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Nguyen MD, Ross AE, Ryals M, et al. Clearance of rapid adenosine release is regulated by nucleoside transporters and metabolism. Pharmacol Res Perspect. 2015;3(6):e00189doi: 10.1002/prp2.189.
Nguyen, M. D., Ross, A. E., Ryals, M., Lee, S. T., & Venton, B. J. (2015). Clearance of rapid adenosine release is regulated by nucleoside transporters and metabolism. Pharmacology research & perspectives, 3(6), e00189. https://doi.org/10.1002/prp2.189
Nguyen, Michael D, et al. "Clearance of rapid adenosine release is regulated by nucleoside transporters and metabolism." Pharmacology research & perspectives vol. 3,6 (2015): e00189. doi: https://doi.org/10.1002/prp2.189
Nguyen MD, Ross AE, Ryals M, Lee ST, Venton BJ. Clearance of rapid adenosine release is regulated by nucleoside transporters and metabolism. Pharmacol Res Perspect. 2015 Nov 16;3(6):e00189. doi: 10.1002/prp2.189. eCollection 2015 Dec. PMID: 27022463; PMCID: PMC4777247.
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Pharmacol Res Perspect. 2015 Nov 16;3(6):e00189. doi: 10.1002/prp2.189. eCollection 2015 Dec.

Clearance of rapid adenosine release is regulated by nucleoside transporters and metabolism.

Pharmacology research & perspectives

Michael D Nguyen, Ashley E Ross, Matthew Ryals, Scott T Lee, B Jill Venton

Affiliations

  1. Department of Chemistry University of Virginia Charlottesville Virginia.

PMID: 27022463 PMCID: PMC4777247 DOI: 10.1002/prp2.189

Abstract

Adenosine is a neuromodulator that regulates neurotransmission in the brain and central nervous system. Recently, spontaneous adenosine release that is cleared in 3-4 sec was discovered in mouse spinal cord slices and anesthetized rat brains. Here, we examined the clearance of spontaneous adenosine in the rat caudate-putamen and exogenously applied adenosine in caudate brain slices. The V max for clearance of exogenously applied adenosine in brain slices was 1.4 ± 0.1 μmol/L/sec. In vivo, the equilibrative nucleoside transport 1 (ENT1) inhibitor, S-(4-nitrobenzyl)-6-thioinosine (NBTI) (1 mg/kg, i.p.) significantly increased the duration of adenosine, while the ENT1/2 inhibitor, dipyridamole (10 mg/kg, i.p.), did not affect duration. 5-(3-Bromophenyl)-7-[6-(4-morpholinyl)-3-pyrido[2,3-d]byrimidin-4-amine dihydrochloride (ABT-702), an adenosine kinase inhibitor (5 mg/kg, i.p.), increased the duration of spontaneous adenosine release. The adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) (10 mg/kg, i.p.), also increased the duration in vivo. Similarly, NBTI (10 μmol/L), ABT-702 (100 nmol/L), or EHNA (20 μmol/L) also decreased the clearance rate of exogenously applied adenosine in brain slices. The increases in duration for blocking ENT1, adenosine kinase, or adenosine deaminase individually were similar, about 0.4 sec in vivo; thus, the removal of adenosine on a rapid time scale occurs through three mechanisms that have comparable effects. A cocktail of ABT-702, NBTI, and EHNA significantly increased the duration by 0.7 sec, so the mechanisms are not additive and there may be additional mechanisms clearing adenosine on a rapid time scale. The presence of multiple mechanisms for adenosine clearance on a time scale of seconds demonstrates that adenosine is tightly regulated in the extracellular space.

Keywords: Adenosine deaminase; adenosine kinase; equilibrative nucleoside transporter; voltammetry

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