Potential value of adenosine 5'-triphosphate (ATP) and adenosine in anaesthesia and intensive care medicine

A. T. P. Skrabanja1,*, E. A. C. Bouman2 and P. C. Dagnelie1

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


    Abstract
 Top
 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
Extracellular adenosine and adenosine triphosphate (ATP) are involved in biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation, signal transduction and secretion in a variety of cell types. They are released from the cytoplasm of several cell types and interact with specific purinergic receptors which are present on the surface of many cells. This review summarizes the evidence on the potential value and applicability of ATP (not restricted to ATP–MgCl2) and adenosine in the field of anaesthesia and intensive care medicine. It focuses, in particular, on evidence and roles in treatment of acute and chronic pain and in sepsis. Based on the evidence from animal and clinical studies performed during the last 20 years, ATP could provide a valuable addition to the therapeutic options in anaesthesia and intensive care medicine. It may have particular roles in pain management, modulation of haemodynamics and treatment of shock.

Keywords: anaesthesia ; nucleotide, adenosine ; nucleotide, ATP ; complications, sepsis ; pain


    Introduction
 Top
 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
Extracellular adenosine and adenosine triphosphate (ATP) are involved in biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation, signal transduction and secretion in a variety of cell types.31 39 They are released from the cytoplasm of several cell types and interact with specific purinergic receptors which are present on the surface of many cells. Recently, established and potential clinical applications of adenosine,57 ATP in general3 and ATP–MgCl2 in intensive care medicine61 have been reviewed separately. In this review, we summarize the evidence for the potential value and applicability of ATP (not just ATP–MgCl2) and adenosine in the field of anaesthesia and intensive care medicine. In particular, we have focused on results and treatment options for acute and chronic pain and for sepsis. Although a number of reports from animal and human studies show potential applications of adenosine and ATP in different clinical fields, including safety data, the application of both compounds in clinical practice is still very limited.


    Biology of adenosine and ATP
 Top
 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
Adenosine 5'-triphosphate (ATP) is the energy source in living cells. In physiological conditions, the average concentration varies from 3150 µM in mammalian cells94 to 1500–1900 µM in human blood cells.2 91 Plasma ATP concentrations ranging between 0.15 and 3.9 µM have been reported by different groups.42 76 In vivo, ATP is metabolized rapidly, via adenosine diphosphate (ADP) and adenosine monophosphate (AMP), to adenosine.42 Reported physiological plasma concentrations of 0.1–1 µM for these derivatives43 65 are of the same order of magnitude as for ATP.

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 UDP–glucose.

P2X receptors are ligand-gated ion channels, of which currently seven subtypes have been characterized (P2X1–7).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, 11–14).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 UDP–glucose (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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Fig 1 Receptors for ATP and adenosine: schematic overview of the two families of purinergic receptors and their affinities.

 

    Clinical effects of administration of adenosine and ATP
 Top
 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
Continuous i.v. administration of ATP in humans induces a dose-dependent rise in ATP levels in erythrocytes2 93 and liver,2 followed by slow release into the plasma compartment. ATP levels in erythrocytes reach plateau levels at 24 h, and are significantly increased above baseline (more than 50%). At the same time, a significant increase in plasma uric acid concentration is observed. The mean half-life for the disappearance of ATP from erythrocytes is 5.9 h.2 Plasma concentrations are three orders of magnitude lower than within the erythrocytes, partly due to the rapid breakdown of ATP; only 1% of ATP is detectable in whole blood 40 s after bolus injection.73 84

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.


