López-López Gustavo, Moreno Laura, Cogolludo Angel, Galisteo Milagros, Ibarra Manuel, Duarte Juan, Lodi Federica, Tamargo Juan, Perez-Vizcaino Francisco
Department of Pharmacology, School of Medicine, University Complutense of Madrid, 28040 Madrid, Spain.
Mol Pharmacol. 2004 Apr;65(4):851-9. doi: 10.1124/mol.65.4.851.
The flavonoid quercetin reduces blood pressure and endothelial dysfunction in animal models of hypertension. However, the results concerning the relationship between quercetin and NO present a complex picture. We have analyzed the mechanisms involved in the NO scavenging effects of quercetin and its repercussion on NO bioactivity in vascular smooth muscle. Quercetin scavenged NO with apparent zero-order kinetics with respect to NO. This effect was strongly dependent on the O(2) concentrations, so that NO decay at pH 7.4 could be fitted to the equation -d[NO]/dt = k x [O(2)] x [quercetin], where k was 0.15 M(-1) s(-1). The NO scavenger effects were prevented by superoxide dismutase (SOD), reduced by lowering pH, accompanied by O(2)(.) production and correlated with decreased NO bioactivity in rat aortic rings. However, under conditions of increased O(2)(.) concentrations, quercetin was a better scavenger of O(2)(.) than of NO. When NO scavenging by quercetin was prevented by addition of SOD, NO bioactivity was increased. Quercetin also prevented the inhibitory effects of the SOD inhibitor diethyldithiocarbamic acid (DETCA) on NO bioactivity. In the presence of DETCA, quercetin reduced tissue O(2)(.) as measured by nitro blue tetrazolium staining. In conclusion, quercetin exerts dual effects on O(2)(.) and NO. At physiological conditions of pH, O(2) concentrations and NO, quercetin effectively scavenged NO in the low micromolar range, and the rate-limiting step was the autooxidation of quercetin and the formation of O(2)(.). When the extracellular NO scavenging effect was prevented, quercetin increased the biological activity of NO, an effect related to its O(2)(.) scavenger properties and/or its inhibitory effect on tissue O(2)(.) generation.
类黄酮槲皮素可降低高血压动物模型的血压并改善内皮功能障碍。然而，关于槲皮素与一氧化氮（NO）之间关系的研究结果却十分复杂。我们分析了槲皮素清除NO的机制及其对血管平滑肌中NO生物活性的影响。槲皮素清除NO的动力学表现为明显的零级反应，且该效应强烈依赖于氧气（O₂）浓度，在pH 7.4时，NO的衰减可拟合方程-d[NO]/dt = k × [O₂] × [槲皮素]，其中k为0.15 M⁻¹ s⁻¹。超氧化物歧化酶（SOD）可抑制NO清除作用，降低pH可减弱该作用，同时伴有O₂⁻产生，且与大鼠主动脉环中NO生物活性降低相关。然而，在O₂⁻浓度升高的情况下，槲皮素对O₂⁻的清除能力强于对NO的清除能力。当通过添加SOD阻止槲皮素清除NO时，NO生物活性增强。槲皮素还可对抗SOD抑制剂二乙基二硫代氨基甲酸盐（DETCA）对NO生物活性的抑制作用。在存在DETCA的情况下，通过硝基蓝四氮唑染色测定，槲皮素可降低组织中的O₂⁻。总之，槲皮素对O₂⁻和NO具有双重作用。在生理pH值、O₂浓度和NO条件下，槲皮素能在低微摩尔浓度范围内有效清除NO，限速步骤为槲皮素的自动氧化及O₂⁻的形成。当细胞外NO清除作用被阻止时，槲皮素可增强NO的生物活性，这一作用与其清除O₂⁻的特性和/或对组织O₂⁻生成的抑制作用有关。
