Hypertension affects approximately 50 million Americans and progression of this disease significantly increases risk for cardiovascular disease. Recent clinical studies demonstrate that hypertension also is associated with mental health disorders. Specifically, hypertension increases the risk of anxiety disorders, and inversely, anxiety disorders predict the risk and severity of hypertension and cardiovascuiar disease. While the onset of hypertension is attributed to over activity ofthe renin-angiotensin-system (RAS), the development of anxiety is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The effector peptide ofthe RAS, angiotensin II (ANGII), exerts the majority of its biological effects via activation of angiotensin type 1 receptors (AT1R). Interestingly, AT1R are expressed throughout the HPA axis and emerging evidence has implicated ANGII as an important mediator of the stress response. Chronic exposure to stress up-regulates the HPA axis and RAS, thereby negatively affecting cardiovascular and mental health. Given that chronic stress similarly up-regulates the HPA axis and the RAS, it is likely that an Interaction between these systems underlies the effects that chronic stress has on mental health and cardiovascular function. Because repeated stress increases AT1R expression in the brain, it is likely that chronic stress potentiates the influence of ANGII on the HPA axis, thereby inducing cardiovascular and affective disorders. Collectively, these studies suggest that therapies targeting the RAS may influence the onset of brain-basied disorders like anxiety, and therefore, it is important to understand the central angiotensinergic pathways that influence responses to stress. Accordingly, the proposed experiments will to inhibit ATI R in the brains of laboratory rats and mice to detemriine the contribution of these receptors to the cardiovascular, HPA and behavioral responses to chronic exposure to stress. These studies are designed to test the overall hypothesis that inhibition of AT1R in the brain will limit stress responding and alleviate the deleterious consequences of stress related illnesses.

Public Health Relevance

Hypertension increases the risk for cardiovascular disease, the leading cause of death in the United States. Increasing evidence indicates that hypertension is also linked to mental health diseases, namely anxiety disorder. The proposed research examines biological systems that interact to induce hypertension and anxiety. This is relevant because developing a clear understanding of this interaction will provide a novel direction for therapeutic strategies to treat or prevent hypertension and anxiety disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL096830-05
Application #
8511788
Study Section
Special Emphasis Panel (NSS)
Program Officer
Maric-Bilkan, Christine
Project Start
2011-09-09
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$231,852
Indirect Cost
$73,591
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Smith, Justin A; Wang, Lei; Hiller, Helmut et al. (2014) Acute hypernatremia promotes anxiolysis and attenuates stress-induced activation of the hypothalamic-pituitary-adrenal axis in male mice. Physiol Behav 136:91-6
de Kloet, Annette D; Pati, Dipanwita; Wang, Lei et al. (2013) Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity. J Neurosci 33:4825-33
Krause, Eric G; de Kloet, Annette D; Scott, Karen A et al. (2011) Blood-borne angiotensin II acts in the brain to influence behavioral and endocrine responses to psychogenic stress. J Neurosci 31:15009-15