Orallo Francisco, Alvarez Ezequiel, Basaran Hélène, Lugnier Claire
Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur, 15782 Santiago de Compostela (La Coruña), Spain.
Naunyn Schmiedebergs Arch Pharmacol. 2004 Dec;370(6):452-63. doi: 10.1007/s00210-004-0994-6. Epub 2004 Nov 17.
This study investigated the vasorelaxant activity, superoxide radicals (O2(-))-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 microM) or by a high extracellular KCl concentration (60 mM) in intact rat isolated thoracic aorta rings. However, hesperetin (10 microM-0.3 mM) did not affect the contractile response induced by okadaic acid (OA, 1 microM). Mechanical removal of endothelium and/or pretreatment of aorta rings with glibenclamide (GB, 10 microM), tetraethylammonium (TEA, 2 mM) or nifedipine (0.1 microM) did not significantly modify the vasorelaxant effects of this flavonoid. Hesperetin (10 microM-0.1 mM) did not affect the basal uptake of (45)Ca(2+) but decreased the influx of (45)Ca(2+) induced by NA and KCl in endothelium-containing and endothelium-denuded rat aorta. Hesperetin (10 microM-0.1 mM) did not scavenge O2(-) 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 microM) 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 IC(50) values of about 74 microM and 70 microM respectively. In contrast, the 7-rhamnoglucoside of hesperetin, hesperidin (10 microM-0.1 mM), was inactive in practically all experiments, although it inhibited basal and cGMP-activated PDE2 isolated from platelets (IC(50) values of 32+/-4 microM and 137+/-34 microM respectively). These results suggest that the vasorelaxant effects of hesperetin are basically due to the inhibition of PDE1 and PDE4 activities.
本研究调查了橙皮苷和橙皮素这两种主要从柑橘类水果中分离得到的黄酮类化合物的血管舒张活性、超氧阴离子自由基（O2(-)）清除能力以及环核苷酸磷酸二酯酶（PDE）抑制作用。橙皮素能浓度依赖性地舒张完整大鼠离体胸主动脉环中由去甲肾上腺素（NA，1微摩尔）或高细胞外氯化钾浓度（60毫摩尔）诱导的等长收缩。然而，橙皮素（10微摩尔至0.3毫摩尔）对冈田酸（OA，1微摩尔）诱导的收缩反应没有影响。机械去除内皮和/或用格列本脲（GB，10微摩尔）、四乙铵（TEA，2毫摩尔）或硝苯地平（0.1微摩尔）预处理主动脉环并没有显著改变这种黄酮类化合物的血管舒张作用。橙皮素（10微摩尔至0.1毫摩尔）不影响（45）Ca(2+)的基础摄取，但能减少NA和氯化钾在含内皮和去内皮大鼠主动脉中诱导的（45）Ca(2+)内流。橙皮素（10微摩尔至0.1毫摩尔）不能清除由吩嗪硫酸甲酯（PMS）还原的β-烟酰胺腺嘌呤二核苷酸（NADH）系统产生的O2(-)。橙皮素（0.1毫摩尔）能显著逆转NA（1微摩尔）和高钾（60毫摩尔）对培养的大鼠主动脉平滑肌细胞中环核苷酸（cAMP和cGMP）生成的抑制作用。橙皮素优先抑制从牛主动脉中分离得到的钙调蛋白（CaM）激活的PDE1和PDE4，其半数抑制浓度（IC(50)）值分别约为74微摩尔和70微摩尔。相比之下，橙皮素的7-鼠李糖苷，即橙皮苷（10微摩尔至0.1毫摩尔），在几乎所有实验中均无活性，尽管它能抑制从血小板中分离得到的基础型和cGMP激活的PDE2（IC(50)值分别为32±4微摩尔和137±34微摩尔）。这些结果表明，橙皮素的血管舒张作用主要是由于对PDE1和PDE4活性的抑制。
