Skip to main content
Log in

Purine metabolism in the heart

Strategies for protection against myocardial ischaemia

  • Published:
Pharmacy World and Science Aims and scope Submit manuscript

Abstract

Adenosine has recently received much attention for the protection it provides against the deleterious effects of ischaemia reperfusion. Whenever the demand for oxygen exceeds its supply, adenosine triphosphate in myocytes is rapidly dephosphorylated to adenosine. Adenosine may then protect the myocardium against ischaemia-reperfusion damage. However, the accumulation of adenosine is limited by its rapid uptake and catabolism in the endothelium and in red blood cells. The strict compartmentalization of the enzyme pathways involved in the metabolism ofadenosine, e.g. adenosine production by myocytes, its pharmacological action in the interstitium, its catabolism in the endothelium and in red blood cells, and its carrier-mediated transport across membranes, provides a unique target for pharmacological interventions. Blockade of adenosine uptake may indeed result in prolonged adenosine accumulation specifically in those regions of the heart where it is produced. In recentyears considerable evidence has been gathered on the adenosine-mediated cardioprotective actions of nucleoside transport inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Drury AN, Szent-Györgi A. The physiological activity of adenine compounds with special reference to their action upon the mammalian heart. J Physiol (Lond) 1929;68:213–7.

    Google Scholar 

  2. Belardinelli L, Linden J, Berne RM. The cardiac effects of adenosine. Prog Cardiovasc Dis 1989;32:73–97.

    PubMed  Google Scholar 

  3. Ely SW, Berne RM. Protective effects of adenosine in myocardial ischemia. Circulation 1992;85:893–904.

    PubMed  Google Scholar 

  4. Berne RM, Knabb RM, Ely SW, Rubio R. Adenosine in the local regulation of blood flow: a brief overview. Fed Proc 1983;42:3136–42.

    PubMed  Google Scholar 

  5. Headrick JP, Berne RM. Endothelium-dependent and -independent relaxations to adenosine in guinea pig aorta. Am J Physiol 1990;259:H62–7.

    PubMed  Google Scholar 

  6. Richardt G, Waas W, Kranzhöfer R, Cheng B, Lohse ML, Schömig A. Interaction between the release of adenosine and noradrenaline during sympathetic stimulation: a feedback mechanism in rat heart. J Mol Cell Cardiol 1989;21:269–77.

    PubMed  Google Scholar 

  7. Romano FD, Naimi TS, Dobson JG Jr. Adenosine attenuation of catecholamine-enhanced contractility in rat heartin vivo. Am J Physiol 1991;260:H1635–9.

    PubMed  Google Scholar 

  8. Schömig A, Richardt G. Cardiac sympathetic activity in myocardial ischemia: release and effects of noradrenaline. Basic Res Cardiol 1990;85(Suppl I):9–30.

    Google Scholar 

  9. Sollevi A, Torsell I, Fredholm BB, Settergren G, Blombäck M. Adenosine spares platelets during cardiopulmonary bypass in man without causing systemic vasodilation. Scand J Thorac Cardiovasc Surg 1985;19:155–9.

    PubMed  Google Scholar 

  10. Kitakaze M, Hori M, Sato H, Takashima S, Inoue M, Kitabatake A, et al. Endogenous adenosine inhibits platelet aggregation during myocardial ischemia in dogs. Circ Res 1991;69:1402–8.

    PubMed  Google Scholar 

  11. Mullane KM, Smith CW. The role of leukocytes in ischemic damage, reperfusion injury and repair of the myocardium. In: Piper HM, editor. Pathophysiology of severe ischemic myocardial injury. Dordrecht: Kluwer Academic Publishers, 1990;239–67.

    Google Scholar 

  12. Engler RL. Free radical and granulocyte-mediated injury during myocardial ischemia and reperfusion. Am J Cardiol 1989;63:19E-23E.

    PubMed  Google Scholar 

  13. Barroso-Aranda J, Schmid-Schönbein GW, Zweifach BW, Engler RL. Granulocytes and no-reflow phenomenon in irreversible hemorrhagic shock. Circ Res 1988;63:437–47.

