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Inhibition of type 4 phosphodiesterase by rolipram and Ginkgo biloba extract (EGb 761) decreases agonist-induced rises in internal calcium in human endothelial cells.
Campos-Toimil, M; Lugnier, C; Droy-Lefaix, M T; Takeda, K.
Afiliación
  • Campos-Toimil M; Pharmacologie et Physico-chimie des Interactions Cellulaires et Moléculaires, UMR CNRS 7034, Faculté de Pharmacie, Université Louis Pasteur de Strasbourg, Illkirch, France.
Arterioscler Thromb Vasc Biol ; 20(9): E34-40, 2000 Sep.
Article en En | MEDLINE | ID: mdl-10978267
ABSTRACT
The effects of Gingko biloba extract EGb 761 on 5 isolated, vascular, cyclic nucleotide phosphodiesterase (PDE) isoforms were evaluated. EGb 761 preferentially inhibited PDE4 (IC(50)=25.1 mg/L), the isoform that is mainly present in endothelial cells, in a competitive manner (K(i)=12.5 mg/L). Because changes in cyclic nucleotide levels may affect intracellular calcium ([Ca(2+)](i)) levels in endothelial cells, we examined the effects of EGb 761 on both resting [Ca(2+)](i) levels and agonist-induced rises in [Ca(2+)](i) in single human umbilical vein endothelial cells (HUVECs) in culture. The effects of EGb 761 were compared with those of rolipram, a selective PDE4 inhibitor that increases cellular cAMP levels, and the cAMP analogue dibutyryl cAMP (db-cAMP). EGb 761 (20 and 100 mg/L), rolipram (50 micromol/L), and db-cAMP (100 micromol/L) significantly inhibited histamine-, ATP-, and thrombin-induced [Ca(2+)](i) increases in HUVECs without modifying resting [Ca(2+)](i) levels. Similar results were obtained by using a Ca(2+)-free bath solution. EGb 761 (100 mg/L), but not rolipram (50 micromol/L) or db-cAMP (100 micromol/L), also inhibited Ca(2+) influx into cells having thapsigargin-depleted internal Ca(2+) stores and bathed in a Ca(2+)-free external solution. Our results are consistent with an inhibition of PDE activity that causes a reduction of agonist-induced increases in [Ca(2+)](i) in HUVECs, mainly by inhibition of Ca(2+) mobilization from internal stores. It thus may be that the cardiovascular effects of EGb 761 involve inhibition of PDE4 activity and subsequent modification of Ca(2+) signaling in endothelial cells.
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Bases de datos: MEDLINE Asunto principal: Inhibidores de Fosfodiesterasa / Flavonoides / Endotelio Vascular / Extractos Vegetales / Calcio / 3',5'-AMP Cíclico Fosfodiesterasas / Rolipram Idioma: En Revista: Arterioscler Thromb Vasc Biol Año: 2000 Tipo del documento: Article País de afiliación: Francia
Buscar en Google
Bases de datos: MEDLINE Asunto principal: Inhibidores de Fosfodiesterasa / Flavonoides / Endotelio Vascular / Extractos Vegetales / Calcio / 3',5'-AMP Cíclico Fosfodiesterasas / Rolipram Idioma: En Revista: Arterioscler Thromb Vasc Biol Año: 2000 Tipo del documento: Article País de afiliación: Francia