1 Department of Epidemiology, NUTRIM, Maastricht University, Maastricht, The Netherlands. 2 Department of Anaesthesiology, University Hospital Maastricht, The Netherlands
* Corresponding author. E-mail: arno.skrabanja{at}epid.unimaas.nl
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Abstract |
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Keywords: anaesthesia ; nucleotide, adenosine ; nucleotide, ATP ; complications, sepsis ; pain
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Introduction |
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Biology of adenosine and ATP |
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A large family of membrane-bound receptors mediates cell signalling by ATP and adenosine. These purinergic receptors ultimately determine the variety of effects induced by extracellular ATP and adenosine. So far, two families of purinergic receptors have been identified, namely P1 and P2 receptors which respond principally to adenosine and ATP, respectively.74
P1 receptors are G-protein coupled receptors, of which four types have been identified so far (A1, A2A, A2B, A3). Although all the P1 receptor subtypes are primarily activated by adenosine, each shows a different degree of affinity for its physiological agonists. Thus, besides adenosine itself, its breakdown product inosine has also been shown to exert an agonist action on A1 and A3 receptors, but not on A2 receptors.34 51 However, this agonist action of inosine appears to have a low efficacy compared with adenosine, especially at A3 receptors.34
The P2 receptor family is divided in P2X and P2Y receptors, with a number of different subtypes which have varying affinities for ATP, ADP, uridine triphosphate (UTP), uridine diphosphate (UDP) and UDPglucose.
P2X receptors are ligand-gated ion channels, of which currently seven subtypes have been characterized (P2X17).52 62 All are primarily activated by their physiological agonist ATP. P2Y receptors are G-protein coupled receptors, of which eight subtypes have been identified to date (P2Y1, 2, 4, 6, 1114).10 48 96 In contrast with P2X receptors, P2Y receptor subtypes have specific agonist and affinity profiles. More specifically, P2Y receptors can be subdivided into two groups based on sequence homology.1 10 Group 1 consists of specific purinergic receptors (P2Y1, P2Y11), specific pyrimidinergic receptors (P2Y4, P2Y6) and receptors of mixed specificity (P2Y2). Group 2 contains two specific ADP receptors (P2Y12, P2Y13) and a recently identified receptor for UDPglucose (P2Y14).
P1 and P2 receptors are widely distributed in body tissue. The extent of receptor expression on individual cells or in specific tissues partially determines the potency of receptor-mediated effects of ATP and adenosine.
Overall, signalling by P1 and P2 receptors depends on a wide variety of factors, such as receptor expression, receptor sensitivity for physiological agonists and extracellular levels of nucleotides/nucleosides. Purinergic signalling is even more complex in inflammatory conditions during which it is subjected to additional modulating factors, including the release of nucleotides/nucleosides. A schematic overview of different receptors is given in Figure 1.
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Clinical effects of administration of adenosine and ATP |
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Some of the pharmacological effects observed after ATP administration in humans are believed to be due to the action of the degradation products of ATP, especially adenosine and inosine.
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Cardiology |
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I.V. or intracoronary adenosine is also used to achieve maximal hyperaemia of the coronary microcirculation in the evaluation of the significance of coronary stenosis.14 The use of adenosine in ischaemia and reperfusion has gained increasing interest over the last decade. Adenosine exerts cardioprotective effects during myocardial ischaemia and reperfusion. Exogenous administration of adenosine prior to zero-flow ischaemia has been shown to reduce infarct size and improve functional recovery. Exogenous administration during low-flow ischaemia can improve functional recovery and reduce cellular injury, thereby slowing ATP depletion and delaying ischaemic contracture.88 Nevertheless, because of its haemodynamic side-effects and short half-life in blood (0.51.5 s), adenosine is not routinely used for the treatment of acute myocardial ischaemia. As adenosine produces coronary vasodilatation with only minor effects on the systemic circulation, its use for the prevention of early occlusion of coronary artery bypass grafts has been suggested.92
A new application for adenosine is its use in myocardial contrast echo cardiography.60
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Control of arterial pressure |
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I.V. infusion of ATP or adenosine 50350 µg kg1min1 induced dose-related reductions of 2043% in arterial pressure. A major decrease in systemic vascular resistance (3667%) and an increase in cardiac output (1442%), but only a small increase in heart rate (316%), occurred at higher doses. Haemodynamic values returned to their baseline immediately after stopping the infusion.36 38 No observations of tachyphylaxis and rebound hypertension have been reported.25 36 38 6769 87 Other studies25 68 69 79 83 87 have shown no change in arterial pressure during infusion of adenosine 80 µg kg1min1 in patients undergoing abdominal, breast or shoulder surgery. This is probably due to differences in dosing of adenosine.
