Genomes and Genes
Glucocorticoids, Stress and Blood Pressure Regulation
Principal Investigator: Deborah A Scheuer
Abstract: DESCRIPTION (provided by applicant): Prolonged elevations of glucocorticoids cause cardiovascular disease by generating risk factors including hypertension, abdominal obesity, hyperglycemia, insulin resistance, elevated triglycerides and cardiac arrhythmia. Stress is a common cause of moderately elevated glucocorticoids, and stress is also a risk factor for hypertension, obesity and cardiovascular disease. Despite the strong relationship between glucocorticoids, stress and cardiovascular disease, the precise mechanisms linking increased glucocorticoid activity and cardiovascular disease have not been elucidated. Our long-term goal is to identify the central neural pathways and mechanisms by which glucocorticoids and stress modulate central nervous system control of cardiovascular function in order to discover potential new opportunities for clinical intervention. Based on published data and our preliminary results, we have formulated the hypothesis that the naturally occurring glucocorticoid corticosterone (Cort) acts via both mineralocorticoid (MR) and glucocorticoid (GR) receptors to modulate stress responsiveness and baroreflex function by diminishing inhibitory and/or recruiting excitatory effects of catecholaminergic neurons in the nucleus of the solitary tract (NTS). The NTS is a region in the dorsal hindbrain that is important for blood pressure regulation. Experiments will be performed in male Wistar-Kyoto and Borderline Hypertensive Rats (BHR). We hypothesize that the increased genetic susceptibility to stress-induced hypertension in the BHR is due in part to an increased sensitivity to the adverse effects of Cort. Aims 1 and 2 utilize a validated technique to chronically deliver steroids selectively to the dorsal hindbrain by implantation of small pellets. The pellets will be composed of the following steroids: Cort, Mifepristone (a GR receptor antagonist), eplerenone (an MR receptor antagonist) and/or cholesterol. The secretion of endogenous Cort will be stimulated by stress. Aims 2 and 3 utilize AAV2 viral vector-mediated gene delivery by local microinjection into the NTS. The vectors will mediate expression of either green fluorescent protein or 11ss-hydroxysteroid dehydrogenase 2, which is the enzyme that metabolizes Cort into an inactive steroid. The synthetic dopamine-ss-hydroxylase promoter PRSx8 will be used to drive expression of the transgenes selectively in catecholaminergic neurons. The expression of GFP will be used as a control in Aim 2, and to label NTS catecholaminergic neurons in Aim 3. Microinjection of the viral vector constructs into the NTS will ensure that the transgene expression is regionally specific. Aims 1 and 2 are comprised of physiological experiments that will be performed in conscious rats using radiotelemetry to measure blood pressure. Aim 3 uses anatomical approaches to test the hypothesis that that GR and MR are expressed in discrete sub-populations of NTS catecholaminergic projection neurons that express unique phenotypic markers that differ between BHR and Wistar-Kyoto rats. The results of these experiments will increase our understanding of the mechanisms that link stress and cardiovascular disease.
Funding Period: 2004-03-01 - 2015-06-30
more information: NIH RePORT
- Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rateAndrea G Bechtold
Division of Pharmacology, University of Missouri Kansas City, Kansas City, Missouri 64108, USA
Am J Physiol Regul Integr Comp Physiol 290:R1003-11. 2006..51 +/- 0.28 and 3.37 +/- 0.27 beats x min(-1) x mmHg(-1), P < 0.05). We conclude that Cort acts in the DHB to increase the midpoint and reduce the gain of the heart rate baroreflex function...
- Chronic activation of dorsal hindbrain corticosteroid receptors augments the arterial pressure response to acute stressDeborah A Scheuer
School of Medicine, University of Florida, Gainesville 32610 0274, USA
Hypertension 49:127-33. 2007..We conclude that corticosterone can act selectively in the dorsal hindbrain in rats with normal plasma corticosterone levels to augment the arterial pressure response to restraint stress...
- Genetic predisposition to hypertension sensitizes borderline hypertensive rats to the hypertensive effects of prenatal glucocorticoid exposureAndrea G Bechtold
Department of Medical Pharmacology, University of California, Davis, Davis, CA 95616, USA
J Physiol 586:673-84. 2008..In contrast, prenatal Dex enhanced cardiovascular reactivity to stress in both BHR and WKY rats...
- Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stressAndrea G Bechtold
Department of Medical Pharmacology, School of Medicine, University of California Davis, Davis, California, USA
Am J Physiol Regul Integr Comp Physiol 296:R1445-54. 2009..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...
- Regulation of the stress response in rats by central actions of glucocorticoidsDeborah A Scheuer
University of Florida, 1600 SW Archer Road, Room M552, PO Box 100274, Gainesville, FL 32610 0274, USA
Exp Physiol 95:26-31. 2010..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...
- Nucleus of the solitary tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in ratsDaisy L Daubert
Ferris State University, Department of Biological Sciences, Big Rapids, MI 49307, USA
J Physiol 590:4881-95. 2012..The data suggest that NTS catecholaminergic neurons normally inhibit the arterial pressure response, but help maintain the corticosterone response to restraint stress...
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