Pinaud Frederic, Bocquet Arnaud, Dumont Odile, Retailleau Kevin, Baufreton Christophe, Andriantsitohaina Ramaroson, Loufrani Laurent, Henrion Daniel
Centre National de la Recherche Scientifique Unité Mixte de Recherche (CNRS UMR) 6214, Université d'Angers, Angers, France.
Hypertension. 2007 Jul;50(1):96-102. doi: 10.1161/HYPERTENSIONAHA.106.085035. Epub 2007 May 7.
The role of angiotensin II type 2 receptors (AT2Rs) remains a matter of controversy. Its vasodilatory and antitrophic properties are well accepted. Nevertheless, in hypertensive rats, AT2R stimulation induces a vasoconstriction counteracting flow-mediated dilation (FMD). This contraction is reversed by hydralazine. Because FMD is also decreased in aging, another risk factor for cardiovascular diseases, we hypothesized that AT2R function might be altered in old-rat resistance arteries. Mesenteric resistance arteries (250 mum in diameter) were isolated from old (24 months) and control (4 months) rats receiving hydralazine (16 mg/kg per day; 2 weeks) or water. FMD, NO-mediated dilation, and endothelial NO synthase expression were lower in old versus control rats. AT2R blockade improved FMD in old rats, suggesting that AT2R stimulation produced vasoconstriction. AT2R expression was higher in old rats and mainly located in the smooth muscle layer. In old rats, AT2R stimulation induced endothelium-independent contraction, which was suppressed by the antioxidant Tempol. Reactive oxygen species level was higher in old-rat arteries than in controls. Hydralazine improved FMD and NO-dependent dilation in old rats without change in AT2R expression and location. In old rats treated with hydralazine, reactive oxygen species level was reduced in endothelial and smooth muscle cells, and AT2R-dependent contraction was abolished. Thus, AT2R stimulation induced vasoconstriction through activation of reactive oxygen species production, contributing to decrease FMD in old-rat resistance arteries. Hydralazine suppressed AT2R-dependent reactive oxygen species production and AT2R-dependent contraction, improving FMD. Importantly, endothelial alterations in aging were reversible. These findings are important to consider in the choice of vasoactive drugs in aging.
血管紧张素 II 2型受体（AT2Rs）的作用仍存在争议。其血管舒张和抗增殖特性已得到广泛认可。然而，在高血压大鼠中，刺激AT2R会诱导血管收缩，抵消血流介导的血管舒张（FMD）。这种收缩可被肼屈嗪逆转。由于FMD在衰老过程中也会降低，而衰老是心血管疾病的另一个危险因素，我们推测老年大鼠阻力动脉中的AT2R功能可能发生了改变。从接受肼屈嗪（每天16mg/kg；2周）或饮水的老年（24个月）和对照（4个月）大鼠中分离出肠系膜阻力动脉（直径250μm）。与对照大鼠相比，老年大鼠的FMD、一氧化氮介导的血管舒张和内皮型一氧化氮合酶表达较低。阻断AT2R可改善老年大鼠的FMD，提示刺激AT2R会产生血管收缩。老年大鼠的AT2R表达较高，主要位于平滑肌层。在老年大鼠中，刺激AT2R会诱导不依赖内皮的收缩，而抗氧化剂Tempol可抑制这种收缩。老年大鼠动脉中的活性氧水平高于对照组。肼屈嗪可改善老年大鼠的FMD和一氧化氮依赖性血管舒张，而AT2R的表达和定位没有变化。在用肼屈嗪治疗的老年大鼠中，内皮细胞和平滑肌细胞中的活性氧水平降低，且AT2R依赖性收缩被消除。因此，刺激AT2R通过激活活性氧生成诱导血管收缩，导致老年大鼠阻力动脉的FMD降低。肼屈嗪抑制AT2R依赖性活性氧生成和AT2R依赖性收缩，从而改善FMD。重要的是，衰老过程中的内皮改变是可逆的。这些发现在选择老年患者的血管活性药物时具有重要参考价值。