ATP and adenosine (150300 µg kg1 min1 i.v.) have been used successfully to antagonize the vasoconstrictive actions of norepinephrine and/or sympathetic nerve stimulation.5
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Pain reduction |
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Raising extracellular levels of adenosine through inhibition of adenosine kinase in animal models induced an analgesic effect.26 49 101 Unlike the direct effects of adenosine receptor agonists, use of adenosine kinase inhibitors does not have an effect on cardiovascular functions.54 97 The effects of adenosine are related to peripheral sensitization/activation of nociceptive afferents79 and influence the need for anaesthetics.
Adenosine induces release of neurotransmitters in spinal antinociception, acting both pre- and post-synaptically. Pre-synaptically it reduces neurotransmitter release, and post-synaptically it hyperpolarizes the spinal cord neurones by interaction with ATP-sensitive K+ channels to increase the conductance.77
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Anaesthesia and acute pain |
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Chronic pain |
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It is known that adenosine acts both pre- and post-synaptically. Pre-synaptically it reduces neurotransmitter release, and post-synaptically it hyperpolarizes the spinal cord neurones by interaction with ATP-sensitive K+ channels to increase the conductance.77
Recent electrophysiological, behavioural and biochemical studies have shown that ATP is also involved in nociception by facilitating spinal pain transmission via ionotropic P2X nucleotide receptors.6 30 46 47 77
An animal study by Sawynok and Reid78 provided evidence in support of a P2X-purinoreceptor-mediated augmentation of the pain signal by ATP. The pronociceptive effects of ATP were examined in the low-concentration formalin model (0.5%) by co-administering ATP, ATP analogues and antagonists with formalin and determining the effects on the expression of flinching behaviour.
P2X3 ligand-gated cation channels mediate the excitatory effects of ATP on sensory neurones.22 56 After nerve injury, P2X3 receptors are upregulated in dorsal root ganglia. Activation of P2X3 receptors contributes to the expression of chronic inflammatory and neuropathic pain states. ATP acts via P2X3-containing channels as a nociceptive neurotransmitter.47 Unlike P2X receptors, activation of UTP-sensitive P2Y receptors produces inhibitory effects on spinal pain transmission.
Overall, these data demonstrate that activation of P2X3 receptors contributes to the expression of chronic inflammatory and neuropathic pain states. It is possible that relief from these forms of chronic pain might be achieved by selective blockade of the expression of P2X3 receptors.
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Sepsis and shock |
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In the early 1980s, Chaudry and colleagues20 reported beneficial effects of ATPMgCl2 in the treatment of haemorrhagic shock. Although this was originally attributed to restoration of energy supplies, the total amount of ATPMgCl2 applied was minimal in relation to total body stores of ATP. The discovery of purinergic receptors provided a scientific explanation for the beneficial effects of ATPMgCl2, such as improvement of blood flow, microcirculation, energy balance, and cellular and mitochondrial functions.90 However, some of the effects of ATPMgCl2 infusion described by Chaudry and colleagues may be due to magnesium. Magnesium is a cofactor for more than 300 enzymes, some of which catalyse oxidative phosphorylation, activating energy storage and metabolizing ATP.61 Furthermore, magnesium is involved in the regulation of cell membrane permeability and arteriolar tone, and enhances the binding of agonists to P1 receptors.64 Paskitti and Reid71 reported that vanadate may play a role in the ATPMgCl2 effect, as the ATP used was derived from equine muscle and not from bacterial sources and therefore contained trace amounts of vanadate. Both ATP and vanadate given alone had a smaller but still significant effect.
