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.

Studies on the chemical composition and possible mechanisms underlying the antispasmodic and bronchodilatory activities of the essential oil of Artemisia maritima L.

“…5C). It is likely that the distinctly high dose required for the cardiac depressant effect of the essential oil, is due to by interference of PDE inhibitory constituents, which are known to be stimulants in the heart (Brain and Hoffman, 2001;Orallo et al, 2005), a pattern similar to that observed with papaverine. Thus, the co-existence of PDE inhibitory and CCB constituents in the essential oil is likely to offset the cardiac side-effects and offering added advantage when used for gut and airways hyperactivity disorders.…”

Glycosidase Inhibitory Flavonoids from Sophora flavescens

“…The comparison of 1 with other flavonoids indicates that a 4Ј-hydroxy group in C-ring has a significant effect upon the inhibition of b-amylase. Most lavandulylated flavanones (1)(2)(3)(4)(5) showed much stronger inhibitory activities against both glycosidases in comparison to prenylated ones (6, 7). Moreover, lavandulylated chalcone, kuraridine (8), exhibited IC 50 value of 57 mM against a-glucosidase, which is the first report of a chalcone displaying glycosidase inhibition properties.…”

“…[1][2][3][4][5][6] In recent years, flavonoids have been the focus of target compounds for glycosidase inhibitor. For instance, genistein, 7) anthocyanins 8) and luteolin 9) showed potent inhibitory activities for glycosidases.…”

Anti-ischemic effect of Aurantii Fructus on contractile dysfunction of ischemic and reperfused rat heart

“…It is known that AF contains several chemicals (Table 3), and of these components, naringin and hesperidin have been most widely recognized as having anti-ischemic effects that could potentially prevent Ca 2+ overload or intake by the cell (Calderone et al, 2004;Singh and Chopra, 2004). In more detail, it has been reported that hesperidin and hesperetin, a major metabolite of hesperidin in vivo significantly activated vasorelaxation through potassium channel activation (Calderone et al, 2004), and naringenin, a major metabolite of naringin in vivo significantly inhibited Ca 2+ uptake induced by phenylephrine in rat aorta (Orallo et al, 2005) and in voltage operated calcium channel in clonal rat pituitary GH C cells (Summanen et al, 2001). Reactive oxygen species and metabolites are known to play important roles in the pathogenesis of ischemia/perfusion and anoxia/reoxygenation injury.…”