Inhibition of human platelet cyclic AMP phosphodiesterase and of platelet aggregation by a hemisynthetic flavonoid, amentoflavone hexaacetate.

Amentoflavone hexaacetate (AmAc) was synthesized from natural amentoflavone (Am), a biflavonoid extracted from Viburnum lantana L. Am does not inhibit aggregation of intact platelets up to a concentration of 100 microM but inhibits human platelet cAMP phosphodiesterase (IC50 = 22.0 microM). AmAc is a potent inhibitor of the aggregation of washed human platelets induced by ADP (IC50 = 2.3 microM) or collagen (IC50 = 4.7 microM). AmAc inhibits crude (IC50 = 8.6 microM) or partially purified (IC50 = 42.2 microM) human platelet cAMP phosphodiesterase. In the presence of prostaglandin E1, AmAc (10 microM) induces a 3.7-fold increase in total platelet cAMP. The characteristics of this action suggest a role for cAMP in the mechanism of action of AmAc. The incubation of AmAc with intact platelets for 5 min is necessary for its activity.

[1]  F. B. Davis,et al.  Inhibition by quercetin of thyroid hormone stimulation in vitro of human red blood cell Ca2+-ATPase activity. , 1983, Cell calcium.

[2]  A. Barzilai,et al.  Inhibition of Ca2+-transport ATPase from synaptosomal vesicles by flavonoids. , 1983, Biochimica et biophysica acta.

[3]  M. Ruckstuhl,et al.  Flavonoids are selective cyclic GMP phosphodiesterase inhibitors. , 1979, Biochemical pharmacology.

[4]  J. Cazenave,et al.  Adherence of platelets to a collagen-coated surface: development of a quantitative method. , 1973, The Journal of laboratory and clinical medicine.

[5]  J. Mustard,et al.  Factors responsible for ADP-induced release reaction of human platelets. , 1975, The American journal of physiology.

[6]  K. Sekiya,et al.  Selective inhibition of platelet lipoxygenase by baicalein. , 1982, Biochemical and biophysical research communications.

[7]  T. Mabry,et al.  The Systematic Identification of Flavonoids , 1970, Springer Berlin Heidelberg.

[8]  V. Kakkar,et al.  Effect of Adenyl-Cyclase Activators, Phosphodiesterase Inhibitors and Pyridoxal-5-Phosphate on Platelet Aggregation and Adenosine-3’-5’-Cyclic Monophosphate Accumulation , 1984, Thrombosis and Haemostasis.

[9]  K. K. Chexal,et al.  Biflavonyls from guttifereae—garcinia livingstonII , 1971 .

[10]  R. Chayoth,et al.  Elevation of cyclic AMP level in Ehrlich ascites tumor cells by quercetin. , 1977, Biochemical pharmacology.

[11]  J. Cazenave,et al.  Role of cyclic AMP in the inhibition of human platelet aggregation by quercetin, a flavonoid that potentiates the effect of prostacyclin. , 1982, Biochemical pharmacology.

[12]  R. Aster,et al.  PLATELET SEQUESTRATION IN MAN. I. METHODS. , 1964, The Journal of clinical investigation.

[13]  C. Fiedler-Nagy,et al.  In vitro inhibition of the biosynthesis of slow reacting substance of anaphylaxis (SRS-A) and lipoxygenase activity by quercetin. , 1983, Biochemical pharmacology.

[14]  B. Gomperts,et al.  Effect of flavone inhibitors of transport ATPases on histamine secretion from rat mast cells , 1977, Nature.

[15]  C. Wermuth,et al.  Tissue and substrate specificity of inhibition by alkoxy-aryl-lactams of platelet and arterial smooth muscle cyclic nucleotide phosphodiesterases relationship to pharmacological activity. , 1983, Biochemical and biophysical research communications.

[16]  S. Yamamoto,et al.  Flavonoids: potent inhibitors of arachidonate 5-lipoxygenase. , 1983, Biochemical and biophysical research communications.

[17]  M. Joly,et al.  Inhibition of 3',5'–AMP Phosphodiesterase by Biflavonoids and Xanthones , 1979, Planta medica.

[18]  Tang Ss,et al.  Inhibition of platelet function by antithrombotic agents which selectively inhibit low-Km cyclic 3',5'-adenosine monophosphate phosphodiesterase. , 1980 .

[19]  H. Schatzmann,et al.  Inhibition of the red cell calcium pump by quercetin , 1980 .

[20]  M. Schlick.  Raum und Zeit in der gegenwärtigen Physik: Zur Einführung in das Verständnis der allgemeinen Relativitätstheorie , 1917 .

[21]  M. Steiner,et al.  Inhibition in vitro of platelet aggregation and arachidonic acid metabolism by flavone. , 1984, Biochemical pharmacology.

[22]  G. Némoz,et al.  Pentasubstituted quercetin analogues as selective inhibitors of particulate 3':5'-cyclic-AMP phosphodiesterase from rat brain. , 1982, Journal of Medicinal Chemistry.

[23]  R. Colman,et al.  Purification and characterization of a human platelet cyclic nucleotide phosphodiesterase. , 1984, Biochemistry.

[24]  M. Steiner,et al.  Modification of platelet function and arachidonic acid metabolism by bioflavonoids. Structure-activity relations. , 1984, Biochemical pharmacology.

[25]  R. Ortmann,et al.  Phloretin and related compounds inhibit agonist stimulated cAMP accumulation in cultured cells of CNS origin. , 1979, Biochemical pharmacology.

[26]  S. Colowick,et al.  Methods in Enzymology , Vol , 1966 .

[27]  M. Ruckstuhl,et al.  Inhibition of lung cyclic AMP- and cyclic GMP-phosphodiesterases by flavonoids and other chromone-like compounds. , 1981, Biochemical pharmacology.

[28]  R. Anton,et al.  HPLC Separation and Quantitative Determination of Biflavones in Leaves from Ginkgo biloba , 1983, Planta medica.

[29]  H. Hidaka,et al.  Human blood platelet 3': 5'-cyclic nucleotide phosphodiesterase. Isolation of low-Km and high-Km phosphodiesterase. , 1976, Biochimica et biophysica acta.

[30]  Chen Fa-Ching,et al.  Biflavonyls from drupes of Rhus succedanea , 1974 .

[31]  A. Katz,et al.  Quercetin stimulation of calcium release from rabbit skeletal muscle sarcoplasmic reticulum. , 1983, Life sciences.

[32]  H. Hidaka,et al.  Selective inhibitor of platelet cyclic adenosine monophosphate phosphodiesterase, cilostamide, inhibits platelet aggregation. , 1979, The Journal of pharmacology and experimental therapeutics.

[33]  J. N. Wells,et al.  Cyclic nucleotide phosphodiesterase activities of pig coronary arteries. , 1975, Biochimica et biophysica acta.