Chaudry and colleagues15 17 18 20 21 reported that ATPMgCl2 infusion was beneficial for the survival of rats and mini-pigs after haemorrhagic shock, sepsis and peritonitis. ATPMgCl2 accelerated the recovery of renal function after ischaemia. However, bolus administration of ATPMgCl2 had profound circulatory effects, and was suggested as a cause of shock.
The short-lived response to i.v. ATPMgCl2 infusion in a clinically relevant hypoxichypotensive rat model confirmed the necessity of prolonged continuous infusion of ATPMgCl2.73 84 In vivo animal studies indicate that infusion of ATPMgCl2 after haemorrhagic shock has a favourable effect on survival.15 16 23 33 44 45 63 100 Other studies suggest that ATP and adenosine have protective effects on tissue injury following reperfusion after a period of ischaemia. The beneficial effect of ATPMgCl2 in shock could be due to provision of energy directly to tissue with low levels of ATP.21 ATPMgCl2 has been shown to improve the function of rat kidney,21 66 rat liver,18 dog heart,53 58 rabbit lung50 and rat gut85 after a period of ischaemia. The use of i.m. ATPMgCl2 was also protective in rats with burns.100
Another animal study98 indicated that administration of ATPMgCl2 early after the onset of sepsis attenuated the impaired endothelium-dependent vascular relaxation. In this way, ATP may be effective in maintaining endothelial cell function during the hyperdynamic stage of sepsis.
A mouse model of sepsis was used to investigate the influence of ATPMgCl2 infusion on high-energy phosphate stores and immune function in lymphocytes.59 Treatment with ATPMgCl2 at the onset of sepsis significantly increased lymphocyte ATP levels and the proliferation response to mitogenic stimuli. Moreover, improved lymphocyte function in this group correlated with a significant increase in overall survival of the animals. It was suggested that decreased lymphocyte ATP levels might be the cause of defective lymphocyte proliferation capacity in late sepsis. In a porcine model, it was shown that ATPMgCl2 normalized the lipopolysaccharide-induced rise in the ilealmucosal PCO2 gap and attenuated hepatic lactate clearance.4
ATP production by mitochondrial oxidative phosphorylation accounts for more than 90% of total oxygen consumption. Brealey and colleagues13 postulated that mitochondrial dysfunction results in organ failure, possibly because of production of nitric oxide which is known to inhibit mitochondrial respiration in vitro and is produced in excess in sepsis. In a group of 28 critically ill septic patients, these authors showed that skeletal muscle concentrations of ATP were significantly lower in the12 patients who subsequently died (7.6 nmol mg1 dry weight) compared with both the 16 patients who survived (15.8 nmol mg1) and controls (12.5 nmol mg1). In septic patients, an association was found between nitric oxide overproduction, antioxidant depletion, mitochondrial dysfunction and decreased intracellular ATP concentrations. Addition of extracellular ATP may replace this deficit. The repletion of intracellular ATP pools during ATP infusion in humans has been observed using 31P magnetic resonance spectroscopy in patients with cancer cachexia.27 55
In the light of these findings, studies to evaluate the use of ATP infusions in relation to sepsis61 have been proposed. A particular target is the treatment of impaired microcirculation29 95 where ATP or adenosine could provide a valuable alternative to the current use of vasopressor medication to increase arterial pressure.89 After restoring volume depletion, the combined ATP effects of vasodilation and increased cardiac output could be used to improve microcirculation and tissue perfusion, and to increase oxygen delivery/extraction.
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Conclusion |
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Acknowledgments |
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References |
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