Comparative study of the vasorelaxant activity, superoxide-scavenging ability and cyclic nucleotide phosphodiesterase-inhibitory effects of hesperetin and hesperidin

This study investigated the vasorelaxant activity, superoxide radicals (O-2(.-))-scavenging capacity and cyclic nucleotide phosphodiesterase (PDE)-inhibitory effects of hesperidin and hesperetin, two flavonoids mainly isolated from citrus fruits. Hesperetin concentration-dependently relaxed the isometric contractions induced by noradrenaline (NA, 1 muM) or by a high extracellular KCl concentration (60 mM) in intact rat isolated thoracic aorta rings. However, hesperetin (10 muM-0.3 mM) did not affect the contractile response induced by okadaic acid (OA, 1 muM). Mechanical removal of endothelium and/or pretreatment of aorta rings with glibenclamide (GB, 10 muM), tetraethyl ammonium (TEA, 2 mM) or nifedipine (0.1 muM) did not significantly modify the vasorelaxant effects of this flavonoid. Hesperetin (10 muM-0.1 mM) did not affect the basal uptake of Ca-45(2+) but decreased the influx of Ca-45(2+) induced by NA and KCl in endothelium-containing and endothelium-denuded rat aorta. Hesperetin (10 muM-0.1 mM) did not scavenge O-2(.-) generated by the phenazine methosulfate (PMS)reduced beta-nicotinamide adenine dinucleotide (NADH) system. Hesperetin (0.1 mM) significantly reversed the inhibitory effects of NA (1 muM) and high KCl (60 mM) on cyclic nucleotide (CAMP and cGMP) production in cultured rat aortic myocytes. Hesperetin preferentially inhibited calmodulin (CaM)-activated PDE1 and PDE4 isolated from bovine aorta with IC50 values of about 74 muM and 70 muM respectively. In contrast, the 7-rhamnoglucoside of hesperetin, hesperidin (10 muM-0.1 mM), was inactive in practically all experiments, although it inhibited basal and cGMP-activated PDE2 isolated from platelets (IC50 values of 32+/-4 muM and 137+/-34 muM respectively). These results suggest that the vasorelaxant effects of hesperetin are basically due to the inhibition of PDE1 and PDE4 activities.