are present at a high density in the nucleus of the solitary tract (NTS), an area of the dorsal hindbrain (DHB) that is critical for blood pressure regulation. However, whether these receptors play any role in the regulation of blood pressure is unknown. We tested the hypothesis that glucocorticoids act in the DHB to increase arterial pressure using two experimental strategies. In one approach, we implanted pellets of corticosterone (Cort) or sham pellets onto the DHB over the NTS. Compared with rats with sham pellets, rats with DHB Cort pellets had an increased (P Ͻ 0.05) mean arterial pressure (111 Ϯ 2 vs. 104 Ϯ 1 mmHg) and heart rate (355 Ϯ 9 vs. 326 Ϯ 5 beats/min) after 4 days. In the second approach, we implanted subcutaneous Cort pellets to increase the systemic Cort concentration and then subsequently implanted pellets of the GR antagonist mifepristone (Mif; previously RU-38486) or sham pellets onto the DHB. Two days of DHB Mif treatment reduced (P Ͻ 0.05) mean arterial pressure in those rats with elevated plasma Cort levels (118 Ϯ 2 vs. 108 Ϯ 1 mmHg for sham vs. Mif DHB pellets). Cort and Mif pellets placed on the dura had no effects on arterial pressure or heart rate, ruling out systemic cardiovascular effects of the steroids. DHB Cort treatment had no effects on plasma Cort concentration or adrenal weight, indicating that the contents of the DHB Cort pellet did not diffuse into the systemic circulation or into the forebrain areas that regulate plasma Cort concentration in concentrations sufficient to produce physiological effects. Immunohistochemistry for the occupied GRs demonstrated that the Cort and Mif from the DHB pellets were delivered to the DHB with minimal diffusion to the ventral hindbrain or forebrain. We conclude that glucocorticoids act in the DHB to increase arterial pressure.corticosterone; nucleus of the solitary tract; brain; hypertension GLUCOCORTICOIDS ARE IMPORTANT for the maintenance of normal baseline arterial pressure in both rats and humans. Adrenal insufficiency or blockade of type II glucocorticoid receptors (GRs) can lower blood pressure (18,22,61). The effects of adrenalectomy to lower blood pressure can be reversed by glucocorticoid, but not mineralocorticoid, replacement (61). It is also established that elevated glucocorticoids produce doserelated increases in arterial pressure, and sufficiently high levels of glucocorticoids, due to either exogenous administration or endogenous overproduction, cause hypertension in both experimental animals and humans (22,43,44,54). Long-term administration of glucocorticoids, commonly prescribed because of their anti-inflammatory and immunosupressive therapeutic effects, results in a 20% incidence of iatrogenic hypertension (23). There is also increasing evidence that prolonged mild elevations in glucocorticoids or increased sensitivity to the actions of glucocorticoids promote the development and maintenance of essential hypertension. Several studies have reported elevations in plasma and/or urinary glucocorticoids in essential hyperte...

The effect of glucocorticoids on arterial baroreceptor reflex control of heart rate (HR) was determined in conscious rats. Corticosterone (Cort) treatment for 4-6 days doubled plasma Cort in Cort-treated relative to control rats. Cort had no significant effect on mean arterial pressure (MAP) or HR. Ramped changes in MAP were produced using infusions of phenylephrine and nitroprusside. Baroreflex control of HR was analyzed using a four-parameter logistic function. The midpoint of the baseline baroreflex function curve was significantly increased in Cort-treated (n = 14) relative to control (n = 14) rats (112 +/- 2 vs. 98 +/- 2 mmHg, n = 14), and the slope was significantly decreased (0.065 +/- 0.002 vs. 0.091 +/- 0.007). Three hours after the glucocorticoid type II receptor antagonist mifepristone (Mif) was administered to Cort-treated rats (n = 8), the midpoint of the baroreflex function was significantly reduced from 113 +/- 4 to 99 +/- 2 mmHg, and the slope was significantly increased from 0.061 +/- 0.004 to 0.083 +/- 0.005. Mif decreased HR in Cort-treated rats from 355 +/- 17 to 330 +/- 14 beats/min (P = 0.04) but did not alter MAP (111 +/- 2 to 107 +/- 3 mmHg, P = 0.14). Mif had no significant effects on baroreflex function in control rats. Therefore, a moderate elevation in Cort for several days causes pressure-independent modulation of baroreflex control of HR.

