Aguilera G, Kiss A, Luo X
Section on Endocrine Physiology, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
J Neuroendocrinol. 1995 Oct;7(10):775-83. doi: 10.1111/j.1365-2826.1995.tb00714.x.
Double staining in situ hybridization studies have shown that angiotensin II (AII) type 1 receptors (AT1) in the hypothalamic paraventricular nucleus (PVN) are located primarily in corticotropin releasing hormone (CRH) neurons of the parvicellular subdivision. The purpose of these studies was to investigate the role of AII regulating the hypothalamic-pituitary adrenal (HPA) axis, by correlating AT1 receptor expression levels in the PVN with the known changes in activity of the HPA axis under different stress paradigms, and manipulation of circulating glucocorticoids. AT1 receptor mRNA was measured by in situ hybridization using 35S-labelled cRNA probes and AII binding by autoradiography using 125I[Sar1,Ile8]AII in slide mounted hypothalamic sections. AT1 receptor mRNA levels and AII binding in the PVN were reduced by about 20% 18 h after adrenalectomy remaining at these levels up to 6 days after. This effect was prevented by corticosterone administration in the drinking water, or dexamethasone injection (100 mg, s.c., daily). Conversely, dexamethasone injection in intact rats caused a 20% increase in AT1 receptor mRNA in the PVN. AT1 receptor mRNA and binding in the PVN increased 4 h after exposure to stress paradigms associated with activation of the HPA axis (immobilization for 1 h, or i.p. injection of 1.5 M NaCl), and remained elevated after repeated daily stress for 14 days. Unexpectedly, two osmotic stress models associated with inhibition of the HPA axis (60 h water deprivation or 12 days of 2% saline intake) also resulted in increased AT1 receptor mRNA levels and AII binding in the parvicellular PVN. In intact rats, the stimulatory effect of acute stress on AT1 receptor mRNA in the PVN was significantly enhanced by dexamethasone administration (100 micrograms, s.c., 14 h and 1 h prior to stress), while in adrenalectomized rats, with or without glucocorticoid replacement, stress reduced rather than increased, AT1 receptor mRNA. Dexamethasone, 100 micrograms, injected sc within 1 min the beginning of immobilization in adrenalectomized rats, increased AT1 receptor mRNA in the PVN to levels significantly higher than those after dexamethasone alone, indicating that the stress induced glucocorticoid surge is required for the stimulatory effect of stress on AT1 receptor mRNA. The data suggest that AT1 receptor expression in the PVN is under dual control during stress: stress-activated inhibitory pathways and the stimulatory effect of glucocorticoids. The lack of specificity of the changes in AT1 receptor expression in the PVN following stressors with opposite effects on ACTH secretion (osmotic and physical-psychological stress) does not support a role for AII as a major determinant of the response of the HPA axis during stress.
双重原位杂交研究表明，下丘脑室旁核（PVN）中的血管紧张素II（AII）1型受体（AT1）主要位于小细胞亚群的促肾上腺皮质激素释放激素（CRH）神经元中。这些研究的目的是通过将PVN中AT1受体的表达水平与不同应激模式下HPA轴活性的已知变化以及循环糖皮质激素的调控相关联，来研究AII对下丘脑-垂体-肾上腺（HPA）轴的调节作用。使用35S标记的cRNA探针通过原位杂交测量AT1受体mRNA，并使用125I[Sar1，Ile8]AII通过放射自显影在载玻片上的下丘脑切片中检测AII结合。肾上腺切除术后18小时，PVN中的AT1受体mRNA水平和AII结合减少约20%，并在术后6天内维持在这些水平。通过在饮用水中给予皮质酮或注射地塞米松（100 mg，皮下注射，每日）可预防这种效应。相反，在完整大鼠中注射地塞米松会使PVN中的AT1受体mRNA增加20%。在暴露于与HPA轴激活相关的应激模式（固定1小时或腹腔注射1.5 M NaCl）后4小时，PVN中的AT1受体mRNA和结合增加，并在每天重复应激14天后保持升高。出乎意料的是，与HPA轴抑制相关的两种渗透应激模型（60小时水剥夺或2%盐水摄入12天）也导致小细胞PVN中AT1受体mRNA水平和AII结合增加。在完整大鼠中，地塞米松给药（100微克，皮下注射，在应激前14小时和1小时）显著增强了急性应激对PVN中AT1受体mRNA的刺激作用，而在肾上腺切除的大鼠中，无论是否进行糖皮质激素替代，应激都会降低而不是增加AT1受体mRNA。在肾上腺切除的大鼠中，在固定开始后1分钟内皮下注射100微克地塞米松，可使PVN中的AT1受体mRNA增加到显著高于单独使用地塞米松后的水平，表明应激诱导的糖皮质激素激增是应激对AT1受体mRNA刺激作用所必需的。数据表明，应激期间PVN中AT1受体的表达受双重控制：应激激活的抑制途径和糖皮质激素的刺激作用。对应激分泌ACTH有相反作用的应激源（渗透和身心应激）后PVN中AT1受体表达变化缺乏特异性，不支持AII作为应激期间HPA轴反应的主要决定因素的作用。
