009 RRevised:evised: 31.03.2009 that adenosine plays pivotal role in different physiological functions, such as induction AAccepted:ccepted: 08.06.2009 of sleep, neuroprotection and protection against oxidative stress. Until now adenosine was used for certain conditions like paroxysmal supraventricular tachycardia (PSVT) and DDOI:OI: 10.4103/0253-7613.55202 Wolff Parkinson White (WPW) syndrome. Now there is a growing evidence that adenosine CCorrespondenceorrespondence tto:o: receptors could be promising therapeutic targets in a wide range of conditions including Dr. S. Manjunath cardiac, pulmonary, immunological and inflammatory disorders. After more than three E-mail: manjunath_pharmacology@ decades of research in medicinal chemistry, a number of selective agonists and antagonists yahoo.com 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. KKEYEY WWORDS:ORDS: Anaesthesia and critical care, asthma, epilepsy, inflammatory bowel diseases, ischaemia/reperfusion injury, Parkinson’s disease, refractory primary pulmonary hypertension Introduction was mainly used for terminating paroxysmal supraventricular tachycardia (PSVT) and Wolff Parkinson White (WPW) syndrome. Adenosine is a metabolite of adenosine triphosphate (ATP), having a very short half-life (1.5 s) due to its rapid metabolism Now, with advances in understanding of adenosine receptors and [Figure 1]. It accumulates in the area where ATP is utilised development of agonists and antagonists [Table 2], adenosine but not reformed, for example during ischaemia and possibly receptors have emerged as potential newer therapeutic targets. during sepsis. Unlike ATP, adenosine exists free in cytosol of all Mainly, A2a receptor plays an important role in mediating [3] cells and is transported in and out of the cell by a membrane inflammatory and immune responses. Its actions through the transporter. It is not a conventional transmitter but a sort of various adenosine receptor subtypes, bring about a decrease local hormone or better say ‘homeostatic modulator’. in energy demand and an increase in energy supply and thus Adenosine is an endogenous purine nucleoside that mediates are protective.[4] Similar to endocannabinoid, the neuromodular a wide variety of physiological functions by interacting with four adenosine plays a very important integrative role in striatal cell surface receptors namely A1, A2a, A2b and A3 [Table 1]. function.[5] Adenosine and dopamine receptor interactions, Adenosine is an intermediate metabolite in many important also have integrative mechanism in basal ganglia.[6] In addition, biochemical pathways and has been shown to play a role in several drugs act through modulation of adenosine effect like the regulation of coronary and systemic vascular tone, platelet methylxanthine, dipyridamole, ketamine, beta blockers, calcium function and lipolysis in adipocytes.[1,2] In addition, it mediates channel blockers, dopamine, cannabinoids etc. Adenosine important functions like induction of sleep, antioxidant and, also plays an important role in renal function. Renal tubular antiseizure effects, neuroprotection etc. Until now adenosine sodium transport is the principal consumer of ATP.[7] Sodium Indian J Pharmacol | Jun 2009 | Vol 41 | Issue 3 | 97-105 97 Manjunath and Sakhare: Adenosine: Newer therapeutic perspective Table 1 Figure 1: Metabolism of adenosine. ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate. Modulating Adenosine receptor – Mediated effects in various organ systems various enzymes/transporters will increase endogenous adenosine concentrations Receptor Effects on Stimulating the Receptors subtypes A1 Cardiovascular • Slows AV nodal conduction (negative dromotropy) ATP ADP AMP • ↓ heart rate (negative chronotropy) Adenosine kinase 5’ Nucleotidase • ↓ atrial contractility (negative inotropy) Adenosine • ↓ β-adrenergic tone (AMP or Adenosine diffuse extracellularly) • Inhibits pacemaker and L-type calcium currents Nucleoside Nucleoside Transport Renal inhibits transport (Moves adenosine into endothelial cells) • Inhibits release of renin inhibitors • ↑ reabsorption of sodium in proximal convoluted tubule e.g. R75231 Adenosine Deaminase • Vasoconstriction