title: Implication of cyclic nucleotide phosphodiesterase inhibition in the vasorelaxant activity of the citrus-fruits flavonoid (+/-)-naringenin.
abstract: The potential vasorelaxant, antioxidant and cyclic nucleotide phosphodiesterase (PDE) inhibitory effects of the citrus-fruit flavonoids naringin and (+/-)-naringenin were comparatively studied for the first time in this work. (+/-)-Naringenin (1 microM - 0.3 mM) did not affect the contractile response induced by okadaic acid (OA, 1 microM). However, (+/-)-naringenin relaxed, in a concentration-dependent manner, the contractions elicited by phenylephrine (PHE, 1 microM) or by a high extracellular KCl concentration (60 mM) in intact rat aortic rings. Mechanical removal of endothelium and/or pretreatment of aorta rings with glibenclamide (GB, 10 microM) or tetraethylammonium (TEA, 2 mM) did not significantly modify the vasorelaxant effects of this flavanone. (+/-)-Naringenin (10 microM - 0.1 mM) did not alter the basal uptake of 4) Ca2+ but decreased the influx of 45Ca2+ induced by PHE and KCl in endothelium-containing and endothelium-denuded rat aorta. (+/-)-Naringenin (10 microM - 0.1 mM) was ineffective to scavenge superoxide radicals (O*2-) generated by the hypoxanthine (HX)-xanthine oxidase (XO) system and/or to inhibit XO activity. (+/-)-Naringenin (0.1 mM) significantly increased the production of cGMP and cAMP decreased by PHE (1 microM) and high KCl (60 mM) in cultured rat aortic myocytes. (+/-)-Naringenin preferentially inhibited calmodulin (CaM)-activated PDE1, PDE4 and PDE5 isolated from bovine aorta with IC50 values of about 45 microM, 60 microM and 68 microM, respectively. In contrast, the 7-rhamnoglucoside of (+/-)-naringenin, naringin (1 microM - 0.3 mM), was totally inactive in all experiments. These results indicate that the vasorelaxant effects of (+/-)-naringenin seem to be basically related to the inhibition of PDE1, PDE4 and PDE5 activities.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela (La Coruña), Spain. fforallo@usc.es
authors.forename: Francisco
authors.initials: F
authors.lastname: Orallo
authors.forename: Mercedes
authors.initials: M
authors.lastname: Camiña
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Alvarez
authors.forename: Hélène
authors.initials: H
authors.lastname: Basaran
authors.forename: Claire
authors.initials: C
authors.lastname: Lugnier
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002957:Citrus; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D044950:Flavanones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005638:Fruit; D020128:Inhibitory Concentration 50; D008297:Male; D009712:Nucleotides, Cyclic; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D008517:Phytotherapy; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D044950:Flavanones; D005419:Flavonoids; D009712:Nucleotides, Cyclic; D014665:Vasodilator Agents; D010727:Phosphoric Diester Hydrolases; C005273:naringenin; D002118:Calcium