    PubMed  Google Scholar 

  14. Cronstein BN, Kramer SB, Weissmann G, Hirschhorn R. Adenosine: a physiological modulator of superoxide anion generation by human neutrophils. J Exp Med 1983;158:1160–77.

    PubMed  Google Scholar 

  15. De la Harpe J, Nathan CF. Adenosine regulates the respiratory burst of cytokine-triggered human neutrophils adherent to biologic surfaces. J Immunol 1989;143:596–602.

    PubMed  Google Scholar 

  16. Olafsson B, Forman MB, Puett DW, Pou A, Cates CU, Friesinger GC, et al. Reduction of reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon. Circulation 1987;76:1135–45.

    PubMed  Google Scholar 

  17. Jesmok GJ, Gross Gj, Hardman HF. The effect of adenosine on myocardial metabolism and oxygen consumption in the isolated dog heart preparation. J Mol Cell Cardiol 1978;10:249–61.

    PubMed  Google Scholar 

  18. Wyatt DA, Edmunds MC, Rubio R, Berne RM, Lasley RD, Mentzer RM. Adenosine stimulates glycolytic flux in isolated perfused rat hearts by A1-adenosine receptors. Am J Physiol 1989;257:H1952–7.

    PubMed  Google Scholar 

  19. Law WR, Raymond RM. Adenosine potentiates insulinstimulated myocardial glucose uptakein vivo. Am J Physiol 1988;254:H970–5.

    PubMed  Google Scholar 

  20. Owen P, Dennis S, Opie LH. Glucose flux regulates onset of ischemic contracture in globally underperfused rat hearts. Circ Res 1990;66:344–54.

    PubMed  Google Scholar 

  21. Lerman BB, Belardinelli L, Cardiac electrophysiology of adenosine. Basic and clinical concepts. Circulation 1991;83:1499.

    PubMed  Google Scholar 

  22. Sugiyama S, Ozawa T. Biochemical basis for reperfusion arrhythmias. J Mol Cell Cardiol 1987;19(Suppl V):67–75.

    PubMed  Google Scholar 

  23. Kuzuya T, Hoshida S, Suzuki K, Sasaki T, Kitabatake A, Kamada T, et al. Polymorphonuclear leukocyte activity and ventricular arrhythmia in acute myocardial infarction. Am J Cardiol 1988;62:868–72.

    PubMed  Google Scholar 

  24. Velasco CE, Turner M, Cobb MA, Virmani R, Forman MB. Myocardial reperfusion injury in the canine model after 40 min of ischemia: effect of intracoronary adenosine. Am Heart J 1991;122:1561–70.

    PubMed  Google Scholar 

  25. Pitarys CJ, Virmani R, Vildibill HD, Jackson EK, Forman M. Reduction of myocardial reperfusion injury by intravenous adenosine administered during the early reperfusion period. Circulation 1991;83:237–47.

    PubMed  Google Scholar 

  26. Babbitt DG, Virmani R, Forman MB. Intracoronary adenosine administered after reperfusion limits vascular injury after prolonged ischaemia in the canine model. Circulation 1989;80:1388–99.

    PubMed  Google Scholar 

  27. Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 1991;84:350–6.

    PubMed  Google Scholar 

  28. Jennings RB, Steenbergen C Jr. Nucleotide metabolism and cellular damage in myocardial ischemia. Annu Rev Physiol 1985;47:727–49.

    PubMed  Google Scholar 

  29. Van Belle H, Wynants J, Xhonneux R, Flameng W. Changes in creatine phosphate, inorganic phosphate, and the purine pattern in dog hearts with time of coronary artery occlusion and effect there on of mioflazine, a nucleoside transport inhibitor. Cardiovasc Res 1986;20:658–64.

    PubMed  Google Scholar 

  30. Van Belle H, Wynants J, Goossens F. Formation and release of nucleosides in the ischemic myocardium. Is the guineapig the exception? Basic Res Cardiol 1985;80:653–60.

    PubMed  Google Scholar 

  31. Van Belle H, Goossens F, Wynants J. Formation and release of purine catabolites during hypoperfusion, anoxia, and ischemia. Am J Physiol 1987;252:H886–93.

    PubMed  Google Scholar 

  32. Borst MM, Schrader J. Adenine nucleotide release from isolated perfused guinea pig hearts and extracellular formation of adenosine. Circ Res 1991;68:797–806.

