Increases in Interstitial Adenosine and Cerebral Blood Flow with Inhibition of Adenosine Kinase and Adenosine Deaminase

Sciotti, Veronica M.; Wylen, D. G. L. Van

doi:10.1038/jcbfm.1993.24

Cited by 56 publications

(37 citation statements)

References 26 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As the K m value for AK is 2 mM, whereas that for ADA is in the range of 17-45 mM [Phillips and Newsholme, 1979], it is likely that under normoxic conditions phosphorylation will be the predominant pathway for metabolism. Inhibition of AK with 5 0 -iodotubercidin increased basal rat caudate dialysate adenosine levels by a factor of X2.5, whereas ADA inhibition with erythro-2-(2-hydroxy-3-nonyl/adenine (EHNA) increased adenosine efflux X2 [Sciotti and Van Wylen, 1993]. The effects of deoxycoformycin, an inhibitor of adenosine deaminase, on purine release from the rat cerebral cortex were studied with the cortical cup technique.…”

Section: Extracellular Levels Of Adenosine and Its Metabolitesmentioning

confidence: 99%

In vivo studies of the release of adenine 5′‐nucleotides, adenosine, and its metabolites from the rat brain

Phillis

O’Regan

2003

Drug Development Research

View full text Add to dashboard Cite

Adenosine 5 0 -triphosphate (ATP) and adenosine function as an excitatory neurotransmitter and a neuromodulator, respectively, in the central nervous system. Neuroexcitatory effects of ATP are mediated by P2X receptors: neuromodulator effects of adenosine by A 1 , A 2 , or A 3 receptors. There is also evidence that ATP, acting a P2Y receptor, is involved in osmoregulatory responses to cell swelling. Studies on the release of ATP and/or adenosine into the interstitial fluid of the brain have served to clarify their roles in cerebral function. ATP release occurs during electrical or K + -induced depolarization of cerebral tissues. Released ATP is rapidly hydrolyzed by ectonucleotidases, which may be released concurrently, to form adenosine 5 0 -diphosphate (ADP) and adenine 5 0 -monophosphate (AMP). In addition to synaptic release from neurons, there is evidence of glial release via gap-junction hemichannels. Hydrolysis of AMP to adenosine initiates a further metabolic cascade with the formation of inosine, hypoxanthine, xanthine, and uric acid by adenosine deaminase, purine nucleoside phosphorylase, and xanthine oxidase. Hypoxanthine can be converted to inosine monophosphate by hypoxanthine phosphoribosyl transferase and thus used to replenish ATP. Cerebral ischemia causes ATP utilization, and adenosine formation. Adenosine can then be transported across the plasma membrane and released into the interstitial space. Hypoxemia-evoked adenosine release from the cerebral cortex is inhibited by blockers of adenosine transport. Inhibition of purine metabolism by blockers of adenosine deaminase, purine nucleoside phosphorylase, and xanthine oxidase elevates upstream levels of adenosine and its metabolites. Exposure of the in vivo rat cerebral cortex to cerebrospinal fluid containing swelling-inducing monocarboxylic acids elevated interstitial fluid levels of ADP and AMP, but not of adenosine. Taken together, these studies have led to a greater understanding of the metabolism and release of adenosine and the adenine nucleotides in the normoxic and ischemic brain. Drug Dev. Res.

show abstract

Section: Extracellular Levels Of Adenosine and Its Metabolitesmentioning

confidence: 99%

In vivo studies of the release of adenine 5′‐nucleotides, adenosine, and its metabolites from the rat brain

Phillis

O’Regan

2003

Drug Development Research

View full text Add to dashboard Cite

show abstract

“…AK inhibition with iodotubercidin increased regional brain adenosine levels by 170% and CBF by 140%, whereas adenosine deaminase inhibition by EHNA increased adenosine levels by 58% and CBF 27% only. 51 Inhibition of adenosine kinase 58 and adenosine deaminase 59 increased brain adenosine levels. Even though we do not have data on the effects of GP683 on brain adenosine levels under different experimental conditions (including focal brain ischemia), data from experiments with other AKIs suggest that inhibition of the enzyme adenosine kinase is associated with a robust increase in extracellular brain adenosine concentrations in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…24 Iodotubercidin increased CBF more than the adenosine deaminase inhibitor, erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA), whereas their combination was more effective. 51 A novel adenosine kinase inhibitor GP515 showed not only antiinflammatory effects 52 that were mediated by adenosine 53 but also inhibition of neutrophil adhesion to endothelial cells in rats. 54 The neuroprotective effect of AKIs is because of their ability to further elevate the already elevated brain adenosine levels during ischemia.…”

Section: Discussionmentioning

confidence: 99%

Delayed Treatment With an Adenosine Kinase Inhibitor, GP683, Attenuates Infarct Size in Rats With Temporary Middle Cerebral Artery Occlusion

