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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Inhibition of Platelet Aggregation with Glyceryl Trinitrate and Xanthine Oxidoreductase

Sharon O'Byrne, Cheerag Shirodaria, Timothy Millar, Cliff Stevens, David Blake and Nigel Benjamin
Journal of Pharmacology and Experimental Therapeutics January 2000, 292 (1) 326-330;
Sharon O'Byrne
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Cheerag Shirodaria
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Timothy Millar
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Cliff Stevens
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David Blake
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Nigel Benjamin
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Abstract

Xanthine oxidoreductase (XOR) is a mammalian enzyme that possesses a series of redox centers, which use either NAD+ or molecular oxygen for oxidation of the purines xanthine and hypoxanthine to uric acid. The ability of XOR to act as an NADH oxidase is a less well recognized function of the enzyme, and it is this function that we used to explore the metabolism of glyceryl trinitrate. The antiplatelet effect of nitric oxide (NO) on platelet aggregation was used as a bioassay to assess the bioconversion of glyceryl trinitrate to NO by XOR. The thromboxane mimetic U46619, 2 μM, was used to stimulate platelet aggregation in platelet-rich plasma prepared from healthy drug-free human volunteers. All incubations were carried out at 37°C for 2 min after the addition of U46619. XOR produced a dose-dependent antiaggregant effect when incubated with glyceryl trinitrate (GTN), 220 μM. This did not occur when GTN or XOR was incubated with platelet-rich plasma independently. The antiaggregant effect of XOR plus GTN was dose dependently inhibited by allopurinol, with an IC50 of 100 μM. The addition of superoxide dismutase (SOD), 100 U/ml produced a shift to the left in the antiaggregant dose-response curve for XOR. The IC50 for XOR at 200 U/l without SOD was decreased to 80 U/l with SOD. Oxyhemoglobin, an extracellular NO scavenger, produced a dose-dependent, noncompetitive inhibition of the antiaggregant effect of XOR plus GTN. These findings suggest that GTN may be reduced to NO in vitro by the enzyme XOR in sufficient amounts to inhibit platelet aggregation.

Footnotes

  • Send reprint requests to: Dr. S. O'Byrne, Department of Clinical Pharmacology, St. Bartholomew's and the Royal London Hospital School of Medicine & Dentistry, Charterhouse Square, London EC1M 6BQ, UK. E-mail: S.R.O'Byrne{at}mds.qmw.ac.uk

  • Abbreviations:
    GTN
    glyceryl trinitrate
    NO
    nitric oxide
    Fe/S
    iron sulfur center
    ONOO−
    peroxynitrite
    PRP
    platelet-rich plasma
    SOD
    superoxide dismutase
    U46619
    11α,9α-epoxymethano-prostaglandin H2 (a thromboxane mimetic)
    XDH
    xanthine dehydrogenase
    XO
    xanthine oxidase
    XOR
    xanthine oxidoreductase
    • Received July 15, 1999.
    • Accepted September 24, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 1
1 Jan 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Inhibition of Platelet Aggregation with Glyceryl Trinitrate and Xanthine Oxidoreductase

Sharon O'Byrne, Cheerag Shirodaria, Timothy Millar, Cliff Stevens, David Blake and Nigel Benjamin
Journal of Pharmacology and Experimental Therapeutics January 1, 2000, 292 (1) 326-330;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Inhibition of Platelet Aggregation with Glyceryl Trinitrate and Xanthine Oxidoreductase

Sharon O'Byrne, Cheerag Shirodaria, Timothy Millar, Cliff Stevens, David Blake and Nigel Benjamin
Journal of Pharmacology and Experimental Therapeutics January 1, 2000, 292 (1) 326-330;
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