    PubMed  Google Scholar 

  33. Sedaa KO, Bjur RA, Shinozuka K, Westfall DP. Nerve and drug-induced release of adenine nucleosides and nucleotides from rabbit aorta. J Pharmacol Exp Ther 1990;252:1060–7.

    PubMed  Google Scholar 

  34. Nees S, Gerlach E. Adenine nucleotide and adenosine metabolism in cultured coronary endothelial cells: formation and release of adenine compounds and possible functional implications. In: Berne RM, Rall TW, Rubio R, editors. Regulatory functions of adenosine. The Hague: Martinus Nijhoff Publishers, 1983:347–60.

    Google Scholar 

  35. Smolenski RT, Suitters A, Yacoub MH. Adenine nucleotide catabolism and adenosine formation in isolated human cardiomyocytes. J Mol Cell Cardiol 1992;24:91–6.

    PubMed  Google Scholar 

  36. Frick GP, Lowenstein JM. Vectorial production of adenosine by 5′-nucleotidase in the perfused rat heart. J Biol Chem 1978;253:1240–4.

    PubMed  Google Scholar 

  37. Rovetto MJ. Myocardial nucleotide transport. Annu Rev Physiol 1985;47:605–16.

    PubMed  Google Scholar 

  38. Nees S. Coronary flow increases induced by adenosine and adenine nucleotides are mediated by the coronary endothelium: a new principle of the regulation of coronary flow. Eur Heart J 1989;10:28–35.

    Google Scholar 

  39. Nees S, Dendorfer A. Der Einfluβ des koronaren Mikrogefäß-systems auf den Adeninnukleotidstoffwechsel und daraus abgeleitete Funktionen des Herzens. Internist 1990;31:617–24.

    PubMed  Google Scholar 

  40. Gordon JL. Extracellular ATP: effects, sources and fate. Biochem J 1986;233:309–19.

    PubMed  Google Scholar 

  41. Pearson JD, Gordon JL. Nucleotide metabolism by endothelium. Annu Rev Physiol 1985;47:617–27.

    PubMed  Google Scholar 

  42. Fredholm BB, Hedqvist P, Lindström K, Wennmalm M. Release of nucleosides and nucleotides from the rabbit heart by sympathetic nerve stimulation. Acta Physiol Scand 1982;116:285–95.

    PubMed  Google Scholar 

  43. Deussen A, Schrader J. Cardiac adenosine production is linked to myocardial pO2. J Mol Cell Cardiol 1991;23:495–504.

    PubMed  Google Scholar 

  44. Schrader WP, West CA. Localization of adenosine deaminase and adenosine deaminase complexing protein in rabbit heart. Circ Res 1990;66:754–62.

    PubMed  Google Scholar 

  45. Van Belle H. Uptake and deamination of adenosine by blood: species differences, effect of pH, ions, temperature and metabolic inhibitors. Biochim Biophys Acta 1969;192:124–32.

    PubMed  Google Scholar 

  46. Catravas JD, Bassingthwaighte JB, Sparks HV Jr. Adenosine transport and uptake by cardiac and pulmonary endothelial cells. In: Ryan US, editor. Endothelial cells. Vol 1. Boca Raton: CRC Press, 1988;65–84.

    Google Scholar 

  47. Parkinson FE, Clanachan AS. Heterogeneity of nucleoside transport inhibitory sites in heart: a quantitative autoradiographical analysis. Br J Pharmacol 1989;97:361–70.

    PubMed  Google Scholar 

  48. Van Belle H, Xhonneux R, Flameng W, Wynants J. Oral pretreatment with mioflazine completely changes the pattern and remarkably prolongs the accumulation of nucleosides in ischemic and reperfused myocardium. Basic Res Cardiol 1986;81:407–16.

    PubMed  Google Scholar 

  49. Van Belle H, Goossens F, Wynants J. Biochemical and functional effects of nucleoside transport inhibition in the isolated cat heart. J Mol Cell Cardiol 1989;21:797–805.

    PubMed  Google Scholar 

  50. Van Belle H, Janssen PAJ. Comparative pharmacology of nucleoside transport inhibitors. Nucleosides Nucleotides 1991;10:975–82.

