Increased Microparticle Production and Impaired Microvascular Endothelial Function in Aldosterone-Salt-Treated Rats: Protective Effects of Polyphenols

We aimed to characterize circulating microparticles in association with arterial stiffness, inflammation and endothelial dysfunction in aldosterone-salt-induced hypertension in rats and to investigate the preventive effects of red wine polyphenols. Uninephrectomized male Sprague-Dawley rats were treated with aldosterone-salt (1 µg.h−1), with or without administration of either red wine polyphenols, Provinols™ (20 mg.kg−1.day−1), or spironolactone (30 mg.kg−1.day−1) for 4 weeks. Microparticles, arterial stiffness, nitric oxide (NO) spin trapping, and mesenteric arterial function were measured. Aldosterone-salt rats showed increased microparticle levels, including those originating from platelets, endothelium and erythrocytes. Hypertension resulted in enhanced aortic stiffness accompanied by increased circulating and aortic NO levels and an upregulation of aortic inducible NO-synthase, NFκB, superoxide anions and nitrotyrosine. Flow-induced dilatation was reduced in mesenteric arteries. These effects were prevented by spironolactone. Provinols™ did not reduce arterial stiffness or systolic hypertension but had effects similar to those of spironolactone on endothelial function assessed by flow-mediated vasodilatation, microparticle generation, aortic NO levels and oxidative stress and apoptosis in the vessel wall. Neither the contractile response nor endothelium-dependent relaxation in mesenteric arteries differed between groups. The in vivo effects of Provinols™ were not mediated by mineralocorticoid receptors or changes in shear stress. In conclusion, vascular remodelling and endothelial dysfunction in aldosterone-salt-mediated hypertension are associated with increased circulating microparticles. Polyphenols prevent the enhanced release of microparticles, macrovascular inflammation and oxidative stress, and microvascular endothelial dysfunction independently of blood pressure, shear stress and mineralocorticoid receptor activation in a model of hyperaldosteronism.本研究旨在明确大鼠醛固酮盐诱导的高血压模型中，循环微粒与动脉僵硬度、炎症及内皮功能障碍的关联，并探究红酒多酚的预防作用。选取单侧肾切除的雄性斯普拉格-道利大鼠，给予醛固酮盐（1 µg·h⁻¹）处理，同时分别或联合给予红酒多酚、Provinols™（20 mg·kg⁻¹·d⁻¹）或螺内酯（30 mg·kg⁻¹·d⁻¹），持续干预4周。检测指标涵盖循环微粒、动脉僵硬度、一氧化氮（nitric oxide，NO）自旋捕获以及肠系膜动脉功能。醛固酮盐处理组大鼠的循环微粒水平显著升高，包括来源于血小板、内皮细胞与红细胞的微粒。该高血压模型大鼠出现主动脉僵硬度升高，同时循环及主动脉组织的NO水平升高，主动脉组织中诱导型一氧化氮合酶、核因子κB（NFκB）、超氧阴离子及硝基酪氨酸的表达上调。肠系膜动脉的血流介导的舒张功能受损，螺内酯可阻断上述所有病理改变。Provinols™无法降低动脉僵硬度或收缩期高血压，但在血流介导的血管舒张评估的内皮功能、微粒生成、主动脉NO水平以及血管壁氧化应激与细胞凋亡方面，其作用与螺内酯相似。各组肠系膜动脉的收缩反应及内皮依赖性舒张功能均无显著差异。Provinols™的体内作用并非通过盐皮质激素受体或剪切应力变化介导。综上，醛固酮盐介导的高血压中的血管重构与内皮功能障碍，与循环微粒水平升高密切相关。在高醛固酮血症模型中，多酚类物质可抑制微粒生成增加、大血管炎症与氧化应激，以及微血管内皮功能障碍，且该作用不依赖于血压、剪切应力及盐皮质激素受体激活。