Glucocorticoids, Stress and Blood Pressure Regulation

Summary

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

Top Publications

  1. ncbi Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate
    Andrea 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
  2. ncbi Chronic activation of dorsal hindbrain corticosteroid receptors augments the arterial pressure response to acute stress
    Deborah A Scheuer
    School of Medicine, University of Florida, Gainesville 32610 0274, USA
    Hypertension 49:127-33. 2007
  3. pmc Genetic predisposition to hypertension sensitizes borderline hypertensive rats to the hypertensive effects of prenatal glucocorticoid exposure
    Andrea G Bechtold
    Department of Medical Pharmacology, University of California, Davis, Davis, CA 95616, USA
    J Physiol 586:673-84. 2008
  4. pmc Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress
    Andrea 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
  5. ncbi Regulation of the stress response in rats by central actions of glucocorticoids
    Deborah 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
  6. pmc Nucleus of the solitary tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in rats
    Daisy L Daubert
    Ferris State University, Department of Biological Sciences, Big Rapids, MI 49307, USA
    J Physiol 590:4881-95. 2012

Detail Information

Publications6

  1. ncbi Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate
    Andrea 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...
  2. ncbi Chronic activation of dorsal hindbrain corticosteroid receptors augments the arterial pressure response to acute stress
    Deborah 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...
  3. pmc Genetic predisposition to hypertension sensitizes borderline hypertensive rats to the hypertensive effects of prenatal glucocorticoid exposure
    Andrea 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...
  4. pmc Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress
    Andrea 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...
  5. ncbi Regulation of the stress response in rats by central actions of glucocorticoids
    Deborah 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...
  6. pmc Nucleus of the solitary tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in rats
    Daisy 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...

Research Grants30

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  2. Autonomic and Antihypertensive Actions of Neuronal CGRP/RAMP1 Receptors
    Mark W Chapleau; Fiscal Year: 2013
    ..Inhibition of Ang II-mediated effects by activation of CGRP/RAMP1 receptors has widespread implications in hypertension and heart failure. ..
  3. ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
  4. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  5. PPG-Genetic and Signaling Mechanisms in the Central Regulation of Blood Pressure
    CURT DANIEL SIGMUND; Fiscal Year: 2013
    ..The findings will clarify important mechanisms, which may allow translation into improved treatment for cardiovascular and metabolic dysfunction in hypertension and obesity-hypertension. ..
  6. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  7. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  8. Central Endocannabinoid System Dysfunction and Hypertension
    Jeanne L Seagard; Fiscal Year: 2013
    ....
  9. Understanding Pain of Gastrointestinal Origin in Women that Serve in OEF/OIF
    Beverley Greenwood-Van Meerveld; Fiscal Year: 2013
    ..Moreover, we will examine whether rats exposed to ELS show altered behavioral responses to chronic stress in adulthood compared to age-matched controls ..
  10. HEALTHY AGING AND SENILE DEMENTIA
    John Morris; Fiscal Year: 2013
    ..Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease. ..
  11. Mechanims of CNS Autonomic Regulation by EA
    John C Longhurst; Fiscal Year: 2013
    ..The current application will provide important new information on both efficacy and mechanism of action in acupuncture treatment of either elevated or low blood pressure. ..
  12. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  13. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  14. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  15. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
  16. Cardiovascular disease, depression, and oxytocin
    MELISSA SCOTTI; Fiscal Year: 2013
    ..abstract_text> ..
  17. Genes, environmental stressors, and the biobehavioral pathways to CVD
    Redford B Williams; Fiscal Year: 2013
    ..End of Abstract) ..
  18. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..