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Adenosine A1 and A2 receptor agonists reduce endotoxin-induced cellular energy depletion and oedema formation in the lung

Published online by Cambridge University Press:  01 March 2007

A. R. Heller ,
J. Rothermel ,
M. A. Weigand ,
K. Plaschke ,
J. Schmeck ,
M. Wendel ,
H. J. Bardenheuer  and
T. Koch
A. R. Heller
Affiliation:
University Hospital Carl Gustav Carus, Harvard Medical International Associated Institution, Department of Anesthesiology and Intensive Care Medicine, Dresden, Germany
J. Rothermel
Affiliation:
University Hospital, Department of Anesthesiology and Intensive Care Medicine, Mannheim, Germany
M. A. Weigand
Affiliation:
Ruprecht-Karls University Heidelberg, Department of Anesthesiology and Intensive Care Medicine, Germany
K. Plaschke
Affiliation:
Ruprecht-Karls University Heidelberg, Department of Anesthesiology and Intensive Care Medicine, Germany
J. Schmeck
Affiliation:
University Hospital, Department of Anesthesiology and Intensive Care Medicine, Mannheim, Germany
M. Wendel
Affiliation:
University Hospital Carl Gustav Carus, Harvard Medical International Associated Institution, Department of Anesthesiology and Intensive Care Medicine, Dresden, Germany
H. J. Bardenheuer
Affiliation:
Ruprecht-Karls University Heidelberg, Department of Anesthesiology and Intensive Care Medicine, Germany
T. Koch
Affiliation:
University Hospital Carl Gustav Carus, Harvard Medical International Associated Institution, Department of Anesthesiology and Intensive Care Medicine, Dresden, Germany
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Summary

Background and objective

Tissue depletion of adenosine during endotoxaemia has previously been described in the lung. Therapeutic approaches to prevent adenosine depletion and the role of A1 and A2 receptor agonists, however, have not been investigated until now.

Methods

In isolated and ventilated rabbit lungs, it was tested whether pretreatment with adenosine A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 10−7 mol, n = 6) or A2 receptor agonist 5′-(N-cyclopropyl)-carboxyamido adenosine (CPCA; 10−7 mol, n = 6) prior to injection of lipopolysaccharide (LPS) (500 pg mL−1) influenced pulmonary artery pressure (PAP), pulmonary energy content and oedema formation as compared with controls, solely infused with LPS (n = 6). Release rates of adenosine and uric acid were determined by high-performance liquid chromatography. Pulmonary tissue concentrations of high-energy phosphates were measured and the adenine nucleotide pool, adenosine 5′-triphosphate (ATP)/adenosine 5′-diphosphate (ADP) ratio and adenylate energy charge of the pulmonary tissue were calculated.

Results

Administration of LPS induced increases in PAP within 2 h up to 20.8 ± 2.9 mmHg (P < 0.01). While pretreatment with the A1 agonist merely decelerated pressure increase (13.8 ± 1.1 mmHg, P < 0.05), the A2 agonist completely suppressed the pulmonary pressure reaction (9.6 ± 1.0 mmHg, P < 0.01). Emergence of lung oedema after exclusive injection of LPS up to 12.0 ± 2.9 g was absent after A1 (0.6 ± 0.5 g) and A2 (−0.3 ± 0.2 g) agonists. These observations were paralleled by increased adenosine release rates compared with LPS controls (P < 0.05). Moreover, tissue concentrations of ADP, ATP, guanosine 5′-diphosphate, guanosine 5′-triphosphate, nicotinamide-adenine-dinucleotide and creatine phosphate were significantly reduced after LPS. Consequently, the calculated tissue adenine nucleotide pool and the adenylate energy charge increased after adenosine receptor stimulation (P = 0.001).

Conclusions

Adenosine A1- and A2-receptor agonists reduced LPS-induced vasoconstriction and oedema formation by maintenance of tissue energy content. Thus, adenosine receptor stimulation, in particular of the A2 receptor, might be beneficial during acute lung injury.