A single bout of mild to moderate exercise can lead to a postexercise decrease in blood pressure in hypertensive subjects, namely postexercise hypotension (PEH). The full expression of PEH requires a functioning baroreflex, hypertension, and activation of muscle afferents (exercise), suggesting that interactions in the neural networks regulating exercise and blood pressure result in this fall in blood pressure. The nucleus tractus solitarii (NTS) is the first brain site that receives inputs from nerves carrying blood pressure and muscle activity information, making it an ideal site for integrating cardiovascular responses to exercise. During exercise, muscle afferents excite NTS GABA neurons via substance P and microinjection of a substance P-neurokinin 1 receptor (NK1-R) antagonist into the NTS attenuates PEH. The data suggest that an interaction between the substance P NK1-R and GABAergic transmission in the NTS may contribute to PEH. We performed voltage clamping on NTS baroreceptor second-order neurons in spontaneously hypertensive rats (SHRs). All animals were killed within 30 min and the patch-clamp recordings were performed 2-8 h after the sham/exercise protocol. The data showed that a single bout of exercise reduces (1) the frequency but not the amplitude of GABA spontaneous IPSCs (sIPSCs), (2) endogenous substance P influence on sIPSC frequency, and (3) sIPSC frequency response to exogenous application of substance P. Furthermore, immunofluorescence labeling in NTS show an increased substance P NK1-R internalization on GABA neurons. The data suggest that exercise-induced NK1-R internalization results in a reduced intrinsic inhibitory input to the neurons in the baroreflex pathway.

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...

Bechtold, Andrea G., and Deborah A. Scheuer. Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate. Am J Physiol Regul Integr Comp Physiol 290: R1003-R1011, 2006. First published November 3, 2005 doi:10.1152/ajpregu.00345.2005.-Systemic corticosterone (Cort) modulates arterial baroreflex control of both heart rate and renal sympathetic nerve activity. Because baroreceptor afferents terminate in the dorsal hindbrain (DHB), an area with dense corticosteroid receptor expression, we tested the hypothesis that prolonged activation of DHB Cort receptors increases the midpoint and reduces the gain of arterial baroreflex control of heart rate in conscious rats. Small (3-4 mg) pellets of Cort (DHB Cort) or Silastic (DHB Sham) were placed on the surface of the DHB, or Cort was administered systemically by placing a Cort pellet on the surface of the dura (Dura Cort). Baroreflex control of heart rate was determined in conscious male Sprague Dawley rats on each of 4 days after initiation of treatment. Plots of arterial pressure vs. heart rate were analyzed using a four-parameter logistic function. After 3 days of treatment, the arterial pressure midpoint for baroreflex control of heart rate was increased in DHB Cort rats (123 Ϯ 2 mmHg) relative to both DHB Sham (108 Ϯ 3 mmHg) and Dura Cort rats (109 Ϯ 2 mmHg, P Ͻ 0.05). On day 4, baseline arterial pressure was greater in DHB Cort (112 Ϯ 2 mmHg) compared with DHB Sham (105 Ϯ 2 mmHg) and Dura Cort animals (106 Ϯ 2 mmHg, P Ͻ 0.05), and the arterial pressure midpoint was significantly greater than mean arterial pressure in the DHB Cort group only. Also on day 4, maximum baroreflex gain was reduced in DHB Cort (2.72 Ϯ 0.12 beats ⅐ min Ϫ1 ⅐ mmHg Ϫ1 ) relative to DHB Sham and Dura Cort rats (3.51 Ϯ 0.28 and 3.37 Ϯ 0.27 beats ⅐ min Ϫ1 ⅐ mmHg Ϫ1 , P Ͻ 0.05). We conclude that Cort acts in the DHB to increase the midpoint and reduce the gain of the heart rate baroreflex function. corticosterone; nucleus of the solitary tract; glucocorticoid receptors; brain; stress ELEVATED GLUCOCORTICOIDS INCREASE the risk for cardiovascular disease (13,20,46,58,59). Accumulating evidence further indicates that altered glucocorticoid activity or sensitivity, even in the absence of elevated plasma glucocorticoid levels, may play a role in the etiology of human essential hypertension, a primary risk factor for cardiovascular disease (27,47,56,57). Altered glucocorticoid activity has also been implicated in the pathogenesis of metabolic syndrome, a condition whose symptoms include obesity, elevated blood pressure, and insulin resistance or diabetes (55). Genetic factors appear to increase sensitivity to the adverse cardiovascular effects of glucocorticoids, since several recently identified polymorphisms of the human glucocorticoid receptor (GR) gene have been linked to hypertension and cardiovascular disease (25,26,34,35). Complementing the data from humans, a glucocorticoid-dependent mechanism of hypertension has been demonstrated in several rat strains, including s...