Dpto. Química Biológica, IQUIFIB-CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Brain Res. 2012 May 9;1453:1-7. doi: 10.1016/j.brainres.2012.03.022. Epub 2012 Mar 15.
Increased blood pressure in hypertension is hypothesized to be caused by high sympathetic nervous system (SNS) activity. Since Ang (1-7) exerts an inhibitory neuromodulatory effect on the SNS through a NO-mediated mechanism, we tested the hypothesis that Ang (1-7) alters centrally nitric oxide synthase (NOS) activity and expression in spontaneously hypertensive rats (SHR). Since NOS activity is altered in relation to the development of hypertension in rats, we evaluated the effect of Ang-(1-7) on hypothalamic NOS activity in two different ages in SHR, corresponding to a prehypertensive phase (3-4 weeks) and a established hypertension (13-14 weeks) and compared with age-matched Wistar-Kyoto (WKY) rats. NOS activity was measured by the conversion of [³H]L-arginine to citrulline. Ang-(1-7) caused an impairment in NOS activity in prehypertensive SHR (26 ± 4% reduction), while it induced an increase in NOS activity at established hypertension (48 ± 9% increase). In contrast, Ang-(1-7) did not modify NOS activity in age-matched WKY rats. In another set of experiments, Ang-(1-7) was injected into the anterior hypothalamic area, mean arterial blood pressure (MAP) was registered and after 30, 60 and 180 min nNOS expression was evaluated by Western-blot. Ang-(1-7) decreased MAP after 10 min of injection and this effect was blocked by a NOS inhibitor. nNOS expression increased after 180 min of Ang-(1-7) intrahypothalamic injection in both WKY and SHR (WKY: 3.6-fold increase above basal; SHR: 1.85-fold increase above basal). Our results suggest that Ang-(1-7) upregulates hypothalamic NOS in a hypertensive state as a compensatory and protective mechanism to combat hypertension.
高血压患者的血压升高被假设是由于交感神经系统 (SNS) 活性增加所致。由于 Ang（1-7）通过 NO 介导的机制对 SNS 发挥抑制性神经调节作用，因此我们测试了 Ang（1-7）改变自发性高血压大鼠 (SHR) 中枢一氧化氮合酶 (NOS) 活性和表达的假设。由于 NOS 活性与大鼠高血压的发展有关，因此我们评估了 Ang-(1-7) 对 SHR 中两个不同年龄的下丘脑 NOS 活性的影响，分别对应于高血压前期（3-4 周）和已建立的高血压（13-14 周），并与同龄的 Wistar-Kyoto (WKY) 大鼠进行了比较。NOS 活性通过[³H]L-精氨酸转化为瓜氨酸来测量。Ang-(1-7) 导致高血压前期 SHR 的 NOS 活性受损（减少 26±4%），而在已建立的高血压中诱导 NOS 活性增加（增加 48±9%）。相比之下，Ang-(1-7) 并未改变同龄的 WKY 大鼠的 NOS 活性。在另一组实验中，将 Ang-(1-7) 注入下丘脑前区，记录平均动脉血压 (MAP)，并在 30、60 和 180 分钟后通过 Western blot 评估 nNOS 表达。Ang-(1-7) 在注射后 10 分钟降低 MAP，该作用被 NOS 抑制剂阻断。Ang-(1-7) 在下丘脑内注射 180 分钟后，WKY 和 SHR 中的 nNOS 表达均增加（WKY：基础值的 3.6 倍增加；SHR：基础值的 1.85 倍增加）。我们的结果表明，Ang-(1-7) 在高血压状态下上调下丘脑 NOS，作为一种代偿和保护机制来对抗高血压。
