Department of Psychology, Cardiovascular Center, University of Iowa, 11 Seashore Hall E, Iowa City, IA 52242, USA.
Am J Physiol Heart Circ Physiol. 2011 Feb;300(2):H555-64. doi: 10.1152/ajpheart.00847.2010. Epub 2010 Nov 26.
Many studies have implicated both angiotensin II (ANG II) and aldosterone (Aldo) in the pathogenesis of hypertension, the progression of renal injury, and cardiac remodeling after myocardial infarction. In several cases, ANG II and Aldo have been shown to have synergistic interactions in the periphery. In the present studies, we tested the hypothesis that ANG II and Aldo interact centrally in Aldo- and ANG II-induced hypertension in male rats. In rats with blood pressure (BP) and heart rate (HR) measured by DSI telemetry, intracerebroventricular (icv) infusions of the mineralocorticoid receptor (MR) antagonists spironolactone and RU28318 or the angiotensin type 1 receptor (AT1R) antagonist irbesartan significantly inhibited Aldo-induced hypertension. In ANG II-induced hypertension, icv infusion of RU28318 significantly reduced the increase in BP. Moreover, icv infusions of the reactive oxygen species (ROS) scavenger tempol or the NADPH oxidase inhibitor apocynin attenuated Aldo-induced hypertension. To confirm these effects of pharmacological antagonists, icv injections of either recombinant adeno-associated virus carrying siRNA silencers of AT1aR (AT1aR-siRNA) or MR (MR-siRNA) significantly attenuated the development of Aldo-induced hypertension. The immunohistochemical and Western blot analyses of AT1aR-siRNA- or MR-siRNA-injected rats showed a marked reduction in the expression of AT1R or MR in the paraventricular nucleus compared with scrambled siRNA rats. When animals from all studies underwent ganglionic blockade with hexamethonium, there was a smaller reduction in the fall of BP in animals receiving icv AT1R or MR antagonists. These results suggest that ANG II and Aldo interact in the brain in a mutually cooperative manner such that the functional integrity of both brain AT1R and MR are necessary for hypertension to be induced by either systemic ANG II or Aldo. The pressor effects produced by systemic ANG II or Aldo involve increased central ROS and sympathetic outflow.
许多研究表明血管紧张素 II (ANG II) 和醛固酮 (Aldo) 都与高血压的发病机制、肾损伤的进展以及心肌梗死后的心脏重构有关。在某些情况下，ANG II 和 Aldo 在周围组织中表现出协同相互作用。在本研究中，我们检验了一个假设，即 ANG II 和 Aldo 在雄性大鼠的 Aldo 和 ANG II 诱导的高血压中中枢相互作用。在通过 DSI 遥测测量血压 (BP) 和心率 (HR) 的大鼠中，脑室内 (icv) 输注盐皮质激素受体 (MR) 拮抗剂螺内酯和 RU28318 或血管紧张素类型 1 受体 (AT1R) 拮抗剂伊贝沙坦显着抑制了 Aldo 诱导的高血压。在 ANG II 诱导的高血压中，icv 输注 RU28318 显着降低了血压升高。此外，icv 输注活性氧 (ROS) 清除剂 tempol 或 NADPH 氧化酶抑制剂 apocynin 可减轻 Aldo 诱导的高血压。为了证实这些药理学拮抗剂的作用，icv 注射携带 AT1aR (AT1aR-siRNA) 或 MR (MR-siRNA) 的 siRNA 沉默腺相关病毒重组体显着减轻了 Aldo 诱导的高血压的发展。AT1aR-siRNA 或 MR-siRNA 注射大鼠的免疫组织化学和 Western blot 分析显示，与 scrambled siRNA 大鼠相比，室旁核中 AT1R 或 MR 的表达显着减少。当所有研究的动物均用六烃季铵进行神经节阻滞时，接受 icv AT1R 或 MR 拮抗剂的动物的 BP 下降幅度较小。这些结果表明，ANG II 和 Aldo 在大脑中以相互合作的方式相互作用，使得大脑 AT1R 和 MR 的功能完整性对于由全身 ANG II 或 Aldo 引起的高血压都是必需的。全身 ANG II 或 Aldo 产生的升压作用涉及中央 ROS 和交感神经输出的增加。