    Cardiology
 Top
 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
Adenosine has an established clinical application in cardiology as an anti-arrhythmic agent. It is administered, usually as an i.v. bolus at doses up to 15 mg,72 to restore sinus rhythm in patients with supraventricular tachycardia and for the diagnosis of broad and narrow complex tachycardia.12 32 40 72 75

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 (0.5–1.5 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


    Control of arterial pressure
 Top
 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
ATP and adenosine have been used experimentally for a number of years to induce hypotension during anaesthesia and surgery in patients. In 1951, Davies and colleagues28 demonstrated that an i.v. or intra-arterial bolus injection of ATP 40 mg induced a moderate fall in arterial pressure without change in heart rate. The haemodynamic effects of ATP and adenosine have been investigated in >150 patients undergoing different types of surgery,36 38 including oral,37 orthopaedic,24 abdominal aortic aneurysm68 70 and cerebral aneurysm.24 67 87

I.V. infusion of ATP or adenosine 50–350 µg kg–1min–1 induced dose-related reductions of 20–43% in arterial pressure. A major decrease in systemic vascular resistance (36–67%) and an increase in cardiac output (14–42%), but only a small increase in heart rate (3–16%), 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 kg–1min–1 in patients undergoing abdominal, breast or shoulder surgery. This is probably due to differences in dosing of adenosine.

ATP and adenosine (150–300 µg kg–1 min–1 i.v.) have been used successfully to antagonize the vasoconstrictive actions of norepinephrine and/or sympathetic nerve stimulation.5


    Pain reduction
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 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
Adenosine plays an important role in the perception of pain in the central and peripheral nervous system. The spinal cord contains adenosine A1, A2A, A2B and A3 receptors. The A1 receptor plays a key role in spinal antinociception, whereas the functions of the A2A, A2B and A3 receptors are not clearly defined. At peripheral sites, A2A and A3 receptors mediate pain transmission, whereas the A1 receptor seems to play a central role in antinociception.77

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


    Anaesthesia and acute pain
 Top
 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
Several double-blind placebo-controlled cross-over studies in healthy human subjects have shown pain-reducing effects of i.v. adenosine infusion at doses of 50–70 µg kg–1 min–1.80 In addition, the effectiveness of adenosine in reducing ischaemic pain (70 µg kg–1 min–1 i.v. for 30 min) is comparable to morphine (20 µg kg–1 min–1 i.v. for 5 min) or ketamine (20 µg kg–1 min–1 i.v. for 5 min). Furthermore, adenosine given in combination with morphine or ketamine has an additive effect on pain reduction.81 In two double-blind randomized trials in patients undergoing breast surgery (75 patients)79 and gynaecological abdominal surgery (43 patients),82 systemic adenosine infusion (80 µg kg–1 min–1 i.v.) significantly reduced perioperative isoflurane requirements and postoperative pain. In addition, in both studies, the need for opioids was reduced by approximately 25% in the adenosine group during the first postoperative 24 h.82 83 A recent study35 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 µg kg–1 min–1) 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. In all these aspects, adenosine was superior to remifentanil (0.05–0.5 µg kg–1 min–1). These results suggest that adenosine acts by inhibiting nociceptive transmission. This may be mediated by central A1-receptor-mediated antinociception, and inhibition of peripheral inflammatory processes via A2A and possibly A3 receptors. It is possible that both central and peripheral mechanisms are involved. This is in line with the finding that, during surgical tissue injury and subsequent inflammatory processes, inhibition of both central and peripheral sensitization is necessary to prevent postoperative pain.99


    Chronic pain
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 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
Several reports have provided evidence that low doses of adenosine (50 µg kg–1 min–1) alleviate neuropathic pain, hyperalgesia and allodynia without inducing other pain symptoms.7 86 Adenosine, infused for 45–60 min, induced improvement of spontaneous or evoked pain in six of seven patients with peripheral neuropathic pain for periods lasting from 6 h to 4 days.7 This positive finding was unexpected, as adenosine is eliminated from the blood within 1–2 min.7 The effects of adenosine on central hyperexcitability persist longer than the direct action of adenosine on the receptors.86 A role for adenosine in analgesia is further supported by the observation of reduced adenosine levels in the blood and cerebrospinal fluid of patients with neuropathic pain compared with patients who have nervous system lesions but no pain.41

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.


