Heart Center, The First Hospital of Hebei Medical University, Hebei Medical University, Shijiazhuang, People's Republic of China.
PLoS One. 2010 Dec 20;5(12):e15607. doi: 10.1371/journal.pone.0015607.
Atrial natriuretic peptide (ANP) provides a potent defense mechanism against volume overload in mammals. Its primary receptor, natriuretic peptide receptor-A (NPR-A), is localized mostly in the kidney, but also is found in hypothalamic areas involved in body fluid volume regulation. Acute glucocorticoid administration produces potent diuresis and natriuresis, possibly by acting in the renal natriuretic peptide system. However, chronic glucocorticoid administration attenuates renal water and sodium excretion. The precise mechanism underlying this paradoxical phenomenon is unclear. We assume that chronic glucocorticoid administration may activate natriuretic peptide system in hypothalamus, and cause volume depletion by inhibiting dehydration-induced water intake. Volume depletion, in turn, compromises renal water excretion. To test this postulation, we determined the effect of dexamethasone on dehydration-induced water intake and assessed the expression of NPR-A in the hypothalamus. The rats were deprived of water for 24 hours to have dehydrated status. Prior to free access to water, the water-deprived rats were pretreated with dexamethasone or vehicle. Urinary volume and water intake were monitored. We found that dexamethasone pretreatment not only produced potent diuresis, but dramatically inhibited the dehydration-induced water intake. Western blotting analysis showed the expression of NPR-A in the hypothalamus was dramatically upregulated by dexamethasone. Consequently, cyclic guanosine monophosphate (the second messenger for the ANP) content in the hypothalamus was remarkably increased. The inhibitory effect of dexamethasone on water intake presented in a time- and dose-dependent manner, which emerged at least after 18-hour dexamethasone pretreatment. This effect was glucocorticoid receptor (GR) mediated and was abolished by GR antagonist RU486. These results indicated a possible physiologic role for glucocorticoids in the hypothalamic control of water intake and revealed that the glucocorticoids can act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume.
心房利钠肽 (ANP) 为哺乳动物提供了一种针对容量超负荷的有效防御机制。其主要受体，利钠肽受体-A (NPR-A)，主要定位于肾脏，但也存在于参与体液容量调节的下丘脑区域。急性糖皮质激素给药会产生强大的利尿和利钠作用，可能通过作用于肾利钠肽系统。然而，慢性糖皮质激素给药会减弱肾脏对水和钠的排泄。这种矛盾现象的确切机制尚不清楚。我们假设慢性糖皮质激素给药可能会激活下丘脑的利钠肽系统，并通过抑制脱水引起的饮水来导致容量耗竭。容量耗竭反过来又会损害肾脏的水排泄。为了验证这一假设，我们测定了地塞米松对脱水诱导的饮水的影响，并评估了 NPR-A 在下丘脑的表达。大鼠被剥夺水 24 小时以达到脱水状态。在自由饮水之前，水剥夺大鼠用地塞米松或载体预处理。监测尿量和饮水量。我们发现地塞米松预处理不仅产生了强大的利尿作用，而且还显著抑制了脱水引起的饮水。Western blot 分析显示，地塞米松显著上调了下丘脑 NPR-A 的表达。因此，下丘脑中环磷酸鸟苷 (ANP 的第二信使) 的含量显著增加。地塞米松对饮水的抑制作用呈时间和剂量依赖性，至少在 18 小时的地塞米松预处理后才出现。这种作用是糖皮质激素受体 (GR) 介导的，被 GR 拮抗剂 RU486 所阻断。这些结果表明糖皮质激素在调节下丘脑对水的摄入方面可能具有生理作用，并表明糖皮质激素可以通过中枢和外周作用来协助维持细胞外液容量的正常化。