Keywords

NEUTROPHILSENDOTHELIUMINFLAMMATIONADENOSINE, receptorsADENOSINE TRIPHOSPHATEACUTE RESPIRATORY DISTRESS SYNDROMERABBITENDOTOXIN
Type
Research Article
Information
European Journal of Anaesthesiology , Volume 24 , Issue 3 , March 2007 , pp. 258 - 266
Copyright
Copyright © European Society of Anaesthesiology 2006

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References

1.Sayeed, MM, Murthy, PN. Adenine nucleotide and lactate metabolism in the lung in endotoxin shock. Circ Shock 1981; 8: 657–666.Google ScholarPubMed
2.Thiel, M, Kreimeier, U, Holzer, K, Moritz, S, Peter, K, Messmer, K. Effects of adenosine on cardiopulmonary functions and oxygen-derived variables during endotoxemia. Crit Care Med 1998; 26: 322–337.CrossRefGoogle ScholarPubMed
3.Kutzsche, S, Lyberg, T, Bjertnaes, LJ. Effects of adenosine on extravascular lung water content in endotoxemic pigs. Crit Care Med 2001; 29: 2371–2376.CrossRefGoogle ScholarPubMed
4.Adkins, WK, Barnard, JW, Moore, TM, Allison, RC, Prasad, VR, Taylor, AE. Adenosine prevents PMA-lung injury via an A2 receptor mechanism. J Appl Physiol 1993; 74: 982–988.CrossRefGoogle ScholarPubMed
5.Neely, CF, Keith, IM. A1 adenosine receptor antagonists block ischemia-reperfusion injury of the lung. Am J Physiol 1995; 268: L1036–L1046.Google ScholarPubMed
6.Wakai, A, Wang, JH, Winter, DC, Street, JT, O’Sullivan, RG, Redmond, HP. Adenosine inhibits neutrophil vascular endothelial growth factor release and transendothelial migration via A2B receptor activation. Shock 2000; 15: 297–301.CrossRefGoogle Scholar
7.Cronstein, BN. Adenosine, an endogenous anti-inflammatory agent. J Appl Physiol 1994; 76: 5–13.Google Scholar
8.Thiel, M, Chambers, D, Chouker, A, Bardenheuer, HJ, Arfors, K, Peter, K. Effects of adenosine on the expression of β2-integrins and shedding of l-selectin of human polymorphonuclear leukocytes. J Leukoc Biol 1996; 59: 671–686.Google Scholar
9.Thiel, M, Bardenheuer, H. Regulation of oxygen radical production of human polymorphonuclear leukocytes by adenosine: the role of calcium. Pflügers Arch 1992; 420: 522–528.CrossRefGoogle ScholarPubMed
10.Ohta, A, Sitkovsky, M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 2001; 414: 916–920.CrossRefGoogle Scholar
11.Motew, SJ, Mourelatos, MG, Miller, RN, Ferguson, JL, Law, WR. Evidence that adenosine contributes to maintenance of hepatosplanchnic blood flow during peritoneal sepsis in rats. Shock 1997; 7: 439–446.Google Scholar
12.Weigand, MA, Michel, A, Eckstein, HH, Martin, E, Bardenheuer, HJ. Adenosine: a sensitive indicator of cerebral ischemia during carotid endarterectomy. Anesthesiology 1999; 91: 414–421.CrossRefGoogle ScholarPubMed
13.Schmidt, H, Weigand, MA, Schmidt, W, Plaschke, K, Martin, E, Bardenheuer, HJ. Effect of dopexamine on intestinal tissue concentrations of high-energy phosphates and intestinal release of purine compounds in endotoxemic rats. Crit Care Med 2000; 28: 1979–1984.Google Scholar
14.Deitch, EA, Specian, RD, Berg, RD. Endotoxin induced bacterial translocation and mucosal permeability: role of xanthine oxidase, complement activation and macrophage products. Crit Care Med 1991; 19: 785–791.CrossRefGoogle ScholarPubMed
15.Conley, KE, Kemper, WF, Crowther, GJ. Limits to sustainable muscle performance: interaction between glycolysis and oxidative phosphorylation. J Exp Biol 2001; 204: 3189–3194.CrossRefGoogle ScholarPubMed
16.Heller, AR, Fiedler, F, Braun, P, Stehr, SN, Bodeker, H, Koch, T. Clusterin protects the lung from leukocyte-induced injury. Shock 2003; 20: 166–170.CrossRefGoogle ScholarPubMed