    Google Scholar 

  51. Van Belle H, Wynants J, Ver Donck K. Comparison of the existing nucleoside transport inhibitors:in vitro andin vivo data. In: Elion G, Harkness A, Zollner N, editors. Purine and pyrimidine metabolism in man. New York: Plenum Press, 1992:419–22.

    Google Scholar 

  52. Yzerman AP, Thedinga KH, Custers AFCM, Hoos B, Van Belle H. Inhibition of nucleoside transport by a new series of compounds related to lidoflazine and mioflazine. Eur J Pharmacol 1989;172:273–81.

    PubMed  Google Scholar 

  53. Knabb RM, Gidday JM, Ely SW, Rubio R, Berne RM. Effects of dipyridamole on myocardial adenosine and active hyperemia. Am J Physiol 1984;247:H804–10.

    PubMed  Google Scholar 

  54. Hladovec J. Effects of antithrombotics and results of drug screening: dipyridamole. In: Hladovec J, editor. Antithrombotic drugs in thrombosis models. Boca Raton: CRC Press, 1989:87–94.

    Google Scholar 

  55. Prigent AF, Fougier S, Nemoz G, Anker G, Pacheco H, Lugnier C, et al. Comparison of cyclic nucleotide phosphodiesterase isoforms from rat heart and bovine aorta. Separation and inhibition by selective reference phosphodiesterase inhibitors. Biochem Pharmacol 1988;37:3671–81.

    PubMed  Google Scholar 

  56. Blass K-E, Block H-U, Förster W, Pönicke K. Dipyridamole: a potent stimulator of prostacyclin (PGI2) biosynthesis. Br J Pharmacol 1980;68:71–3.

    PubMed  Google Scholar 

  57. Gresele P, Zoja C, Deckmyn H, Arnout J, Vermylen J, Verstraete M. Dipyridamole inhibits platelet aggregation in whole blood. Thromb Haemostasis 1983;50:852–6.

    Google Scholar 

  58. Parks RE, Dawicki DD, Agarwal KC, Chen S-F, Stoeckler JD. Role of nucleoside transport in drug action. The adenosine deaminase inhibitor, deoxycoformycin, and the antiplatelet drugs, dipyridamole and dilazep. Ann NY Acad Sci 1985;451:188–203.

    PubMed  Google Scholar 

  59. Agarwal KC, Zielinski BA, Maitra RS. Significance of plasma adenosine in the antiplatelet activity of forskolin: potentiation by dipyridamole and dilazep. Thromb Haemostasis 1989;61:106–10.

    Google Scholar 

  60. Saniabadi AR, Tomiak RHH, Lowe GDO, Barbenel JC, Forbes CD. Dipyridamole inhibits red cell-induced platelet activation. Atherosclerosis 1989;76:149–54.

    PubMed  Google Scholar 

  61. Saniabadi AR, Fisher TC, McLaren M, Belch JF, Forbes CD. Effect of dipyridamole alone and in combination with aspirin on whole blood platelet aggregation, PGI2 generation, and red cell deformability ex vivo in man. Cardiovasc Res 1991;25:177–83.

    PubMed  Google Scholar 

  62. Ver Donck KLA, Verheyen WJL, Van Belle H. Nucleoside transport inhibition and fMLP-stimulated whole blood luminescence. J Mol Cell Cardiol 1991;23:783–5.

    PubMed  Google Scholar 

  63. Meisel M, Meisel P. Ist Adenosin der Mediator für die Regulation des koronaren Blutstroms und für die Wirkung von Koronardilatatoren? Pharmazie 1974;29:561–8.

    Google Scholar 

  64. Van Belle H, Xhonneux R, Borgers M, Flameng W. Cardioprotective effect of adenosine, lidoflazine and R 51 469. In: Berne RM, Rall TW, Rubio R, editors. Regulatory function of adenosine. The Hague: Martinus Nijhoff Publishers, 1983:546.

    Google Scholar 

  65. Parratt JR, Boachie-Ansah G, Kane KA, Wainwright C. Is adenosine an endogenous antiarrhythmic agent under conditions of myocardial ischemia? In: Paton DM, editor. Adenosine and adenine nucleotides: physiology and pharmacology. London: Taylor and Francis, 1988:157–66.