    Sepsis and shock
 Top
 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
Shock and associated multiple organ failure is still a major cause of death in critically ill patients. A common feature of shock is an inadequate circulation leading to diminished perfusion, hypoxia and tissue injury. The resuscitation period after shock is also associated with development of tissue injury and loss of organ function.11 Severe sepsis and septic shock still have a high mortality, and current therapies have not had a substantial effect on survival. The recent development of recombinant activated protein C may hold more promise;8 9 however, the need for better medication remains urgent.

In the early 1980s, Chaudry and colleagues20 reported beneficial effects of ATP–MgCl2 in the treatment of haemorrhagic shock. Although this was originally attributed to restoration of energy supplies, the total amount of ATP–MgCl2 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 ATP–MgCl2, such as improvement of blood flow, microcirculation, energy balance, and cellular and mitochondrial functions.90 However, some of the effects of ATP–MgCl2 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 ATP–MgCl2 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 2021 reported that ATP–MgCl2 infusion was beneficial for the survival of rats and mini-pigs after haemorrhagic shock, sepsis and peritonitis. ATP–MgCl2 accelerated the recovery of renal function after ischaemia. However, bolus administration of ATP–MgCl2 had profound circulatory effects, and was suggested as a cause of shock.

The short-lived response to i.v. ATP–MgCl2 infusion in a clinically relevant hypoxic–hypotensive rat model confirmed the necessity of prolonged continuous infusion of ATP–MgCl2.73 84 In vivo animal studies indicate that infusion of ATP–MgCl2 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 ATP–MgCl2 in shock could be due to provision of energy directly to tissue with low levels of ATP.21 ATP–MgCl2 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. ATP–MgCl2 was also protective in rats with burns.100

Another animal study98 indicated that administration of ATP–MgCl2 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 ATP–MgCl2 infusion on high-energy phosphate stores and immune function in lymphocytes.59 Treatment with ATP–MgCl2 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 ATP–MgCl2 normalized the lipopolysaccharide-induced rise in the ileal–mucosal 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 mg–1 dry weight) compared with both the 16 patients who survived (15.8 nmol mg–1) and controls (12.5 nmol mg–1). 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.


    Conclusion
 Top
 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
Based on the evidence from both animal and clinical studies performed during the last 20 years, ATP could provide a valuable addition to the therapeutic options in anaesthesia and intensive care medicine. In particular, its use in pain management, modulation of haemodynamics and treatment of shock seems promising. Further research is required, particularly on the issue of ATP–MgCl2, to clarify the exact role of ATP, magnesium and the combined compound.


    Acknowledgments
 
The authors would like to thank Professor Dr M. E. Durieux for valuable comments on earlier versions of the review.


    References
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 Abstract
 Introduction
 Biology of adenosine and...
 Clinical effects of...
 Cardiology
 Control of arterial pressure
 Pain reduction
 Anaesthesia and acute pain
 Chronic pain
 Sepsis and shock
 Conclusion
 References
 
1 Abbracchio MP, Boeynaems JM, Barnard EA, et al. Characterization of the UDP–glucose receptor (re-named here the P2Y14 receptor) adds diversity to the P2Y receptor family. Trends Pharmacol Sci 02003; 24: 52–5[CrossRef][ISI][Medline]

2 Agteresch HJ, Dagnelie PC, Rietveld T, van den Berg JW, Danser AH, Wilson JH. Pharmacokinetics of intravenous ATP in cancer patients. Eur J Clin Pharmacol 2000; 56: 49–55[CrossRef][ISI][Medline]

3 Agteresch HJ, Dagnelie PC, van den Berg JW, Wilson JH. Adenosine triphosphate: established and potential clinical applications. Drugs 1999; 58: 211–32[ISI][Medline]

4 Asfar P, Nalos M, Pittner A, et al. Adenosine triphosphate-magnesium dichloride during hyperdynamic porcine endotoxemia: effects on hepatosplanchnic oxygen exchange and metabolism. Crit Care Med 2002; 30: 1826–33[CrossRef][ISI][Medline]

