Clearance of rapid adenosine release is regulated by nucleoside transporters and metabolism. Issue 6 (16th November 2015)

• Record Type: Journal Article
• Authors: Nguyen, Michael D.; Ross, Ashley E.; Ryals, Matthew; Lee, Scott T.; Venton, B. Jill
• Is Part Of: Pharmacology research & perspectives. Volume 3:Issue 6(2015 Dec)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2015-11-16
• Subjects: Adenosine deaminase -- adenosine kinase -- equilibrative nucleoside transporter -- voltammetry; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.189
• Languages: English
• ISSNs: 2052-1707

Abstract

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 μ mol/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 μ mol/L), ABT‐702 (100 nmol/L), or EHNA (20 μ mol/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.