Spencer R L, Kim P J, Kalman B A, Cole M A
Department of Psychology, University of Colorado, Boulder 80309, USA.
Endocrinology. 1998 Jun;139(6):2718-26. doi: 10.1210/endo.139.6.6029.
These studies further evaluated the relative role of mineralocorticoid (type I) and glucocorticoid (type II) receptors in mediating corticosteroid feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Acute treatment of rats with the selective mineralocorticoid receptor antagonist, RU28318 (50 mg/kg sc), produced elevated basal corticosterone levels in the morning, but had no effect on basal corticosterone levels in the evening or on restraint stress corticosterone levels at either time of day. Acute treatment with the selective glucocorticoid receptor antagonist, RU40555 (30 mg/kg sc) had no effect on basal or restraint stress corticosterone levels at either time of day. However, combined treatment with RU28318 and RU40555 produced an elevation of evening basal corticosterone levels (and morning basal on one occasion) and produced an increase in corticosterone levels during and after stress at both times of day. In a separate experiment conducted in the morning, the combined RU28318 and RU40555 treatment also produced elevated ACTH responses during restraint stress. Based on available corticosteroid receptor measures, the RU28318 treatment was estimated to selectively occupy approximately 85% of mineralocorticoid receptors in rat brain, whereas the RU40555 treatment was estimated to selectively occupy approximately 50% of glucocorticoid receptors in rat brain. We conclude that mineralocorticoid receptor activation is necessary and sufficient to maintain low basal corticosterone levels during the circadian trough, whereas glucocorticoid receptor activation is necessary to constrain corticosterone secretion during the circadian peak or during acute stress. However, even during the circadian peak or acute stress, mineralocorticoid receptor activation plays an important role in facilitating the glucocorticoid receptor dependent regulation of HPA axis activity by corticosterone.
这些研究进一步评估了盐皮质激素（I型）和糖皮质激素（II型）受体在介导下丘脑-垂体-肾上腺（HPA）轴的皮质类固醇反馈调节中的相对作用。用选择性盐皮质激素受体拮抗剂RU28318（50mg/kg，皮下注射）对大鼠进行急性处理，导致早晨基础皮质酮水平升高，但对晚上的基础皮质酮水平或一天中任何时间的束缚应激皮质酮水平均无影响。用选择性糖皮质激素受体拮抗剂RU40555（30mg/kg，皮下注射）进行急性处理，对一天中任何时间的基础或束缚应激皮质酮水平均无影响。然而，RU28318和RU40555联合处理导致晚上基础皮质酮水平升高（有一次早晨基础水平也升高），并使一天中两个时间段应激期间及应激后的皮质酮水平增加。在早晨进行的另一项实验中，RU28318和RU40555联合处理还导致束缚应激期间促肾上腺皮质激素（ACTH）反应升高。根据现有的皮质类固醇受体测量结果，估计RU28318处理可选择性占据大鼠脑中约85%的盐皮质激素受体，而RU40555处理可选择性占据大鼠脑中约50%的糖皮质激素受体。我们得出结论，盐皮质激素受体激活对于在昼夜低谷期间维持低基础皮质酮水平是必要且充分的，而糖皮质激素受体激活对于在昼夜高峰期间或急性应激期间抑制皮质酮分泌是必要的。然而，即使在昼夜高峰或急性应激期间，盐皮质激素受体激活在促进皮质酮对HPA轴活性的糖皮质激素受体依赖性调节中也起着重要作用。