5 Aso Y, Tajima A, Suzuki K, et al. Intraoperative arterial pressure control by ATP in pheochromocytoma. Urology 1986; 27: 512–20[CrossRef][ISI][Medline]

6 Barclay J, Patel S, Dorn G, et al. Functional downregulation of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain. J Neurosci 2002; 22: 8139–47[Abstract/Free Full Text]

7 Belfrage M, Sollevi A, Segerdahl M, Sjolund KF, Hansson P. Systemic adenosine infusion alleviates spontaneous and stimulus evoked pain in patients with peripheral neuropathic pain. Anesth Analg 1995; 81: 713–17[Abstract]

8 Bernard GR, Macias WL, Joyce DE, Williams MD, Bailey J, Vincent JL. Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis. Crit Care 2003; 7: 155–63[CrossRef][ISI][Medline]

9 Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699–709[Abstract/Free Full Text]

10 Boeynaems JM, Wilkin F, Marteau F, et al. P2Y receptors: new subtypes, new functions. Drug Dev Res 2003; 59: 30–5[CrossRef][ISI]

11 Bouma MG, van den Wildenberg FA, Buurman WA. The anti-inflammatory potential of adenosine in ischemia-reperfusion injury: established and putative beneficial actions of a retaliatory metabolite. Shock 1997; 8: 313–20[ISI][Medline]

12 Brady WJ, Jr, DeBehnke DJ, Wickman LL, Lindbeck G. Treatment of out-of-hospital supraventricular tachycardia: adenosine vs verapamil. Acad Emerg Med 1996; 3: 574–85[Abstract]

13 Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002; 360: 219–23[CrossRef][ISI][Medline]

14 Casella G, Leibig M, Schiele TM, et al. Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve? Am Heart J 2004; 148: 590–5[CrossRef][ISI][Medline]

15 Chaudry IH. Cellular mechanisms in shock and ischemia and their correction. Am J Physiol 1983; 245: R117–34[ISI][Medline]

16 Chaudry IH. Use of ATP following shock and ischemia. Ann NY Acad Sci 1990; 603: 130–41[Abstract]

17 Chaudry IH, Clemens MG, Baue AE, Alterations in cell function with ischemia and shock and their correction. Arch Surg 1981; 116: 1309–17[Abstract]

18 Chaudry IH, Clemens MG, Ohkawa M, Schleck S, Baue AE. Restoration of hepatocellular function and blood flow following hepatic ischemia with ATP–MgCl2. Adv Shock Res 1982; 8: 177–86[Medline]

19 Chaudry IH, Ohkawa M, Clemens MG. Improved mitochondrial function following ischemia and reflow by ATP–MgCl2. Am J Physiol 1984; 246: R799–804[ISI][Medline]

20 Chaudry IH, Sayeed MM, Baue AE. Depletion and restoration of tissue ATP in hemorrhagic shock. Arch Surg 1974; 108: 208–11[CrossRef][ISI][Medline]

21 Chaudry IH, Sayeed MM, Baue AE. Evidence for enhanced uptake of ATP by liver and kidney in hemorrhagic shock. Am J Physiol 1977; 233: R83–8[ISI][Medline]

22 Chen CC, Akopian AN, Sivilotti L, Colquhoun D, Burnstock G, Wood JN. A P2X purinoceptor expressed by a subset of sensory neurons. Nature 1995; 377: 428–31[CrossRef][ISI][Medline]

23 Cikrit D, Gross K, Katz S. Comparative effects of cytoprotective agents in bowel ischemia. Surg Forum 1983; 34: 208–10[ISI]

24 Coli A, Fabbri G, Lari S, Ballati S, Cipressi M, Lari F. Hypotension controlled with ATP in orthopedic surgery: incidence of atrio-ventricular conduction disorders. Minerva Anestesiol 1994; 60: 21–7[Medline]

