槲皮素及其主要代谢物选择性调节猪离体冠状动脉中环磷酸鸟苷依赖性松弛及其相关的耐受性。
Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery.
机构信息
School of Biomedical Sciences, Faculty of Medical and Health Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
出版信息
Br J Pharmacol. 2010 Feb 1;159(3):566-75. doi: 10.1111/j.1476-5381.2009.00556.x. Epub 2009 Dec 24.
BACKGROUND AND PURPOSE
Quercetin is a major flavonoid that contributes to the reduced risk of cardiovascular disease associated with dietary ingestion of fruits and vegetables. We have pharmacologically characterized the effect of quercetin, and its sulphate and glucuronide metabolites, on vasoconstrictor and vasodilator responses in the porcine isolated coronary artery.
EXPERIMENTAL APPROACH
Segments of the porcine coronary artery were prepared for either isometric tension recording or determination of cyclic GMP content. The effect of quercetin and metabolites on submaximal responses to U46619 was examined in the presence and absence of substance P, bradykinin, forskolin, sodium nitroprusside (SNP) and glyceryl trinitrate (GTN).
KEY RESULTS
Quercetin and quercetin 3'-sulphate inhibited endothelin and U46619-induced contractions with greater potency (three- to fivefold) against the former, while quercetin 3-glucoronide was inactive. Quercetin enhanced both the cyclic GMP content of the artery (threefold) and cyclic GMP-dependent relaxations to GTN and SNP (two to threefold), but forskolin-induced relaxations were unaffected. Although the effect of quercetin was qualitatively similar to that noted for UK-114,542, a selective inhibitor of phosphodiesterase 5, it was still evident against SNP-induced relaxations in the presence of 10 nM UK-114,542. Quercetin and quercetin 3'-sulphate significantly reduced the development of GTN-associated 'tolerance'.
CONCLUSIONS AND IMPLICATIONS
Quercetin and quercetin 3'-sulphate inhibited receptor-mediated contractions of the porcine isolated coronary artery by an endothelium-independent action. Quercetin selectively enhanced cyclic-GMP-dependent relaxations by a mechanism not involving phosphodiesterase 5 inhibition. In addition, quercetin and quercetin 3'-sulphate opposed GTN-induced tolerance in vitro, which may be beneficial for patients treated for angina pectoris.
背景与目的
槲皮素是一种主要的类黄酮，它有助于降低与食用水果和蔬菜有关的心血管疾病的风险。我们已经从药理学上描述了槲皮素及其硫酸盐和葡萄糖醛酸代谢物对猪离体冠状动脉血管收缩和舒张反应的影响。
实验方法
为等长张力记录或环鸟苷酸含量的测定，准备猪冠状动脉段。在有或没有 P 物质、缓激肽、福司柯林、硝普钠（SNP）和甘油三硝酸酯（GTN）的情况下，研究了槲皮素及其代谢物对 U46619 亚最大反应的影响。
主要结果
槲皮素和槲皮素 3'-硫酸盐对内皮素和 U46619 诱导的收缩具有更强的抑制作用（对前者的抑制作用为三到五倍），而槲皮素 3-葡萄糖醛酸苷则无活性。槲皮素增强了动脉中环鸟苷酸的含量（三倍）和 GTN 和 SNP 诱导的环鸟苷酸依赖性舒张（两到三倍），但福司柯林诱导的舒张不受影响。虽然槲皮素的作用与磷酸二酯酶 5 的选择性抑制剂 UK-114542 相似，但在 10 nM UK-114542 存在的情况下，它仍然对 SNP 诱导的舒张有明显的作用。槲皮素和槲皮素 3'-硫酸盐显著减少了 GTN 相关“耐受”的发展。
结论与意义
槲皮素和槲皮素 3'-硫酸盐通过非内皮依赖性作用抑制猪离体冠状动脉的受体介导性收缩。槲皮素通过一种不涉及磷酸二酯酶 5 抑制的机制选择性增强环鸟苷酸依赖性舒张。此外，槲皮素和槲皮素 3'-硫酸盐在体外对抗 GTN 诱导的耐受，这对心绞痛患者的治疗可能是有益的。
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