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 WistarKyoto (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 Յ 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. corticosterone; brain; nucleus of the solitary tract; hypothalamicpituitary-adrenal axis; chronic stress EXAGGERATED CARDIOVASCULAR responses to acute stress and chronic stress increase the risk for hypertension and cardiovascular disease (1,3,13,15,31,38,42,58,68). Acute stress rapidly increases blood pressure, heart rate, plasma glucocorticoid concentration, and blood glucose levels (8), while chronic or repeated stress is associated with increases in baseline blood pressure and glucocorticoids (17). Chronically elevated glucocorticoids increase morbidity and mortality from cardiovascular disease and alterations in the glucocorticoid receptor (GR), and in glucocorticoid metabolizing enzymes are associated with hypertension and cardiovascular disease in humans (28,30,35,36,39,48,49,61, 65,67,70,71). Thus, chronic stress-induced elevations in glucocorticoids likely contribute to the adverse effects of stress on cardiovascular health.The mechanisms by which glucocorticoids modulate cardiovascular stress responses are not fully understood. A review by Sapolsky et al. (52) concluded that glucocorticoids act permissively to enhance the arterial pressure response to many physical stressors, in part by supporting the peripheral effects of catecholamines. Other studies indicate that chronic, systemic elevations in glucocorticoids enhance cardiovascular and catecholamine re...

Endogenous cannabinoid signaling is essential for stress adaptation

“…Consistent with previous reports (4,5,22,23), repeated exposure to restraint stress resulted in an adaptation of the HPA axis that was manifested as a habituation to stress-induced corticosterone secretion, as well as a mild but reliable hypersecretion of basal corticosterone (24,25). Our data demonstrate that AEA and 2-AG are divergently regulated by repeated stress, and independently contribute to distinct forms of HPA axis adaptation.…”

The effect of chronic peripheral nesfatin-1 application on blood pressure in normal and chronic restraint stressed rats: related with circulating level of blood pressure regulators

“…To this point, it has been indicated that chronic stress does not have an effect on BP (Scheuer et al 2007;Bechtold et al 2009;Scheuer 2010) and nesfatin-1 increases BP Samson 2009, 2010;García-Galiano et al 2010). Yosten and his colleagues have showed that intracerebroventricular nesfatin-1 administration increases BP (Yosten and Samson 2009) and this effect of nesfatin-1 occurs via sympathetic system activation (Yosten and Samson 2010).…”

“…Cardiovascular responses occur after acute and chronic stress, which can increase the risk of hypertension and cardiovascular diseases (Bechtold et al 2009). Nesfatin-1 can control appetite in a different pathway than leptin and increases insulin secretion by activation of L-type Ca 2+ channels in pancreatic islet beta cells (Cowley and Grove 2006;Nakata et al 2011).…”

“…It is very well known that stress response correlates with increased basal blood level of mineralocorticoids and glucocorticoids (McEwen 2007;Ulrich-Lai and Herman 2009;Bechtold et al 2009). On the other hand, desensitization to repeated stress exposure has been explained linked with recovery of plasma level of corticosterones and adrenocorticotropic hormone (ACTH).…”

Animal models for the study of arterial hypertension

“…Different types of stress have been applied, such as emotional stimuli, psychosocial stress, immobilization stress, food deprivation and electric stimuli, air jet noise, flashing lights, cold, and interaction of members of a social group as they compete for food and water (Henry 1975;Friedman and Dahl 1975;Papanek et al 1991;Henry et al 1993;Tucker and Hunt 1993;Bechtold et al 2009). …”