25 Colson P, Saussine M, Gaba S, Sequin J, Chaptal PA, Roquefeuil B. Vascular effects of adenosine-triphosphate. Ann Fr Anesth Reanim 1991; 10: 251–4[ISI][Medline]

26 Cronstein BN, Naime D, Firestein G. The antiinflammatory effects of an adenosine kinase inhibitor are mediated by adenosine. Arthritis Rheum 1995; 38: 1040–5[ISI][Medline]

27 Dagnelie PC, Sijens PE, Kraus DJ, Planting AS, van Dijk P. Abnormal liver metabolism in cancer patients detected by (31)P MR spectroscopy. NMR Biomed 1999; 12: 535–44[CrossRef][ISI][Medline]

28 Davies DF, Gropper AL, Schroeder HA. Circulatory and respiratory effects of adenosine triphosphate in man. Circulation 1951; 3: 543–50[ISI][Medline]

29 De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002; 166: 98–104[Abstract/Free Full Text]

30 Eisenach JC, Hood DD, Curry R. Preliminary efficacy assessment of intrathecal injection of an American formulation of adenosine in humans. Anesthesiology 2002; 96: 29–34[CrossRef][ISI][Medline]

31 el Moatassim C, Dornand J, Mani JC. Extracellular ATP and cell signalling. Biochim Biophys Acta 1992; 1134: 31–45[CrossRef][ISI][Medline]

32 Faulds D, Chrisp P, Buckley MM. Adenosine: an evaluation of its use in cardiac diagnostic procedures, and in the treatment of paroxysmal supraventricular tachycardia. Drugs 1991; 41: 596–624[ISI][Medline]

33 Filkins JP, Buchanan BJ. Protection against endotoxin shock and impaired glucose homeostasis with ATP. Circ Shock 1977; 4: 253–8[ISI][Medline]

34 Fredholm BB, Irenius E, Kull B, Schulte G. Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem Pharmacol 2001; 61: 443–8[CrossRef][ISI][Medline]

35 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[CrossRef][ISI][Medline]

36 Fukunaga AF, Ikeda K, Matsuda I. ATP-induced hypotensive anesthesia during surgery. Anesthesiology 1982; 57: A65

37 Fukunaga AF, Kaneko Y, Ichinohe T, Igarashi O, Nakakuki T. Intravenous ATP attenuates surgical stress responses and reduces inhalation anesthetic requirements in humans. Anesthesiology 1990; 73: A400

38 Fukunaga AF, Sodeyama O, Matsuzaki Y, et al. Hemodynamic and metabolic changes of ATP-induced hypotension during surgery. Anesthesiology 1983; 59: A12

39 Gordon JL. Extracellular ATP: effects, sources and fate. Biochem J 1986; 233: 309–19[ISI][Medline]

40 Griffith MJ, Linker NJ, Ward DE, Camm AJ. Adenosine in the diagnosis of broad complex tachycardia. Lancet 1988; i: 672–5

41 Guieu R, Couraud F, Pouget J, Sampieri F, Bechis G, Rochat H. Adenosine and the nervous system: clinical implications. Clin Neuropharmacol 1996; 19: 459–74[ISI][Medline]

42 Harkness RA, Coade SB, Webster AD. ATP, ADP and AMP in plasma from peripheral venous blood. Clin Chim Acta 1984; 143: 91–8[CrossRef][ISI][Medline]

43 Harmsen E, de Jong JW, Serruys PW. Hypoxanthine production by ischemic heart demonstrated by high pressure liquid chromatography of blood purine nucleosides and oxypurines. Clin Chim Acta 1981; 115: 73–84[CrossRef][ISI][Medline]

44 Hirasawa H, Chaundry IH, Baue AE. Improved hepatic function and survival with adenosine triphosphate-magnesium chloride after hepatic ischemia. Surgery 1978; 83: 655–62[ISI][Medline]

45 Hirasawa H, Ohkawa M, Odaka M, Sato H. Improved survival, RES function, and ICG test with ATP–MgCl2 following hepatic ischemia. Surg Forum 1979; 30: 158–60[ISI][Medline]

