Increasing evidence implicates elevated glucocorticoid activity in the pathogenesis of cardiovascular disease, while altered neural control of the circulation has long been identified with cardiovascular disease. Few studies have investigated glucocorticoid-mediated modulation of neural control of the circulation. The long-term goal of this research program is to identify pathways and mechanisms by which glucocorticoids modulate neural control of the circulation. The central hypothesis for the proposed experiments is that prolonged in vivo activation of glucocorticoid receptors in the dorsal hindbrain contributes significantly to effects of glucocorticoids on arterial pressure regulation. To test this hypothesis experiments will be performed in conscious rats with normal or chronically elevated systemic glucocorticoid concentrations, and with the dorsal hindbrain chronically treated with the glucocorticoid corticosterone (cort), or the glucocorticoid type II receptor (GR) antagonist, Mifepristone (Mif).
The Specific Aims are:
Aim 1 : To test the hypothesis that glucocorticoids act within the dorsal hindbrain to reduce the buffering capacity of arterial baroreflex control of renal sympathetic nerve activity and heart rate.
Aim 2 : To test the hypothesis that glucocorticoids act within the dorsal hindbrain to enhance arterial pressure, heart rate and endocrine responses to single and repeated episodes of restraint stress.
Aim 3 : To test the hypothesis subpopulations of the neuronal cells that are activated (detected by c-fos) during increases in blood pressure or restraint stress also express glucocorticoid receptors. Dual label immunohistochemistry will be used to anatomically map subpopulations of dorsal hindbrain neuronal cells that are positive for both c-fos and glucocorticoid receptors following increases in blood pressure or restraint stress. This project is innovative because we have developed a method for prolonged application of glucocorticoid receptor ligands to the dorsal hindbrain that circumvents previous difficulties with delivering these steroids to the central nervous system. The results from these experiments will provide the basis for further studies to identify the specific neurons involved in glucocorticoid-mediated modulation of neural control of blood pressure, providing new opportunities for treatment and prevention of cardiovascular disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076807-06
Application #
7387416
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2004-03-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2010-02-28
Support Year
6
Fiscal Year
2008
Total Cost
$243,090
Indirect Cost
Name
University of Florida
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Erdos, Benedek; Backes, Iara; McCowan, Michael L et al. (2015) Brain-derived neurotrophic factor modulates angiotensin signaling in the hypothalamus to increase blood pressure in rats. Am J Physiol Heart Circ Physiol 308:H612-22
Scheuer, Deborah A (2013) Stimulation of aldosterone synthesis by angiotensin II in the brain: support for positive feedback in hypertension? Hypertension 62:459-60
Daubert, Daisy L; McCowan, Michael; Erdos, Benedek et al. (2012) Nucleus of the solitary tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in rats. J Physiol 590:4881-95
Scheuer, Deborah A (2010) Regulation of the stress response in rats by central actions of glucocorticoids. Exp Physiol 95:26-31
Scheuer, Deborah A (2010) Adrenal corticosteroid effects in the central nervous system on long-term control of blood pressure. Exp Physiol 95:10-2
Bechtold, Andrea G; Patel, Gina; Hochhaus, Guenther et al. (2009) Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress. Am J Physiol Regul Integr Comp Physiol 296:R1445-54
Bechtold, Andrea G; Vernon, Kathy; Hines, Tina et al. (2008) Genetic predisposition to hypertension sensitizes borderline hypertensive rats to the hypertensive effects of prenatal glucocorticoid exposure. J Physiol 586:673-84
Scheuer, Deborah A; Bechtold, Andrea G; Vernon, Kathy A (2007) Chronic activation of dorsal hindbrain corticosteroid receptors augments the arterial pressure response to acute stress. Hypertension 49:127-33
Bechtold, Andrea G; Scheuer, Deborah A (2006) Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate. Am J Physiol Regul Integr Comp Physiol 290:R1003-11