of afferent arteriole - ↓ GFR Inosine CNS Ischemia • ↓ neurotransmitter release Hypoxanthine • Sedation Xanthine oxidase Xanthine dehydrogenase • Anticonvulsant effects Xanthine + Superoxide anions Metabolic • Inhibits lipolysis • ↑ insulin sensitivity There is a growing interest in elucidating the mechanisms A2a Cardiovascular by which adenosine inhibits inflammation. Hence, these • Coronary and peripheral vasodilation inhibitory adenosine receptors (Gi-A1 and A3) and their • Inhibits platelet aggregation downstream signaling pathways are promising targets for A2b Pulmonary newer antiinflammatory therapies. By signalling through the • Vasodilation A2a adenosine receptors, adenosine suppresses the release of [3] • Mast cell release of IL-8 → Potential bronchoconstriction inflammatory mediators, primarily by inhibiting lymphoid or and inß ammation myeloid cells including neutrophils, macrophages, lymphocytes, A3 Pulmonary and platelets. • Mast cell release of allergic mediators → Potential Newer potential therapeutic role of adenosine and its bronchoconstriction receptors AV indicates atrioventricular, GFR, glomerular Þ ltration rate: IL interleukin Bronchial asthma: Adenosine, a primordial signalling molecule, produces a number of physiological and pathophysiological effects in the human body. It has been transport is influenced by changes in glomerular filtration rate shown that stable form of adenosine, i.e. the nucleotide (GFR) and by primary changes in tubular transport. Intrarenal adenosine monophosphate (AMP) induces bronchoconstriction adenosine released by cleavage of ATP, maintains the balance in asthma, but not in normal airways. Following facts convince between energy supply and demand by affecting both of these that adenosine plays a key role in pathophysiology of asthma and processes. In the renal microcirculation, adenosine receptors has an important function in acute bronchoconstrictor [Figure exert control over renal blood flow, GFR, renin release and 2] and airway inflammatory responses in humans. tubuloglomerular feedback.[8] • Adenosine levels are increased in broncho-alveolar- Table 2 Comparison of subtypes Adenosine receptors Receptor Gene Mechanism Agonists Antagonists A1 ADORA1 Gi/o --> cAMP↓ N6-Cyclopentyladenosine Caffeine, Theophylline, 8-Cyclopentyl-1, Inhibition ↓ vesicle release, CCPA, 2’-MeCCPA 3-dimethylxanthine (CPX), ↓ NMDA receptor activity GR 79236, SDZ WAG 994 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), 8-Phenyl 1,3-dipropylxanthine, PSB 36 A2a ADORA2A Gs --> cAMP↑ ATL-146e, CGS-21680, Caffeine, theophylline, istradefylline, SCH-58261, Regadenoson SCH-442,416 ZM-241,385 A2b ADORA2B Gs --> cAMP↑ 5’-N ethylcarboxamidoadenos ne, Theophylline, CVT-6883, MRS-1706, MRS- BAY 60–6583, LUF-5835, LUF-5845. 1754, PSB-603, PSB-0788, PSB-1115 A3 ADORA3 Gi/o --> cAMP↓ 2-(1-Hexynyl)-N methyl adenosine, Theophylline, MRS-1191, MRS-1220, MRS- CF-101 (IB-MECA), 2-Cl-IB-MECA, 1334, MRS-1523, MRS-3777, MRE3008F20, CP-532,903; MRS-3558 PSB-10, PSB-11, VUF-5574 98 Indian J Pharmacol | Jun 2009 | Vol 41 | Issue 3 | 97-105 Manjunath and Sakhare: Adenosine: Newer therapeutic perspective Figure 2: Schematic diagram of the mechanism involved in adenosine-induced bronchoconstriction. Once generated, adenosine activates the adenosine A2b receptors on mast cells. Upon activation of A2b receptors, various inß ammatory mediators that induce bronchoconstriction are released. ADP = adenosine diphosphate: AMP = adenosine monophosphate; ATP = adenosine triphosphate; NT = nucleotidase; NTPD= nucleoside triphosphate diphosphohydrolase. Mast cell ATP ADP NTPDase AMP ATP Adenosine Ecto kinase 5’NTase AR2b Adenosine Adenosine Adenosine Nucleoside (AMP) deaminase transporter Prostanoids, Cytokines leukotriene C4 lonosine Histamine Sensory C fibre nerve Bronchoconstriction Adenosine-producing cell Smooth muscle cells lavage fluid[9] and exhaled breath condensate of patients a serious disease in which the pulmonary vascular resistance with allergic asthma[10] and in the plasma of patients with remains elevated during the neonatal period. It is a clinical exercise-induced asthma.[11] syndrome that may occur in association with