The flavonoid dioclein is a selective inhibitor of cyclic nucleotide phosphodiesterase type 1 (PDE1) and a cGMP-dependent protein kinase (PKG) vasorelaxant in human vascular tissue
Identifieur interne : 001868 ( Main/Exploration ); précédent : 001867; suivant : 001869The flavonoid dioclein is a selective inhibitor of cyclic nucleotide phosphodiesterase type 1 (PDE1) and a cGMP-dependent protein kinase (PKG) vasorelaxant in human vascular tissue
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Abstract
The inhibitory effect of the flavonoid dioclein was assessed on purified vascular cyclic nucleotide phosphodiesterase isoforms (EC 3.1.4.17, PDE1-5) in comparison with 8-methoxymethyl-isobutylmethylxanthine (8-MM-IBMX) and vinpocetine which are currently used as PDE1 inhibitors. The mechanism underlying the vasorelaxant effect of dioclein was investigated in human saphenous vein. Dioclein inhibited PDE1 more selectively than vinpocetine and 8-MM-IBMX, with IC50 values of 2.47 ± 0.26 and 1.44 ± 0.35 μM, respectively in basal- and calmodulin-activated states. Dioclein behaved as a competitive inhibitor for cGMP hydrolysis by PDE1 in basal- and calmodulin-activated states (Ki=0.62±0.14 and 0.55±0.07PM, respectively), indicating this inhibitory effect to be independent of calmodulin interactions. In addition, dioclein induced a concentration-dependent relaxation of human saphenous vein which was independent on the presence of functional endothelium (EC50 values of 7.3 ±3.1 and 11 ± 2.7 μM, respectively with and without endothelium). 8-MM-IBMX relaxed human saphenous vein with an EC50 = 31 ± 16 μM, whereas vinpocetine did not cause any vasorelaxation at concentrations up to 100 pM. Rp-8-pCPT-cGMPS, which inhibits cGMP-dependent protein kinase (PKG), blocked the vasodilator effect of dioclein, whereas H-89, which is a cAMP-dependent protein kinase (PKA) inhibitor, had a minor inhibitory effect. Our data show that dioclein is a potent calmodulin-independent selective inhibitor of PDE1 and that inhibition of PDE1 is involved in the PKG-mediated vasorelaxant effect of dioclein in human saphenous vein. Furthermore, dioclein may represent a new archetype to develop more specific PDE1 inhibitors.
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">The flavonoid dioclein is a selective inhibitor of cyclic nucleotide phosphodiesterase type 1 (PDE1) and a cGMP-dependent protein kinase (PKG) vasorelaxant in human vascular tissue</title><author><name sortKey="Goncalves, Roberta L" uniqKey="Goncalves R">Roberta L. Goncalves</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Physiology and Biophysics, ICB, Federal University of Minas Gerais</s1><s2>Belo Horizonte</s2><s3>BRA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Brésil</country><placeName><settlement type="city">Belo Horizonte</settlement><region type="state">Minas Gerais</region></placeName></affiliation></author><author><name sortKey="Lugnier, Claire" uniqKey="Lugnier C">Claire Lugnier</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>UMR CNRS 7213, Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, BP 60024</s1><s2>67401, Illkirch</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Illkirch</wicri:noRegion><placeName><region type="region" nuts="2">Picardie</region></placeName><orgName type="university">Université de Strasbourg</orgName></affiliation></author><author><name sortKey="Keravis, Therese" uniqKey="Keravis T">Thérèse Keravis</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>UMR CNRS 7213, Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, BP 60024</s1><s2>67401, Illkirch</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Illkirch</wicri:noRegion><placeName><region type="region" nuts="2">Picardie</region></placeName><orgName type="university">Université de Strasbourg</orgName></affiliation></author><author><name sortKey="Lopes, Miguel J" uniqKey="Lopes M">Miguel J. Lopes</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Physiology and Biophysics, ICB, Federal University of Minas Gerais</s1><s2>Belo Horizonte</s2><s3>BRA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Brésil</country><placeName><settlement type="city">Belo Horizonte</settlement><region type="state">Minas Gerais</region></placeName></affiliation></author><author><name sortKey="Fantini, Fernando A" uniqKey="Fantini F">Fernando A. Fantini</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Biocor Hospital</s1><s2>Belo Horizonte</s2><s3>BRA</s3><sZ>5 aut.