17.Seeger, W, Walmrath, D, Grimminger, F et al. . Adult respiratory distress syndrome: model systems using isolated perfused rabbit lungs. Methods Enzymol 1994; 233: 549–584.CrossRefGoogle ScholarPubMed
18.Schmeck, J, Heller, A, Groschler, A et al. . Impact of endothelin-1 in endotoxin-induced pulmonary vascular reactions. Crit Care Med 2000; 28: 2851–2857.CrossRefGoogle ScholarPubMed
19.Behre, G, Schedel, I, Nentwig, B, Wormann, B, Essink, M, Hiddemann, W. Endotoxin concentration in neutropenic patients with suspected Gram-negative sepsis. Antimicrob Agents Chemother 1992; 36: 2139–2146.CrossRefGoogle ScholarPubMed
20.Watling, KJ, ed. The RBI Handbook of Receptor Classification and Signal Transduction, 3rd edn. Natick MA/USA: Research Biochemicals International, 1998: 1–188.Google Scholar
21.Bardenheuer, HJ, Fabry, A, Höfling, B, Peter, K. Adenosine: a sensitive marker of myocardial ischaemia in man. Cardiovasc Res 1994; 28: 656–662.Google Scholar
22.Lehninger, AL. Oxidative phosphorylation, mitochondrial structure and the compartmentalization of respiratory metabolism. In: Lehninger, AL, ed. Biochemistry. New York: Worth, 1975: 538–551.Google Scholar
23.Garcia Soriano, F, Liaudet, L, Marton, A et al. Inosine improves gut permeability and vascular reactivity in endotoxic shock. Crit Care Med 2001; 29: 703–708.CrossRefGoogle ScholarPubMed
24.Sinclair, CJ, Shepel, PN, Geiger, JD, Parkinson, FE. Stimulation of nucleoside efflux and inhibition of adenosine kinase by A1 adenosine receptor activation. Biochem Pharmacol 2000; 59: 477–483.CrossRefGoogle ScholarPubMed
25.McCormack, DG, Clarke, B, Barnes, PJ. Characterization of adenosine receptors in human pulmonary arteries. Am J Phyisol 1989; 256: H41–H56.Google Scholar
26.Olanrewaju, HA, Mustafa, SJ. Adenosine A(2A) and A(2B) receptors mediate nitric oxide production in coronary artery endothelial cells. Gen Pharmacol 2000; 35: 171–177.Google Scholar
27.Wilson, CN, Batra, VK. Lipopolysaccharid binds to and activates A1 adenosine receptors on human pulmonary artery endothelial cells. J Endotoxin Res 2002; 8: 263–271.Google Scholar
28.Neely, CJ, Jin, J, Keith, IM. A1-adenosine receptor antagonists block endotoxin-induced lung injury. Am J Physiol 1997; 272: L353–L361.Google ScholarPubMed
29.Thiel, M, Chouker, A. Acting via A2 receptors, adenosine inhibits the production of tumor necrosis factor-alpha of endotoxin-stimulated human polymorphonuclear leukocytes. J Med 1995; 126: 275–282.Google ScholarPubMed
30.IISam, AD, Sharma, AC, Rice, AN, Ferguson, JL, Law, WR. Adenosine and nitric oxide regulate regional vascular resistance via interdependent and independent mechanisms during sepsis. Crit Care Med 2000; 28: 1931–1939.CrossRefGoogle ScholarPubMed
31.Pastor, CM, Hadengue, A, Nussler, AK. Minor involvement of nitric oxide during chronic endotoxemia in anesthetized pigs. Am J Physiol Gastrointest Liver Physiol 2000; 278: G416–G424.CrossRefGoogle ScholarPubMed
32.Heller, A, Schmeck, J, Heller, S et al. . Endothelin-1 impairs neutrophil respiratory burst and elimination of Escherichia coli in rabbits. Crit Care Med 2000; 28: 1515–1521.CrossRefGoogle ScholarPubMed
33.Jolin, A, Myklebust, R, Olsen, R, Bjertnaes, LJ. Adenosine protects ultrastructure of isolated rat lungs against fat emulsion injury. Acta Anaesthesiol Scand 1994; 38: 75–81.CrossRefGoogle ScholarPubMed
34.Reece, TB, Ellman, PI, Maxey, TS et al. . Adenosine A2 receptor activation reduces inflammation and preserves pulmonary function in an in vivo model of lung transplantation. J Thorac Surg 2005; 129: 1137–1143.CrossRefGoogle Scholar