46 Honore P, Buritova J, Chapman V, Besson JM. UP 202–56, an adenosine analogue, selectively acts via A1 receptors to significantly decrease noxiously-evoked spinal c-Fos protein expression. Pain 1998; 75: 281–93[CrossRef][ISI][Medline]

47 Honore P, Kage K, Mikusa J, et al. Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. Pain 2002; 99: 11–19[CrossRef][ISI][Medline]

48 Jacobson KA, Jarvis MF, Williams M. Purine and pyrimidine (P2) receptors as drug targets. J Med Chem 2002; 45: 4057–93[CrossRef][ISI][Medline]

49 Jarvis MF, Yu H, McGaraughty S, et al. Analgesic and anti-inflammatory effects of A-286501, a novel orally active adenosine kinase inhibitor. Pain 2002; 96: 107–18[CrossRef][ISI][Medline]

50 Jellinek M, Shapiro MJ, Villarreal-Loor B, Pyrros D, Baue AE. The restoration of the phosphoinositide pool in hemorrhagic shock by ATP–MgCl2 and/or inositol in rabbit lung. Circ Shock 1988; 24: 274

51 Jin X, Shepherd RK, Duling BR, Linden J. Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. J Clin Invest 1997; 100: 2849–57[Abstract/Free Full Text]

52 Khakh BS, Burnstock G, Kennedy C, et al. International Union of Pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol Rev 2001; 53: 107–18[Abstract/Free Full Text]

53 Kopf GS, Chaudry I, Condos S, Baue AE. Reperfusion with ATP–MgCl2 following prolonged ischemia improves myocardial performance. J Surg Res 1987; 43: 114–17[CrossRef][ISI][Medline]

54 Kowaluk EA, Jarvis MF. Therapeutic potential of adenosine kinase inhibitors. Expert Opin Investig Drugs 2000; 9: 551–64[ISI][Medline]

55 Leij-Halfwerk S, Dagnelie PC, Kappert P, Oudkerk M, Sijens PE. Decreased energy and phosphorylation status in the liver of lung cancer patients with weight loss. J Hepatol 2000; 32: 887–92[CrossRef][ISI][Medline]

56 Lewis C, Neidhart S, Holy C, North RA, Buell G, Surprenant A. Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 1995; 377: 432–5[CrossRef][ISI][Medline]

57 McCallion K, Harkin DW, Gardiner KR. Role of adenosine in immunomodulation: review of the literature. Crit Care Med 2004; 32: 273–7[CrossRef][ISI][Medline]

58 McGovern PJ, Machiedo GW, Rush BF, Jr. Hemodynamic effects of ATP–MgCl2 following shock. Curr Surg 1982; 39: 82–4[Medline]

59 Meldrum DR, Ayala A, Chaudry IH. Energetics of lymphocyte ‘burnout’ in late sepsis: adjuvant treatment with ATP–MgCl2 improves energetics and decreases lethality. J Surg Res 1994; 56: 537–42[CrossRef][ISI][Medline]

60 Mulvagh SL. Advances in myocardial contrast echocardiography and the role of adenosine stress. Am J Cardiol 2004; 94: 12–17[CrossRef]

61 Nalos M, Asfar P, Ichai C, Radermacher P, Leverve XM, Froba G. Adenosine triphosphate–magnesium chloride: relevance for intensive care. Intensive Care Med 2003; 29: 10–18[ISI][Medline]

62 North RA. Molecular physiology of P2X receptors. Physiol Rev 2002; 82: 1013–67[Abstract/Free Full Text]

63 Ohkawa M, Clemens MG, Chaudry IH. Studies on the mechanism of beneficial effects of ATP–MgCl2 following hepatic ischemia. Am J Physiol 1983; 244: R695–702[ISI][Medline]

