Institute of Experimental and Clinical Pharmacology and Toxicology Institute of Medical Biometry and Statistics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
J Endocrinol. 2010 Jan;204(1):85-92. doi: 10.1677/JOE-09-0363. Epub 2009 Oct 6.
AT(1) blockers attenuate hypothalamo-pituitary-adrenal (HPA) axis reactivity in hypertension independently of their potency to lower blood pressure. A reduced pituitary sensitivity to CRH and a downregulation of hypothalamic CRH expression have been suggested to influence HPA axis activity during chronic AT(1) blockade. This study was aimed at confirming the role of central angiotensin II in regulating HPA reactivity by using the transgenic rat TGR(ASrAOGEN), a model featuring low levels of brain angiotensinogen. Different stress tests were performed to determine HPA reactivity in TGR(ASrAOGEN) and appropriate controls. In TGR(ASrAOGEN), blood pressure was diminished compared to controls. The corticosterone response to a CRH or ACTH challenge and a forced swim test was more distinct in TGR(ASrAOGEN) than it was in controls and occurred independently of a concurrent enhancement in ACTH. Using quantitative real-time PCR, we found increased mRNA levels of melanocortin 2 (Mc2r) and AT(2) receptors (Agtr2) in the adrenals of TGR(ASrAOGEN), whereas mRNA levels of Crh, Pomc, and AT(1) receptors (Agtr1) remained unchanged in hypothalami and pituitary glands. Since stress responses were increased rather than attenuated in TGR(ASrAOGEN), we conclude that the reduced HPA reactivity during AT(1) blockade could not be mimicked in a specific transgenic rat model featuring a centrally inactivated renin-angiotensin-aldosterone system. The ACTH independency of the enhanced corticosterone release during CRH test and the enhanced corticosterone response to ACTH rather indicates an adrenal mechanism. The upregulation of adrenal MC2 and AT(2) receptors seems to be involved in the stimulated facilitation of adrenal corticosterone release for effectuating the stimulated stress responses.
血管紧张素受体阻滞剂（AT1 阻滞剂）可降低血压，独立于其降低血压的效力，减轻下丘脑-垂体-肾上腺（HPA）轴的反应性。有人认为，CRH 对垂体的敏感性降低和下丘脑 CRH 表达下调会影响慢性 AT1 阻断期间的 HPA 轴活性。本研究旨在通过使用低脑血管紧张素原水平的转基因大鼠 TGR(ASrAOGEN)来确认中枢血管紧张素 II 在调节 HPA 反应性中的作用。进行了不同的应激测试以确定 TGR(ASrAOGEN)和适当对照中的 HPA 反应性。与对照组相比，TGR(ASrAOGEN)的血压降低。CRH 或 ACTH 挑战和强迫游泳试验引起的皮质酮反应在 TGR(ASrAOGEN)中比在对照组中更为明显，并且独立于 ACTH 的同时增强而发生。使用定量实时 PCR，我们发现 TGR(ASrAOGEN)肾上腺中的黑素皮质素 2 (Mc2r)和 AT2 受体 (Agtr2)的 mRNA 水平增加，而下丘脑和垂体中的 Crh、Pomc 和 AT1 受体 (Agtr1)的 mRNA 水平保持不变。由于 TGR(ASrAOGEN)中的应激反应增加而不是减弱，我们得出结论，在具有中枢失活肾素-血管紧张素-醛固酮系统的特定转基因大鼠模型中，无法模拟 AT1 阻断期间降低的 HPA 反应性。CRH 测试期间增强的皮质酮释放和 ACTH 增强的皮质酮反应中的 ACTH 独立性，而不是表明肾上腺机制。肾上腺 MC2 和 AT2 受体的上调似乎参与了刺激肾上腺皮质酮释放的促进作用，以实现刺激的应激反应。