    Google Scholar 

  66. Coker SJ, Fagbemi O, Parratt JR. Lidoflazine in the early stages of acute myocardial ischaemia. Br J Pharmacol 1982;72:347–54.

    Google Scholar 

  67. Wainwright CL, Parratt JR, Van Belle H. The antiarrhythmic effects of the nucleoside transport inhibitor R 75 231 in anaesthetized pigs. Br J Pharmacol 1993;109:592–9.

    PubMed  Google Scholar 

  68. Masuda M, Demeulemeester A, Chang-Chun C, Hendrikx M, Van Belle H, Flameng W. Cardioprotective effects of nucleoside transport inhibition in rabbit hearts. Ann Thorac Surg 1991;52:1300–5.

    PubMed  Google Scholar 

  69. Flameng W, Sukehiro S, Möllhoff T, Van Belle H, Janssen PAJ. A new concept of long-term donor heart preservation: nucleoside transport inhibition. J Heart Lung Transplant 1992;10:990–8.

    Google Scholar 

  70. Rona G. Catecholamine cardiotoxicity. J Mol Cell Cardiol 1985;17:291–306.

    PubMed  Google Scholar 

  71. Van Belle H, Verheyen W, Ver Donck K, Janssen PAJ, Robertson JIS. Prevention of catecholamine-induced cardiac damage and death with a nucleoside transport inhibitor. J Cardiovasc Pharmacol 1992;20:173–8.

    PubMed  Google Scholar 

  72. Van Belle H, Ver Donck K, Verheyen W. Role of nucleoside transport inhibition and endogenous adenosine in prevention of catecholamine induced death in rabbits. J Cardiovasc Res 1993;27:111–15.

    Google Scholar 

  73. Roberts AJ, Jacobstein JG, Cipriano PR, Alonso DR, Combes JR, Gay WA. Effectiveness of dipyridamole in reducing the size of experimental myocardial infarction. Circulation 1979;61:228–36.

    Google Scholar 

  74. Hattori M, Nagai S, Ogawa K, Satake T, Sugiyama S, Ozawa T. Protective effects of dilazep on reperfusion injury in dogs. J Mol Cell Cardiol 1985;17(Suppl 1):50.

    Google Scholar 

  75. Wood AJ, Isted K, Hynd J, Main MJ, Noble MIM, Parker J, et al. Mioflazine, a potentially protective drug against ischaemic damage: a study in dogs. Eur Heart J 1985;6:695–701.

    PubMed  Google Scholar 

  76. Vandeplassche G, Hermans C, Borgers M, Xhonneux R, Flameng W. Beneficial effect of mioflazine in limiting myocardial infarct size in the anesthetized dog. Res Comm Chem Pathol Pharmacol 1984;44:167–70.

    Google Scholar 

  77. Flameng W, Daenen W, Borgers M, Thoné F, Xhonneux R, Van de Water A, et al. Cardioprotective effects of lidoflazine during 1-hour normothermic global ischemia. Circulation 1981;64:796–807.

    PubMed  Google Scholar 

  78. Van Belle H. Nucleoside transport inhibition: a therapeutic approach to cardioprotection via adenosine. J Cardiovasc Res 1993;27:68–76.

    Google Scholar 

  79. Bugiardini R, Galvani M, Ferrini D, Gridelli C, Tollemeto D, Macri N, et al. Myocardial ischemia during intravenous prostacyclin administration: hemodynamic findings and precautionary measures. Am Heart J 1877;113:234–240.

    Google Scholar 

  80. Rossen JD, Minor RL, Oskarsson H, Quillen JE, Talman, CL, Winniford MD. Failure of aminophylline to blunt adenosineinduced coronary vasodilation in humans [abstract]. J Am Coll Cardiol 1992;19:331 A.

    Google Scholar 

  81. Gregov D, Jenkins A, Duncan E, Siebert D, Rodgers S, Duncan B, et al. Dipyridamole: pharmacokinetics and effects on aspects of platelet function in man. Br J Clin Pharmacol 1987;24:425–34.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ver Donck, K. Purine metabolism in the heart. Pharm World Sci 16, 69–76 (1994). https://doi.org/10.1007/BF01880658

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01880658

Keywords

Navigation