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. ? ?
