Sánchez Manuel, Galisteo Milagros, Vera Rocío, Villar Inmaculada C, Zarzuelo Antonio, Tamargo Juan, Pérez-Vizcaíno Francisco, Duarte Juan
Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain.
J Hypertens. 2006 Jan;24(1):75-84. doi: 10.1097/01.hjh.0000198029.22472.d9.
Several studies have found that chronic treatment with the dietary flavonoid quercetin lowers blood pressure and restores endothelial dysfunction in hypertensive animal models. We hypothesized that increased endothelial nitric oxide synthase (eNOS) and/or decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein expression and activity, and reduced reactive oxygen species might be involved in the improvement of endothelial function induced by quercetin in spontaneously hypertensive rats (SHR).
Male SHR and Wistar-Kyoto (WKY) rats (5 weeks old) were treated with quercetin (10 mg/kg) or vehicle for 13 weeks. Changes in vascular expression of eNOS, caveolin-1 and p47 were analysed by Western blot, eNOS activity by conversion of [H]arginine to L-[H]citrulline, and NADPH oxidase activity by NADPH-enhanced chemoluminescence of lucigenin.
In SHR, quercetin reduced the increase in blood pressure and heart rate and enhanced the endothelium-dependent aortic vasodilation induced by acetylcholine, but had no effect on the endothelium-independent response induced by nitroprusside. However, quercetin had no effect on endothelium-dependent vasoconstriction and aortic thromboxane B2 production. Compared to WKY, SHR showed upregulated eNOS and p47 protein expression, downregulated caveolin-1 expression, increased NADPH-induced superoxide production but, paradoxically, eNOS activity was reduced. Chronic quercetin treatment prevented all these changes in SHR. In WKY, quercetin had no effect on blood pressure, endothelial function or the expression or activity of the proteins analysed.
Enhanced eNOS activity and decreased NADPH oxidase-mediated superoxide anion (O2) generation associated with reduced p47 expression appear to be essential mechanisms for the improvement of endothelial function and the antihypertensive effects of chronic quercetin.
多项研究发现，用膳食类黄酮槲皮素进行长期治疗可降低血压，并恢复高血压动物模型中的内皮功能障碍。我们推测，内皮型一氧化氮合酶（eNOS）增加和/或烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶蛋白表达及活性降低，以及活性氧减少，可能参与了槲皮素对自发性高血压大鼠（SHR）内皮功能的改善作用。
雄性SHR和Wistar-Kyoto（WKY）大鼠（5周龄）用槲皮素（10毫克/千克）或赋形剂处理13周。通过蛋白质印迹法分析eNOS、小窝蛋白-1和p47的血管表达变化，通过[H]精氨酸转化为L-[H]瓜氨酸分析eNOS活性，通过NADPH增强的光泽精化学发光分析NADPH氧化酶活性。
在SHR中，槲皮素降低了血压和心率的升高，并增强了乙酰胆碱诱导的内皮依赖性主动脉血管舒张，但对硝普钠诱导的非内皮依赖性反应没有影响。然而，槲皮素对内皮依赖性血管收缩和主动脉血栓素B2的产生没有影响。与WKY相比，SHR的eNOS和p47蛋白表达上调，小窝蛋白-1表达下调，NADPH诱导的超氧化物产生增加，但矛盾的是，eNOS活性降低。慢性槲皮素治疗可防止SHR出现所有这些变化。在WKY中，槲皮素对血压、内皮功能或所分析蛋白质的表达或活性没有影响。
eNOS活性增强和NADPH氧化酶介导的超氧阴离子（O2）生成减少以及p47表达降低，似乎是慢性槲皮素改善内皮功能和降压作用的重要机制。