35.Richard, LF, Dahms, TE, Webster, RO. Adenosine prevents permeability increase in oxidant-injured endothelial monolayers. Am J Physiol 1998; 274: 35–42.Google Scholar
36.Harrington, EO, Newton, J, Morin, N, Rounds, S. Barrier dysfunction and Rho A activation are blunted by homocysteine and adenosine in pulmonary endothelium. Am J Physiol Lung Cell Mol Physiol 2004; 287: L1091–L1097.CrossRefGoogle Scholar
37.Lum, H, Gibbs, L, Lai, L, Malik, AB. CD18 integrin-dependent endothelial injury: effects of osponized zymosan and phorbol ester activation. J Leukoc Biol 1994; 55: 58–63.Google Scholar
38.Tauber, AI, Brettler, DB, Kennington, EA, Blumberg, PM. Relation of human neutrophil phorbol ester receptor occupancy and NADPH-oxidase activity. Blood 1982; 60: 333–339.CrossRefGoogle ScholarPubMed
39.Corda, S, Laplace, C, Vicaut, E, Duranteau, J. Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-α is mediated by ceramide. Am J Respir Cell Mol Biol 2001; 24: 762–768.Google Scholar
40.Wang, Q, Doerschuk, CM. Neutrophil-induced changes in the biomechanical properties of endothelial cells: roles of ICAM-1 and adhesion molecules. J Immunol 2000; 164: 6487–6494.CrossRefGoogle Scholar
41.Wakabayashi, Y, Fujita, H, Morita, I, Kawaguchi, H, Murota, S. Conversion of xanthine dehydrogenase to xanthine oxidase in bovine carotid artery endothelial cells induced by activated neutrophils: involvement of adhesion molecules. Biochim Biophys Acta 1995; 1265: 103–109.CrossRefGoogle ScholarPubMed
42.Lum, H, Roebuck, KA. Oxidant stress and endothelial cell dysfunction. Am J Physiol 2001; 280: C719–C741.CrossRefGoogle ScholarPubMed
43.Del Maschio, A, Zanetti, A, Corada, M et al. . Polymorphonuclear leukocyte adhesion triggers the disorganization of endothelial cell-to-cell adherens junctions. J Cell Biol 1996; 135: 497–510.Google Scholar
44.Daly, JW. Adenosine receptors: targets for future drugs. J Med Chem 1982; 25: 197–207.CrossRefGoogle ScholarPubMed
45.Sato, T, Sasaki, N, O’Rourke, B, Marban, E. Adenosine primes the opening of mitochondrial ATP-sensitive potassium channels: a key step in ischemic preconditioning? Circulation 2000; 102: 800–805.CrossRefGoogle ScholarPubMed
46.Narayan, P, JrMentzer, RM, Lasley, RD. Adenosine A1 receptor activation reduces reactive oxygen species and attenuates stunning in ventricular myocytes. J Mol Cell Cardiol 2001; 33: 121–129.Google Scholar
47.Almeida, CG, de Mendoca, A, Cunha, RA, Ribeiro, JA. Adenosine promotes neuronal recovery from reactive oxygen species induced lesion in rat hippocampal slices. Neurosci Lett 2003; 339: 127–130.CrossRefGoogle ScholarPubMed
48.Bürkle, A. Physiology and pathophysiology of poly(ADP-ribosyl)ation. Bioessays 2001; 23: 795–806.Google Scholar
49.Holman, RG, Maier, RV. Oxidant-induced endothelial leak correlates with decreased cellular energy levels. Am Rev Respir Dis 1990; 141: 134–140.CrossRefGoogle ScholarPubMed
50.Rhoades, RA. Isolated perfused lung preparation for studying altered gaseous environments. Environ Health Perspect 1984; 56: 43–50.Google Scholar
51.Sayeed, MM. Pulmonary cellular dysfunction in endotoxin shock: metabolic and transport derangements. Circ Shock 1982; 9: 335–355.Google Scholar
52.Martin, C, Leone, M, Viviand, X, Ayem, ML, Guieu, R. High adenosine plasma concentration as a prognostic index for outcome in patients with septic shock. Crit Care Med 2000; 28: 3198–3202.CrossRefGoogle ScholarPubMed
53.Gutierrez, G. Sepsis, cellular energy metabolism, and tissue adenosine triphosphate concentration. Crit Care Med 2000; 28: 2664–2665.Google Scholar