Regulation of the stress response in rats by central actions of glucocorticoids

Abstract

Chronic stress causes elevations in glucocorticoid secretion and also increases the incidence of hypertension and other manifestations of cardiovascular disease. The extent to which the elevated glucocorticoids mediate the stress-associated increase in cardiovascular disease risk is unknown. Chronically elevated glucocorticoids can cause hypertension by acting in the periphery, but their effects within the brain on blood pressure regulation remain largely unexplored. We developed a method to produce selective chronic increases in the endogenous glucocorticoid corticosterone or the glucocorticoid receptor antagonist mifepristone within the hindbrain region, which includes a key cardiovascular regulatory area, the nucleus of the solitary tract (NTS). Experiments were performed in male Sprague-Dawley, Wistar-Kyoto (WKY) and borderline hypertensive rats (BHR). The results indicate that elevated exogenous corticosterone can act within the hindbrain to enhance the arterial pressure response to novel restraint stress and to reduce the gain and increase the mid-point of the arterial baroreflex. Basal levels of endogenous corticosterone have no effect on the arterial pressure response to stress in normotensive rats but enhance this response in BHR. Chronic stress-induced increases in baseline corticosterone enhance the arterial pressure response to stress in BHR but attenuate the adaptation of the response in WKY rats. Furthermore, an elevated corticosterone concentration within the hindbrain is necessary but not sufficient to cause glucocorticoid-induced hypertension. The effects of corticosterone within the hindbrain on blood pressure regulation are mediated in part by the glucocortiocid receptor, but are also likely to involve mineralocorticoid receptor-mediated effects and NTS catecholaminergic neurons. These data support the hypothesis that elevated glucocorticoids acting within the brain probably contribute to the adverse effects of stress on cardiovascular health in susceptible people.

Figure 1. Tissue corticosterone (Cort) concentrations in the dorsal hindbrain (DHB; A), ventral hindbrain (B) and cortex (C) and plasma Cort concentration (D) in rats treated for 6 days with DHB sham, 10, 50 or 100% Cort pellets, sham or 100% Cort subcutaneous (s.c.) pellets or subjected to restraint stress just prior to killing (acute stress)

Values for the DHB for the 50 and 100% DHB Cort treatment groups were above the high standard in the assay and are not shown. *P < 0.05 compared with the DHB Sham group. +P < 0.05 compared with acute stress.

Figure 2. Hypothesis Model

The diagram illustrates the overall hypothesis that glucocorticoids released during chronic stress act on glucocorticoid receptors (GR) and possibly mineralocorticoid receptors (MR) within the hindbrain to modulate neuronal output of the nucleus of the solitary tract (NTS). The altered NTS neuronal output in turn modulates the activity of other central nervous system (CNS) nuclei that control neuronal and hormonal mediators of cardiovascular function, resulting in an overall increased incidence of hypertension, cardiac arrhythmia and other manifestations of cardiovascular disease in susceptible individuals. (DβH, dopamine-β-hydroxylase.)