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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

The Guanosine-Adenosine Interaction Exists In Vivo

Edwin K. Jackson and Zaichuan Mi
Journal of Pharmacology and Experimental Therapeutics September 2014, 350 (3) 719-726; DOI: https://doi.org/10.1124/jpet.114.216978
Edwin K. Jackson
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Zaichuan Mi
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Abstract

In cultured renal cells and isolated perfused kidneys, extracellular guanosine augments extracellular adenosine and inosine (the major renal metabolite of adenosine) levels by altering the extracellular disposition of these purines. The present study addressed whether this “guanosine-adenosine mechanism” exists in vivo. In rats (n = 15), intravenous infusions of adenosine (1 µmol/kg per minute) decreased mean arterial blood pressure (MABP) from 114 ± 4 to 83 ± 5 mm Hg, heart rate (HR) from 368 ± 11 to 323 ± 9 beats/min), and renal blood flow (RBF) from 6.2 ± 0.5 to 5.3 ± 0.6 ml/min). In rats (n = 15) pretreated with intravenous guanosine (10 µmol/kg per minute), intravenous adenosine (1 µmol/kg per minute) decreased MABP (from 109 ± 4 to 58 ± 5 mm Hg), HR (from 401 ± 10 to 264 ± 20 beats/min), and RBF (from 6.2 ± 0.7 to 1.7 ± 0.3). Two-factor analysis of variance (2F-ANOVA) revealed a significant interaction (P < 0.0001) between guanosine and adenosine for MABP, HR, and RBF. In control rats, the urinary excretion rate of endogenous inosine was 211 ± 103 ng/30 minutes (n = 9); however, in rats treated with intravenous guanosine (10 µmol/kg per minute), the excretion rate of inosine was 1995 ± 300 ng/30 minutes (n = 12; P < 0.0001 versus controls). Because adenosine inhibits inflammatory cytokine production, we also examined the effects of intravenous guanosine on endotoxemia-induced increases in tumor necrosis factor-α (TNF-α). In control rats (n = 7), lipopolysaccharide (LPS; Escherichia coli 026:B6 endotoxin; 30 mg/kg) increased plasma TNF-α from 164 ± 56 to 4082 ± 730 pg/ml, whereas in rats pretreated with intravenous guanosine (10 µmol/kg per minute; n = 6), LPS increased plasma TNF-α from 121 ± 45 to 1821 ± 413 pg/ml (2F-ANOVA interaction effect, P = 0.0022). We conclude that the guanosine-adenosine mechanism exists in vivo and that guanosine may be a useful therapeutic for reducing inflammation.

Footnotes

    • Received May 26, 2014.
    • Accepted July 1, 2014.
  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants R01-HL109002 and R01-HL069846]; and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants R01-DK091190, R01-DK068575, and P30-DK079307].

  • dx.doi.org/10.1124/jpet.114.216978.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 3
1 Sep 2014
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Guanosine-Adenosine Mechanism

Edwin K. Jackson and Zaichuan Mi
Journal of Pharmacology and Experimental Therapeutics September 1, 2014, 350 (3) 719-726; DOI: https://doi.org/10.1124/jpet.114.216978

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Guanosine-Adenosine Mechanism

Edwin K. Jackson and Zaichuan Mi
Journal of Pharmacology and Experimental Therapeutics September 1, 2014, 350 (3) 719-726; DOI: https://doi.org/10.1124/jpet.114.216978
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