Tatlısumak

Takano

Carano

et al. 1998

Stroke

View full text Add to dashboard Cite

Background and Purpose-Brain ischemia is associated with a marked increase in extracellular adenosine levels. This results in activation of cell surface adenosine receptors and some degree of neuroprotection. Adenosine kinase is a key enzyme controlling adenosine metabolism. Inhibition of this enzyme enhances the levels of endogenous brain adenosine already elevated as a result of the ischemic episode. We studied a novel adenosine kinase inhibitor (AKI), GP683, in a rat focal ischemia model. Methods-Four groups of 10 adult Sprague-Dawley rats were exposed to 90 minutes of temporary middle cerebral artery (MCA) occlusion. Animals were injected intraperitoneally with vehicle, 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg of GP683 30, 150, and 270 minutes after the induction of ischemia by a researcher blinded to treatment group. The animals were euthanatized 24 hours after MCA occlusion, and brains were stained with 2,3,5-triphenyltetrazolium chloride. We measured brain temperatures in a separate group of 6 rats before and after administration of 1.0 mg/kg GP683. Results-All treated groups showed a reduction in infarct volumes, but a significant effect was observed only in the 1.0 mg/kg-dose group (44% reduction, Pϭ0.0077). Body weight, physiological parameters, neurological scores, and mortality did not differ among the 4 groups. No apparent behavioral side effects were observed. Brain temperatures did not change after drug injection. Conclusions-Our

show abstract

“…It is difficult to com pare the concentration of EHNA utilized in the pre sent study with previous reports on adenosine re lease into brain extracellular fluid, as EHNA was administered systemically (Zetterstrom et al, 1982) and the concentration of EHNA in the brain was not reported. However, recently, a higher concen tration (1 mM) of EHNA, administered via a dialy sis cannula, was shown to increase the basal inter stitial fluid adenosine levels and CBF (Sciotti et al, 1991).…”

Section: Controlmentioning

confidence: 99%

Changes in Pial Arteriolar Diameter and CSF Adenosine Concentrations during Hypoxia

Meno

Ngai

Winn

1993

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Summary:We measured the changes in pial arteriolar di ameter and CSF concentrations of adenosine, inosine, and hypoxanthine during hypoxia in the absence and presence of topically applied dipyridamole (10-6 M) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; 10-5 M). Closed cranial windows were implanted in halothane anesthetized adult male Sprague-Dawley rats for the ob servation of the pial circulation and collection of CSF. The mean resting arteriolar diameter in mock CSF was 31.2 ± 5.9 fLm. Topically applied dipyridamole and EHNA, in combination, caused a slight but significant (p < 0.05) increase in resting arteriolar diameter (33.8 ± 4.3 fLm). With mock CSF, moderate hypoxia caused a 22. 1 ± 9.7% increase in pial vessel diameter. Topically applied dipyridamole and EHNA significantly (p < 0.0 1) poten tiated pial arteriolar vasodilation in response to hypoxia. Moreover, the potentiating effects of dipyridamole andThe purine nucleoside adenosine is a potent va sodilator in many vascular beds and may be in volved in the regulation of cerebral blood flow (CBF) (Berne et aI., 1974; Winn et aI., 1981a). The adenosine concentration, in brain, correlates tem porally with changes in cerebrovascular resistance during hypoxia, seizures, and ischemia (Winn et aI., 1979(Winn et aI., ,1980a(Winn et aI., ,1981b. Following its release into the extracellular space, adenosine acts on specific cell surface receptors (Olsson et aI., 1976;Fredholm and Hedqvist, 1980). The adenosine receptor antag onist, theophylline, inhibits adenosine-induced va sodilation of pial arterioles and attenuates pial arte riolar as well as CBF responses to hypoxia (Morii et aI., 1987 Abbreviation used: EHNA, erythro-9-(2-hydroxy-3-nonyl)ad enine. 214EHNA during hypoxia were completely abolished by the ophylline (0.20 fLmollg, i.p.; p < 0.05), an adenosine re ceptor antagonist. Resting concentrations of adenosine, inosine, and hypoxanthine in the subwindow CSF were 0.18 ± 0.09, 0.35 ± 0.2 1, and 0.62 ± 0.12 fLM, respec tively. In the absence of dipyridamole and EHNA, these levels were not affected by sustained moderate hypoxia (Pa02 = 36 ± 6 mm Hg). However, in the presence of dipyridamole and EHNA, the concentration of adenosine in the CSF during hypoxia was significantly (p < 0.05) increased. Our data indicate that dipyridamole and EHNA potentiate hypoxic vasodilation of pial arterioles while simultaneously increasing extracellular adenosine levels, thus supporting the hypothesis that adenosine is involved in the regulation of cerebral blood flow.

show abstract

Increases in Interstitial Adenosine and Cerebral Blood Flow with Inhibition of Adenosine Kinase and Adenosine Deaminase

Cited by 56 publications

References 26 publications

In vivo studies of the release of adenine 5′‐nucleotides, adenosine, and its metabolites from the rat brain

In vivo studies of the release of adenine 5′‐nucleotides, adenosine, and its metabolites from the rat brain

Delayed Treatment With an Adenosine Kinase Inhibitor, GP683, Attenuates Infarct Size in Rats With Temporary Middle Cerebral Artery Occlusion

Changes in Pial Arteriolar Diameter and CSF Adenosine Concentrations during Hypoxia

Contact Info

Product

Resources

About