64 Okada M, Kaneko S. Pharmacological interactions between magnesium ion and adenosine on monoaminergic system in the central nervous system. Magnes Res 1998; 11: 289–305[ISI][Medline]

65 Ontyd J, Schrader J. Measurement of adenosine, inosine, and hypoxanthine in human plasma. J Chromatogr 1984; 307: 404–9[Medline]

66 Osias MD, Siegel NJ, Chaudry IH, et al. Postischemic renal failure. Accelerated recovery with adenosine triphosphate-magnesium chloride infusion. Arch Surg 1977; 112: 729–31[Abstract]

67 Owall A, Gordon E, Lagerkranser M, Lindquist C, Rudehill A, Sollevi A. Clinical experience with adenosine for controlled hypotension during cerebral aneurysm surgery. Anesth Analg 1987; 66: 229–34[Abstract]

68 Owall A, Jarnberg PO, Brodin LA, Sollevi A. Effects of adenosine-induced hypotension on myocardial hemodynamics and metabolism in fentanyl anesthetized patients with peripheral vascular disease. Anesthesiology 1988; 68: 416–21[ISI][Medline]

69 Owall A, Lagerkranser M, Sollevi A. Effects of adenosine-induced hypotension on myocardial hemodynamics and metabolism during cerebral aneurysm surgery. Anesth Analg 1988; 67: 228–32[Abstract]

70 Owall A, Sollevi A. Myocardial effects of adenosine- and sodium nitroprusside-induced hypotension: a comparative study in patients anaesthetized for abdominal aortic aneurysm surgery. Acta Anaesthesiol Scand 1991; 35: 216–20[ISI][Medline]

71 Paskitti M, Reid KH. Use of an adenosine triphosphate-based ‘cocktail’ early in reperfusion substantially improves brain protein synthesis after global ischemia in rats. Neurosci Lett 2002; 331: 147–50[CrossRef][ISI][Medline]

72 Pelleg A. Mechanisms of action and therapeutic potential of adenosine and its analogues in the treatment of cardiac arrhythmias. Coron Artery Dis 1993; 4: 109–15[ISI][Medline]

73 Proctor HJ, Thiet M, Palladino GW. ATP–MgCl2 treatment prior to hypoxic-hypotension. Circ Shock 1983; 11: 65–71[ISI][Medline]

74 Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 1998; 50: 413–92[Abstract/Free Full Text]

75 Rankin AC, Oldroyd KG, Chong E, Rae AP, Cobbe SM. Value and limitations of adenosine in the diagnosis and treatment of narrow and broad complex tachycardias. Br Heart J 1989; 62: 195–203[Abstract]

76 Ryan LM, Rachow JW, McCarty BA, McCarty DJ. Adenosine triphosphate levels in human plasma. J Rheumatol 1996; 23: 214–19[ISI][Medline]

77 Sawynok J. Adenosine receptor activation and nociception. Eur J Pharmacol 1998; 347: 1–11[CrossRef][ISI][Medline]

78 Sawynok J, Reid A. Peripheral adenosine 5'-triphosphate enhances nociception in the formalin test via activation of a purinergic p2X receptor. Eur J Pharmacol 1997; 330: 115–21[CrossRef][ISI][Medline]

79 Segerdahl M, Ekblom A, Sandelin K, Wickman M, Sollevi A. Peroperative adenosine infusion reduces the requirements for isoflurane and postoperative analgesics. Anesth Analg 1995; 80: 1145–9[Abstract]

80 Segerdahl M, Ekblom A, Sjolund KF, Belfrage M, Forsberg C, Sollevi A. Systemic adenosine attenuates touch evoked allodynia induced by mustard oil in humans. NeuroReport 1995; 6: 753–6[ISI][Medline]

81 Segerdahl M, Ekblom A, Sollevi A. The influence of adenosine, ketamine, and morphine on experimentally induced ischemic pain in healthy volunteers. Anesth Analg 1994; 79: 787–91[Abstract]