</sZ></inist:fA14><country>Brésil</country><placeName><settlement type="city">Belo Horizonte</settlement><region type="state">Minas Gerais</region></placeName></affiliation></author><author><name sortKey="Schmitt, Martine" uniqKey="Schmitt M">Martine Schmitt</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>UMR CNRS 7213, Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, BP 60024</s1><s2>67401, Illkirch</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Illkirch</wicri:noRegion><placeName><region type="region" nuts="2">Picardie</region></placeName><orgName type="university">Université de Strasbourg</orgName></affiliation></author><author><name sortKey="Cortes, Steyner F" uniqKey="Cortes S">Steyner F. Cortes</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Department of Pharmacology, ICB, Federal University of Minas Gerais</s1><s2>Belo Horizonte</s2><s3>BRA</s3><sZ>7 aut.</sZ></inist:fA14><country>Brésil</country><placeName><settlement type="city">Belo Horizonte</settlement><region type="state">Minas Gerais</region></placeName></affiliation></author><author><name sortKey="Lemos, Virginia S" uniqKey="Lemos V">Virginia S. Lemos</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Physiology and Biophysics, ICB, Federal University of Minas Gerais</s1><s2>Belo Horizonte</s2><s3>BRA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Brésil</country><placeName><settlement type="city">Belo Horizonte</settlement><region type="state">Minas Gerais</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="inist">09-0442927</idno><date when="2009">2009</date><idno type="stanalyst">PASCAL 09-0442927 INIST</idno><idno type="RBID">Pascal:09-0442927</idno><idno type="wicri:Area/Main/Corpus">001B49</idno><idno type="wicri:Area/Main/Curation">000E38</idno><idno type="wicri:Area/Main/Exploration">001868</idno></publicationStmt><seriesStmt><idno type="ISSN">0014-2999</idno><title level="j" type="abbreviated">Eur. j. pharmacol.</title><title level="j" type="main">European journal of pharmacology</title></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>3′,5′-GMP</term><term>Antimigrainous agent</term><term>Cyclic nucleotide</term><term>Endothelium</term><term>Flavonoid</term><term>Human</term><term>Non-specific serine/threonine protein kinase</term><term>Vasodilator agent</term><term>Vein</term><term>Vinpocetine</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Flavonoïde</term><term>Nucléotide cyclique</term><term>GMP-3′,5′</term><term>Non-specific serine/threonine protein kinase</term><term>Homme</term><term>Veine</term><term>Vinpocétine</term><term>Endothélium</term><term>Antimigraineux</term><term>Vasodilatateur</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The inhibitory effect of the flavonoid dioclein was assessed on purified vascular cyclic nucleotide phosphodiesterase isoforms (EC 3.1.4.17, PDE1-5) in comparison with 8-methoxymethyl-isobutylmethylxanthine (8-MM-IBMX) and vinpocetine which are currently used as PDE1 inhibitors. The mechanism underlying the vasorelaxant effect of dioclein was investigated in human saphenous vein. Dioclein inhibited PDE1 more selectively than vinpocetine and 8-MM-IBMX, with IC<sub>50</sub> values of 2.47 ± 0.26 and 1.44 ± 0.35 μM, respectively in basal- and calmodulin-activated states. Dioclein behaved as a competitive inhibitor for cGMP hydrolysis by PDE1 in basal- and calmodulin-activated states (K<sub>i</sub>=0.62±0.14 and 0.55±0.07PM, respectively), indicating this inhibitory effect to be independent of calmodulin interactions. In addition, dioclein induced a concentration-dependent relaxation of human saphenous vein which was independent on the presence of functional endothelium (EC<sub>50</sub> values of 7.3 ±3.1 and 11 ± 2.7 μM, respectively with and without endothelium). 