Vera Rocío, Galisteo Milagros, Villar Inmaculada Concepción, Sánchez Manuel, Zarzuelo Antonio, Pérez-Vizcaíno Francisco, Duarte Juan
Department of Pharmacology, School of Pharmacy, University of Granada, Spain.
J Pharmacol Exp Ther. 2005 Sep;314(3):1300-9. doi: 10.1124/jpet.105.085530. Epub 2005 Jun 15.
The aim of this study was to analyze the effects of the isoflavones genistein and daidzein, and the mammalian estrogen 17beta-estradiol on endothelial function in isolated aortic rings from male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Relaxation to acetylcholine on precontracted rings was impaired and endothelium-dependent contraction to acetylcholine in aortic rings was increased in SHR compared with WKY. Aortic NADPH-stimulated O(2)(-) release and prostaglandin (PG)H(2) production evoked by acetylcholine were increased, whereas nitric-oxide synthase activity was reduced in SHR versus WKY. Genistein, daidzein, or 17beta-estradiol enhanced the relaxant response to acetylcholine and decreased the endothelium-dependent vasoconstrictor responses to acetylcholine in SHR, but not in WKY, and these effects were not modified by the estrogen receptor antagonist ICI 182,780 (7alpha,17beta-[9[(4,4,5,5,5-pentafluoropentyl)-sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol). Moreover, isoflavones enhanced nitric-oxide (NO) synthase activity and inhibited NADPH-stimulated O(2)(-) roduction and endothelial release of PGH(2). The contractions induced by the TP receptor agonist U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha)) in denuded aortic rings were inhibited by genistein, daidzein, and 17beta-estradiol in both strains. In conclusion, the isoflavones genistein and daidzein and 17beta-estradiol restore endothelial function in male SHR through estrogen receptor-independent mechanisms. Increased NO production and protection of NO from O(2)(-)-driven inactivation might be involved in the improvement of vascular relaxation to acetylcholine in aortic rings from SHR. Moreover, isoflavones and 17beta-estradiol inhibited aortic endothelium-dependent contraction to acetylcholine in SHR by reducing the endothelial PGH(2) release and its vasoconstrictor response.
本研究旨在分析异黄酮染料木黄酮和大豆苷元以及哺乳动物雌激素17β-雌二醇对雄性自发性高血压大鼠（SHR）和Wistar Kyoto大鼠（WKY）离体主动脉环内皮功能的影响。与WKY相比，SHR中预收缩环对乙酰胆碱的舒张功能受损，且主动脉环中对乙酰胆碱的内皮依赖性收缩增强。SHR中由乙酰胆碱诱发的主动脉NADPH刺激的O₂⁻释放和前列腺素（PG）H₂生成增加，而与WKY相比，SHR中的一氧化氮合酶活性降低。染料木黄酮、大豆苷元或17β-雌二醇增强了SHR中对乙酰胆碱的舒张反应，并降低了对乙酰胆碱的内皮依赖性血管收缩反应，但对WKY无此作用，且这些作用未被雌激素受体拮抗剂ICI 182,780（7α,17β-[9[(4,4,5,5,5-五氟戊基)-亚磺酰基]壬基]雌-1,3,5(10)-三烯-3,17-二醇）所改变。此外，异黄酮增强了一氧化氮（NO）合酶活性，并抑制了NADPH刺激的O₂⁻生成以及内皮PGH₂释放。在两种品系中，染料木黄酮、大豆苷元和17β-雌二醇均抑制了去内皮主动脉环中TP受体激动剂U46619（9,11-二脱氧-11α,9α-环氧甲撑前列腺素F₂α）诱导的收缩。总之，异黄酮染料木黄酮和大豆苷元以及17β-雌二醇通过不依赖雌激素受体的机制恢复雄性SHR的内皮功能。NO生成增加以及保护NO免受O₂⁻驱动的失活可能参与了SHR主动脉环中对乙酰胆碱血管舒张功能的改善。此外，异黄酮和17β-雌二醇通过减少内皮PGH₂释放及其血管收缩反应，抑制了SHR中主动脉对乙酰胆碱的内皮依赖性收缩。
