Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress

Abstract

Exogenous glucocorticoids act within the hindbrain to enhance the arterial pressure response to acute novel stress. Here we tested the hypothesis that endogenous glucocorticoids act at hindbrain glucocorticoid receptors (GR) to augment cardiovascular responses to restraint stress in a model of stress hyperreactivity, the borderline hypertensive rat (BHR). A 3- to 4-mg pellet of the GR antagonist mifepristone (Mif) was implanted over the dorsal hindbrain (DHB) in Wistar-Kyoto (WKY) and BHRs. Control pellets consisted of either sham DHB or subcutaneous Mif pellets. Rats were either subjected to repeated restraint stress (chronic stress) or only handled (acute stress) for 3-4 wk, then all rats were stressed on the final day of the experiment. BHR showed limited adaptation of the arterial pressure response to restraint, and DHB Mif significantly (P </= 0.05) attenuated the arterial pressure response to restraint in both acutely and chronically stressed BHR. In contrast, WKY exhibited a substantial adaptation of the pressure response to repeated restraint that was significantly reversed by DHB Mif. DHB Mif and chronic stress each significantly increased baseline plasma corticosterone concentration and adrenal weight and reduced the corticosterone response to stress in all rats. We conclude that endogenous corticosterone acts via hindbrain GR to enhance the arterial pressure response to stress in BHR, but to promote the adaptation of the arterial pressure response to stress in normotensive rats. Endogenous corticosterone also acts in the hindbrain to restrain corticosterone at rest but to maintain the corticosterone response to stress in both BHR and WKY rats.

Fig. 1.

Immunohistochemical localization of occupied glucocorticoid receptors (GR). Rats were treated with dorsal hindbrain (DHB) sham (row A) or DHB mifepristone (Mif) (row B) pellets for a total of 6 wk and were adrenalectomized at least 72 h prior to collection of the brains. Each row contains data from a single animal. The rat in row C was adrenal-intact and subjected to restraint stress for 60 min just prior to collection of the brain. Immunohistochemistry was performed using an antibody that has higher affinity for the occupied, compared with the unoccupied, GR. Scale bars are all equal to 100 μm. NTS, nucleus of the solitary tract; RVLM, rostral ventrolateral medulla.

Fig. 2.

Changes in mean arterial pressure (left) and heart rate (right) in response to 60 min of restraint stress in borderline hypertensive rats (BHR) (top) and Wistar-Kyoto (WKY) rats (bottom). Control rats, treated with either a DHB sham pellet or subcutaneous Mif pellet, are shown in solid lines and symbols. DHB Mif-treated rats are shown in dashed lines and open symbols. Chronically stressed rats (circles) were exposed to repeated restraint, while acutely stressed rats (squares) were restrained only on the final day of the experiment. Restraint stress produced a rapid, significant increase in mean arterial pressure and heart rate in all groups of rats (for clarity this statistical significance is not noted in the figure). ^sP ≤ 0.05 for main effect of chronic compared with acute stress; ^mP ≤ 0.05 for main effect for control compared with DHB Mif treatment; ^m(cs)P ≤ 0.05 for significant effect of DHB Mif only in the chronically stressed rats. Baseline values and number of rats per group are in Table 1.

Fig. 3.

Baseline plasma corticosterone (left) and change in plasma corticosterone (right) at 10 and 60 min of restraint stress in BHR (top) and WKY rats (bottom). Control rats were treated with either a DHB sham pellet or subcutaneous Mif pellet. Chronically stressed rats were exposed to repeated restraint, while acutely stressed rats were restrained only on the final day of the experiment. ^sP ≤ 0.05 for main effect of chronic compared with acute stress; ^mP ≤ 0.05 for main effect for control compared with DHB Mif treatment; *P ≤ 0.05 for a difference between BHR and WKY rats (i.e., effect of strain). The number of animals per group is as follows: acute stress control WKY = 11, BHR = 15; acute stress Mif WKY = 7, BHR = 9; chronic stress control WKY = 16, BHR = 17; chronic stress Mif WKY = 7, BHR = 7.

Fig. 4.

Baseline blood glucose (left) and change in blood glucose (right) at 10 and 60 min of restraint stress in BHR (top) and WKY rats (bottom). Control rats were treated with either a DHB sham pellet or subcutaneous Mif pellet. Chronically stressed rats were exposed to repeated restraint, while acutely stressed rats were restrained only on the final day of the experiment. ^sP ≤ 0.05 for main effect of chronic compared with acute stress; *P ≤ 0.05 for a difference between BHR and WKY rats (i.e., effect of strain). The number of rats per group are the same as for arterial pressure (Table 1).

Fig. 5.

Change in body weight from the first day of stress (left) and adrenal weight (right) for BHR (top) and WKY rats (bottom). Control rats, treated with either a DHB sham pellet or subcutaneous Mif pellet, are shown in solid lines and symbols or solid black bars. DHB Mif-treated rats are shown in dashed lines and open symbols or striped bars. Chronically stressed rats were exposed to repeated restraint, while acutely stressed rats were restrained only on the final day of the experiment. ^sP ≤ 0.05 for main effect of chronic compared with acute stress; ^mP ≤ 0.05 for main effect for control compared with DHB Mif treatment; *P ≤ 0.05 for a difference between BHR and WKY rats (i.e., effect of strain). The number of animals per group is as follows: acute stress control: WKY = 12, BHR = 16; acute stress Mif: WKY = 7, BHR = 10; chronic stress control: WKY = 18, BHR = 20; chronic stress Mif: WKY = 9/8 (body wt/adrenal wt), BHR = 10/9 (body wt/adrenal wt).