8-MM-IBMX relaxed human saphenous vein with an EC<sub>50</sub> = 31 ± 16 μM, whereas vinpocetine did not cause any vasorelaxation at concentrations up to 100 pM. Rp-8-pCPT-cGMPS, which inhibits cGMP-dependent protein kinase (PKG), blocked the vasodilator effect of dioclein, whereas H-89, which is a cAMP-dependent protein kinase (PKA) inhibitor, had a minor inhibitory effect. Our data show that dioclein is a potent calmodulin-independent selective inhibitor of PDE1 and that inhibition of PDE1 is involved in the PKG-mediated vasorelaxant effect of dioclein in human saphenous vein. Furthermore, dioclein may represent a new archetype to develop more specific PDE1 inhibitors.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0014-2999</s0></fA01><fA02 i1="01"><s0>EJPHAZ</s0></fA02><fA03 i2="1"><s0>Eur. j. pharmacol.</s0></fA03><fA05><s2>620</s2></fA05><fA06><s2>1-3</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>The flavonoid dioclein is a selective inhibitor of cyclic nucleotide phosphodiesterase type 1 (PDE1) and a cGMP-dependent protein kinase (PKG) vasorelaxant in human vascular tissue</s1></fA08><fA11 i1="01" i2="1"><s1>GONCALVES (Roberta L.)</s1></fA11><fA11 i1="02" i2="1"><s1>LUGNIER (Claire)</s1></fA11><fA11 i1="03" i2="1"><s1>KERAVIS (Thérèse)</s1></fA11><fA11 i1="04" i2="1"><s1>LOPES (Miguel J.)</s1></fA11><fA11 i1="05" i2="1"><s1>FANTINI (Fernando A.)</s1></fA11><fA11 i1="06" i2="1"><s1>SCHMITT (Martine)</s1></fA11><fA11 i1="07" i2="1"><s1>CORTES (Steyner F.)</s1></fA11><fA11 i1="08" i2="1"><s1>LEMOS (Virginia S.)</s1></fA11><fA14 i1="01"><s1>Department of Physiology and Biophysics, ICB, Federal University of Minas Gerais</s1><s2>Belo Horizonte</s2><s3>BRA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ></fA14><fA14 i1="02"><s1>UMR CNRS 7213, Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, BP 60024</s1><s2>67401, Illkirch</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ></fA14><fA14 i1="03"><s1>Biocor Hospital</s1><s2>Belo Horizonte</s2><s3>BRA</s3><sZ>5 aut.</sZ></fA14><fA14 i1="04"><s1>Department of Pharmacology, ICB, Federal University of Minas Gerais</s1><s2>Belo Horizonte</s2><s3>BRA</s3><sZ>7 aut.</sZ></fA14><fA20><s1>78-83</s1></fA20><fA21><s1>2009</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>13322</s2><s5>354000170066860120</s5></fA43><fA44><s0>0000</s0><s1>© 2009 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>1/2 p.</s0></fA45><fA47 i1="01" i2="1"><s0>09-0442927</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>European journal of pharmacology</s0></fA64><fA66 i1="01"><s0>NLD</s0></fA66><fC01 i1="01" l="ENG"><s0>The inhibitory effect of the flavonoid dioclein was assessed on purified vascular cyclic nucleotide phosphodiesterase isoforms (EC 3.1.4.17, PDE1-5) in comparison with 8-methoxymethyl-isobutylmethylxanthine (8-MM-IBMX) and vinpocetine which are currently used as PDE1 inhibitors. The mechanism underlying the vasorelaxant effect of dioclein was investigated in human saphenous vein. Dioclein inhibited PDE1 more selectively than vinpocetine and 8-MM-IBMX, with IC<sub>50</sub> values of 2.47 ± 0.26 and 1.44 ± 0.35 μM, respectively in basal- and calmodulin-activated states. Dioclein behaved as a competitive inhibitor for cGMP hydrolysis by PDE1 in basal- and calmodulin-activated states (K<sub>i</sub>=0.62±0.14 and 0.55±0.07PM, respectively), indicating this inhibitory effect to be independent of calmodulin interactions. In addition, dioclein induced a concentration-dependent relaxation of human saphenous vein which was independent on the presence of functional endothelium (EC<sub>50</sub> values of 7.3 ±3.1 and 11 ± 2.7 μM, respectively with and without endothelium). 8-MM-IBMX relaxed human saphenous vein with an EC<sub>50</sub> = 31 ± 16 μM, whereas vinpocetine did not cause any vasorelaxation at concentrations up to 100 pM. Rp-8-pCPT-cGMPS, which inhibits cGMP-dependent protein kinase (PKG), blocked the vasodilator effect of dioclein, whereas H-89, which is a cAMP-dependent protein kinase (PKA) inhibitor, had a minor inhibitory effect. Our data show that dioclein is a potent calmodulin-independent selective inhibitor of PDE1 and that inhibition of PDE1 is involved in the PKG-mediated vasorelaxant effect of dioclein in human saphenous vein. 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