82 Segerdahl M, Irestedt L, Sollevi A. Antinociceptive effect of perioperative adenosine infusion in abdominal hysterectomy. Acta Anaesthesiol Scand 1997; 41: 473–9[ISI][Medline]

83 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[ISI][Medline]

84 Shapiro MJ, Jellinek M, Pyrros D, Sundine M, Baue AE. Clearance and maintenance of blood nucleotide levels with adenosine triphosphate–magnesium chloride injection. Circ Shock 1992; 36: 62–7[ISI][Medline]

85 Singh G, Chaudry KI, Chaudry IH. ATP–MgCl2 restores gut absorptive capacity early after trauma–hemorrhagic shock. Am J Physiol 1993; 264: R977–83[ISI][Medline]

86 Sollevi A, Belfrage M, Lundeberg T, Segerdahl M, Hansson P. Systemic adenosine infusion: a new treatment modality to alleviate neuropathic pain. Pain 1995; 61: 155–8[CrossRef][ISI][Medline]

87 Sollevi A, Lagerkranser M, Irestedt L, Gordon E, Lindquist C. Controlled hypotension with adenosine in cerebral aneurysm surgery. Anesthesiology 1984; 61: 400–5[ISI][Medline]

88 Sommerschild HT, Kirkeboen KA. Adenosine and cardioprotection during ischaemia and reperfusion—an overview. Acta Anaesthesiol Scand 2000; 44: 1038–55[CrossRef][ISI][Medline]

89 Spronk PE, Ince C, Gardien MJ, Mathura KR, Oudemans-van Straaten HM, Zandstra DF. Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet 2002; 360: 1395–6[CrossRef][ISI][Medline]

90 Thiel M, Caldwell CC, Sitkovsky MV. The critical role of adenosine A(2A) receptors in downregulation of inflammation and immunity in the pathogenesis of infectious diseases. Microbes Infect 2003; 5: 515–26[CrossRef][ISI][Medline]

91 Torrance JD, Whittaker D. Distribution of erythrocyte nucleotides in pyrimidine 5'-nucleotidase deficiency. Br J Haematol 1979; 43: 423–34[ISI][Medline]

92 Torssell L, Ekestrom S, Sollevi A. Adenosine-induced increase in graft flow during coronary bypass surgery. Scand J Thorac Cardiovasc Surg 1989; 23: 235–9[ISI][Medline]

93 Trams EG. A proposal for the role of ecto-enzymes and adenylates in traumatic shock. J Theor Biol 1980; 87: 609–21[CrossRef][ISI][Medline]

94 Traut TW. Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 1994; 140: 1–22[CrossRef][ISI][Medline]

95 Vincent JL. Update on sepsis: pathophysiology and treatment. Acta Clin Belg 2000; 55: 79–87[ISI][Medline]

96 von Kugelgen I, Wetter A. Molecular pharmacology of P2Y-receptors. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 310–23[CrossRef][ISI][Medline]

97 Wang B, Tang J, White PF, et al. The effect of GP683, an adenosine kinase inhibitor, on the desflurane anesthetic requirement in dogs. Anesth Analg 1997; 85: 675–80[Abstract]

98 Wang P, Ba ZF, Cioffi WG, Bland KI, Chaudry IH. Salutary effects of ATP–MgCl2 on the depressed endothelium-dependent relaxation during hyperdynamic sepsis. Crit Care Med 1999; 27: 959–64[CrossRef][ISI][Medline]

99 Woolf CJ, Chong MS. Preemptive analgesia—treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993; 77: 362–79[ISI][Medline]

100 Zaki MS, Burke JF, Trelstad RL. Protective effects of adenosine triphosphate administration in burns. Arch Surg 1978; 113: 605–10[Abstract]

101 Zhu CZ, Mikusa J, Chu KL, et al. A-134974: a novel adenosine kinase inhibitor, relieves tactile allodynia via spinal sites of action in peripheral nerve injured rats. Brain Res 2001; 905: 104–10[CrossRef][ISI][Medline]