Diadenosine polyphosphates inhibit adenosine kinase activity but decrease levels of endogenous adenosine in rat brain.
Identifieur interne : 003B30 ( Main/Exploration ); précédent : 003B29; suivant : 003B31Diadenosine polyphosphates inhibit adenosine kinase activity but decrease levels of endogenous adenosine in rat brain.
Auteurs : Suzanne M. Delaney [Canada] ; G. Michael Blackburn [Royaume-Uni] ; Jonathan D. Geiger [Canada]Source :
- European Journal of Pharmacology [ 0014-2999 ] ; 1997.
Abstract
Findings in peripheral tissues that diadenosine polyphosphates (ApnAs) activate 5′-nucleotidase activity and inhibit adenosine kinase activity in vitro led us to test the hypothesis that ApnAs and analogues thereof, through such actions on purine enzymes, increase brain levels of endogenous adenosine in vivo. Accordingly, we tested ApnAs for their effects on the in vitro activities of adenosine kinase, adenosine deaminase, AMP deaminase and 5′-nucleotidase and, following unilateral microinjections in rat striatum, on in vivo levels of endogenous adenosine. Adenosine kinase activity was not affected significantly by 5′,5‴-P1,P2-diadenosine pyrophosphate (Ap2A) or by 5′,5‴-P1,P3-diadenosine triphosphate (Ap3A), but was inhibited by 5′,5‴-P1,P4-diadenosine tetraphosphate (Ap4A), 5′,5‴-P1,P5-diadenosine pentaphosphate (Ap5A) and 5′,5‴-P1,P6-diadenosine hexaphosphate (Ap6A); apparent IC50 values were 5.0, 3.3 and 500 μM, respectively. Inhibition of adenosine kinase activity by Ap4A and the four metabolically stable analogues of Ap4A tested was uncompetitive. Following unilateral intrastriatal injections, adenosine levels, relative to uninjected contralateral striatum, were decreased significantly (P<0.05) by 48% with Ap4A and by 37% with AppCH2ppA, a metabolically stable analogue of Ap4A. Striatal levels of adenosine were not affected significantly by Ap5A or Ap6A. Cytosolic, but not particulate 5′-nucleotidase activity was inhibited and AMP deaminase activity was increased by some ApnAs. Although adenosine kinase inhibitors increase levels of endogenous adenosine and we showed here that ApnAs were potent inhibitors of this enzyme, these particular actions of ApnAs were not consistent with their effects on levels of endogenous adenosine.
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DOI: 10.1016/S0014-2999(97)01057-1
Affiliations:
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Delaney</name><affiliation wicri:level="4"><country>Canada</country><wicri:regionArea>Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba</wicri:regionArea><orgName type="university">Université du Manitoba</orgName><placeName><settlement type="city">Winnipeg</settlement><region type="state">Manitoba</region></placeName></affiliation></author><author><name sortKey="Blackburn, G Michael" sort="Blackburn, G Michael" uniqKey="Blackburn G" first="G. Michael" last="Blackburn">G. Michael Blackburn</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemistry, Krebs Institute, Sheffield University, Sheffield</wicri:regionArea><wicri:noRegion>Sheffield</wicri:noRegion></affiliation></author><author><name sortKey="Geiger, Jonathan D" sort="Geiger, Jonathan D" uniqKey="Geiger J" first="Jonathan D" last="Geiger">Jonathan D. Geiger</name><affiliation wicri:level="4"><country>Canada</country><wicri:regionArea>Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba</wicri:regionArea><orgName type="university">Université du Manitoba</orgName><placeName><settlement type="city">Winnipeg</settlement><region type="state">Manitoba</region></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Canada</country></affiliation></author></analytic><monogr></monogr><series><title level="j">European Journal of Pharmacology</title><title level="j" type="abbrev">EJP</title><idno type="ISSN">0014-2999</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1997">1997</date><biblScope unit="volume">332</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="35">35</biblScope><biblScope unit="page" to="42">42</biblScope></imprint><idno type="ISSN">0014-2999</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0014-2999</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Findings in peripheral tissues that diadenosine polyphosphates (ApnAs) activate 5′-nucleotidase activity and inhibit adenosine kinase activity in vitro led us to test the hypothesis that ApnAs and analogues thereof, through such actions on purine enzymes, increase brain levels of endogenous adenosine in vivo. Accordingly, we tested ApnAs for their effects on the in vitro activities of adenosine kinase, adenosine deaminase, AMP deaminase and 5′-nucleotidase and, following unilateral microinjections in rat striatum, on in vivo levels of endogenous adenosine. Adenosine kinase activity was not affected significantly by 5′,5‴-P1,P2-diadenosine pyrophosphate (Ap2A) or by 5′,5‴-P1,P3-diadenosine triphosphate (Ap3A), but was inhibited by 5′,5‴-P1,P4-diadenosine tetraphosphate (Ap4A), 5′,5‴-P1,P5-diadenosine pentaphosphate (Ap5A) and 5′,5‴-P1,P6-diadenosine hexaphosphate (Ap6A); apparent IC50 values were 5.0, 3.3 and 500 μM, respectively. Inhibition of adenosine kinase activity by Ap4A and the four metabolically stable analogues of Ap4A tested was uncompetitive. Following unilateral intrastriatal injections, adenosine levels, relative to uninjected contralateral striatum, were decreased significantly (P<0.05) by 48% with Ap4A and by 37% with AppCH2ppA, a metabolically stable analogue of Ap4A. Striatal levels of adenosine were not affected significantly by Ap5A or Ap6A. Cytosolic, but not particulate 5′-nucleotidase activity was inhibited and AMP deaminase activity was increased by some ApnAs. Although adenosine kinase inhibitors increase levels of endogenous adenosine and we showed here that ApnAs were potent inhibitors of this enzyme, these particular actions of ApnAs were not consistent with their effects on levels of endogenous adenosine.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Royaume-Uni</li></country><region><li>Manitoba</li></region><settlement><li>Winnipeg</li></settlement><orgName><li>Université du Manitoba</li></orgName></list><tree><country name="Canada"><region name="Manitoba"><name sortKey="Delaney, Suzanne M" sort="Delaney, Suzanne M" uniqKey="Delaney S" first="Suzanne M" last="Delaney">Suzanne M. Delaney</name></region><name sortKey="Geiger, Jonathan D" sort="Geiger, Jonathan D" uniqKey="Geiger J" first="Jonathan D" last="Geiger">Jonathan D. Geiger</name><name sortKey="Geiger, Jonathan D" sort="Geiger, Jonathan D" uniqKey="Geiger J" first="Jonathan D" last="Geiger">Jonathan D. Geiger</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Blackburn, G Michael" sort="Blackburn, G Michael" uniqKey="Blackburn G" first="G. Michael" last="Blackburn">G. Michael Blackburn</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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