Pflügers Archiv

, Volume 415, Issue 2, pp 127–135 | Cite as

Uric acid as radical scavenger and antioxidant in the heart

  • B. F. Becker
  • N. Reinholz
  • T. Özçelik
  • B. Leipert
  • E. Gerlach
Heart, Circulation, Respiration and Blood; Environmental and Exercise Physiology


Uric acid (UA) is released from the heart of many species, including man, and its site of formation has been shown to be the microvascular endothelium. Since UA reacts with oxygen radicals in vitro, experiments were conducted on guinea pig hearts perfused with Krebs-Henseleit buffer (KHB) to evaluate whether the formation of UA could afford protection from damage by radicals and oxidants. The following results were obtained: (1) Upon addition of the hydroxyl radical scavenger DMSO to the perfusate, the coronary rate of release of endogenous uric acid was increased relative to the precursor purines. (2) UA was degraded during passage through the coronary system and also in KHB in vitro after addition of substances generating hydroxyl radicals or hypochlorite. Superoxide (O 2 ) radicals did not seem to react directly with UA, though UA concentration-dependently quenched the chemiluminescence generated from luminol in the presence of O 2 and OH radicals. (3) Coronary dilatation by acetylcholine (Ach) and sub-μM concentrations of adenosine, induced by both via endothelial mechanisms, was attenuated after prolonged inhibition of endothelial UA formation by allopurinol. Furthermore, the effect of Ach but not of adenosine proved acutely sensitive to methylene blue and O 2 , substances known to inactivate EDRF. This finding suggests involvement of EDRF in Ach-mediated, but not in adenosine-induced dilatation of the intact coronary system. Exogenously applied UA prevented the impairment of vascular responses to Ach and adenosine caused by allopurinol, and to Ach upon generation of O 2 .(4) Hearts performed more pressure-volume work and exhibited greater functional stability when perfused with KHB supplemented with UA in a physiological concentration. It is concluded that uric acid can actually serve as a physiologic radical scavenger and antioxidant, maintaining functional responsiveness of the coronary system and of the myocardium.

Key words

Acetylcholine Adenosine Allopurinol EDRF Hydroxyl radical Hypochlorite Superoxide Xanthine oxidase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Achterberg PW, Stroeve RJ, De Jong JW (1986) Myocardial adenosine cycling rates during normoxia and under conditions of stimulated purine release. Biochem J 235:13–17Google Scholar
  2. 2.
    Ames BN, Cathcart R, Schwiers E, Hochstein P (1981) Uric acid provides an antioxidant defense in humans against oxidantand radical-caused aging and cancer: A hypothesis. Proc Natl Acad Sci USA 78:6858–6862Google Scholar
  3. 3.
    Becker BF, Gerlach E (1984) Acute effects of nicotine on hemodynamic and metabolic parameters of isolated, perfused hearts of guinea pigs and rats. Klin Wochenschr 62 (Suppl II):58–66Google Scholar
  4. 4.
    Becker BF, Gerlach E (1987) Uric acid, the major catabolite of cardiac adenine nucleotides and adenosine, originates in the coronary endothelium. In: Gerlach E, Becker BF (eds) Topics and perspectives in adenosine research. Springer, Berlin Heidelberg New York, pp 209–222Google Scholar
  5. 5.
    Becker BF, Permanetter B, Sebening H, Blömer H, Gerlach E (1987) Uric acid in heart patients: Cardiac production and disappearance in the lung. Pflügers Arch 408 (Suppl I): R14Google Scholar
  6. 6.
    Becker BF, Özçelik T, Reinholz N, Leipert B, Gerlach E (1988) Oxygen radical scavenging, a possible physiologic function of uric acid in the coronary system. Pflügers Arch 411 (Suppl I):R26Google Scholar
  7. 7.
    Betts WH (1985) Detecting oxy radicals by chemiluminescence. In: Greenwald RA (ed) CRC Handbook of methods for oxygen radical research. CRC Press, Boca Raton, Florida, pp 197–201Google Scholar
  8. 8.
    Cadenas E, Sies H (1984) Low-level chemiluminescence as an indicator of singlet molecular oxygen in biological systems. Methods Enzymol 105:221–231Google Scholar
  9. 9.
    Cohen G (1985) The Fenton reaction. In: Greenwald RA (ed) CRC Handbook of methods for oxygen radical research. CRC Press, Boca Raton, Florida, pp 55–64Google Scholar
  10. 10.
    Das DK, Engelman RM, Clement R, Otani H, Prasad MR, Rao PS (1987) Role of xanthine oxidase inhibitor as free radical scavenger: A novel mechanism of action of allopurinol and oxypurinol in myocardial salvage. Biochem Biophys Res Commun 148:314–319Google Scholar
  11. 11.
    Deby C, Deby-Dupont G, Noel F-X, Lavergne L (1981) In vitro and in vivo arachidonic acid conversions into biologically active derivatives are enhanced by uric acid. Biochem Pharmacol 30:2243–2249Google Scholar
  12. 12.
    Dobos D (1975) Electrochemical data. Elsevier, Amsterdam, pp 250–261Google Scholar
  13. 13.
    Freeman BA, Crapo JD (1982) Biology of disease. Free radicals and tissue injury. Lab Invest 47:412–426Google Scholar
  14. 14.
    Gerlach E, Nees S, Becker BF (1985) The vascular endothelium: A survey of some newly evolving biochemical and physiological features. Basic Res Cardiol 80:459–474Google Scholar
  15. 15.
    Grootveld M, Halliwell B (1987) Measurement of allantoin and uric acid in human body fluids. A potential index of free radical reaction in vivo? Biochem J 243:803–808Google Scholar
  16. 16.
    Gryglewski RJ, Palmer RMJ, Moncada S (1986) Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320:454–456Google Scholar
  17. 17.
    Hodgson EK, Fridovich I (1976) The mechanism of the activity-dependent luminescence of xanthine oxidase. Arch Biochem Biophys 172:202–205Google Scholar
  18. 18.
    Howell RR, Wyngaarden JB (1960) On the mechanism of peroxidation of uric acid by hemoproteins. J Biol Chem 235: 3544–3550Google Scholar
  19. 19.
    Jackson CV, Mickelson JK, Stringer K, Rao PS, Lucchesi BR (1986) Electrolysis-induced myocardial dysfunction. A novel method for the study of free radical mediated tissue injury. J Pharmacol Meth 15:305–320Google Scholar
  20. 20.
    Jarasch E-D, Grund C, Bruder G, Heid HW, Keenan TW, Franke WW (1981) Localization of xanthine oxidase in mammary-gland epithelium and capillary endothelium. Cell 25:67–82Google Scholar
  21. 21.
    Komori K, Lorenz RR, Vanhoutte PM (1988) Nitric oxide, Ach and electrical and mechanical properties of canine arterial smooth muscle. Am J Physiol 255: H207-H212Google Scholar
  22. 22.
    Lucchesi BR, Mickelson JK, Homeister JW, Jackson CV (1987) Interaction of the formed elements of blood with the coronary vasculature in vivo. Fed Proc 46:63–72Google Scholar
  23. 23.
    Maples KR, Mason RP (1988) Free radical metabolite of uric acid. J Biol Chem 263:1709–1712Google Scholar
  24. 24.
    Martin W, Villani GM, Jothianandan D, Furchgott RF (1985) Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther 232:708–716Google Scholar
  25. 25.
    McCord JM (1987) Oxygen-derived radicals: A link between reperfusion injury and inflammation. Fed Proc 46:2402–2406Google Scholar
  26. 26.
    Nees S, Herzog V, Becker BF, Böck M, Des Rosiers Ch, Gerlach E (1985) The coronary endothelium: A highly active metabolic barrier for adenosine. Basic Res Cardiol 80:515–529Google Scholar
  27. 27.
    Ogino N, Yamamoto S, Hayaishi O, Tokkuyama T (1979) Isolation of an activator for prostaglandin hydroperoxidase from bovine vesicular gland cytosol and its identification as uric acid. Biochem Biophys Res Commun 87:184–191Google Scholar
  28. 28.
    Orowan E (1955) The origin of man. Nature 175:683–684Google Scholar
  29. 29.
    Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526Google Scholar
  30. 30.
    Pincemail J, Deby C, Thirion A, Dethier A, Deby-Dupont G, Goutier R (1986) Stimulation of cyclooxygenase by activated human neutrophils is enhanced by uric acid. Prostaglandins 32:101–105Google Scholar
  31. 31.
    Repine JE, Eaton JW, Anders MW, Hoidal JR, Fox RB (1979) Generation of hydroxyl radical by enzymes, chemicals, and human phagocytes in vitro. J Clin Invest 64:1642–1651Google Scholar
  32. 32.
    Rubanyi G, Vanhoutte PM (1985) Endothelium-removal decreases relaxations of canine coronary arteries caused by β-adrenergic agonists and adenosine. J Cardiovasc Pharmacol 7:139–144Google Scholar
  33. 33.
    Rubanyi GM, Vanhoutte PM (1986) Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol 250:H822-H827Google Scholar
  34. 34.
    Salin ML, McCord JM (1974) Superoxide dismutases in polymorphonuclear leukocytes. J Clin Invest 1005–1009Google Scholar
  35. 35.
    Spector T (1977) Inhibition of urate production by allopurinol. Biochem Pharmacol 26:355–358Google Scholar
  36. 36.
    Stewart DJ, Pohl U, Dézsi L, Bassenge E (1987) The role of endothelium-derived relaxing factor (EDRF) in the acetylcholine-induced dilation of coronary resistance vessels. Pflügers Arch 408 (Suppl I):R22Google Scholar
  37. 37.
    Usuda N, Reddy MK, Hashimoto T, Rao MS, Reddy JK (1988) Tissue specificity and species differences in the distribution of urate oxidase in peroxisomes. Lab Invest 58:100–111Google Scholar
  38. 38.
    Warren JS, Ward PA (1986) Review: Oxidative injury to the vascular endothelium. Am J Med Sci 292:97–103Google Scholar
  39. 39.
    Wayner DDM, Burton GW, Ingold KU, Barclay LRC, Locke SJ (1987) The relative contributions of vitamin E, urate, ascorbate and proteins to the total peroxyl radical-trapping antioxidant activity of human blood plasma. Biochim Biophys Acta 924:408–419Google Scholar
  40. 40.
    Zimmerman BJ, Parks DA, Grisham MB, Granger DN (1988) Allopurinol does not enhance antioxidant properties of extracellular fluid. Am J Physiol 255: H202-H206Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • B. F. Becker
    • 1
  • N. Reinholz
    • 1
  • T. Özçelik
    • 1
  • B. Leipert
    • 1
  • E. Gerlach
    • 1
  1. 1.Department of PhysiologyUniversity of MunichMünchenFederal Republic of Germany

Personalised recommendations