This program project renewal application is an integrated multidisciplinary program including four closely related projects examining the roles of stress, lifestyle behaviors and genetic predisposition in the development of preclinical measures of essential hypertension. New to the renewal application will be the incorporation of adiposity as a mediating factor into our gene/environment interaction model. Four vasoactive pathways will be examined which may link impaired sodium regulation during stress and exaggerated cardiovascular reactivity to stress to the development of preclinical measures of hypertension. These pathways are the sympathetic nervous system, the renin-angiotensin-aldosterone system, the endothelial system, and the hypothalamic-pituitary-adrenal axis. Specifically, Projects 1 and 4 will focus on the role of the renin-angiotensin-aldosterone system in human and animal models of stress-induced salt sensitive hypertension. Projects 2 (human) and 3 (animal) will continue in the evaluation of blood pressure hyper-reactivity. Project 2 will continue to evaluate this model in a cohort of subjects with a family history of hypertension that will have been continuously evaluated for 22 years. Also, new to this application will be evaluation of the hypothalamic-pituitary-adrenal axis. Project 3 will use air jet stress in Dahl salt-sensitive rats to examine acute changes in endothelin and oxidative stress. All four projects will examine a potential mediating role of increased adiposity. In addition, each of these four projects will be supported by an Administrative (Core A), Bioassay (Core B), Biomedical (Core C), and Data Management and Statistics (Core D) cores.

Public Health Relevance

to public health: High blood pressure, or hypertension, remains a significant health problem in industrialized nations. The results of this study will help further define the interactive effects of genetic predisposition and environmental stress in the development of hypertension, particularly in overweight individuals. The pharmacologic and pharmacogenetic interventions will provide evidence for effective management of stress-related hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-PPG-Z (O2))
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Kaufmann, Peter G
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Georgia Regents University
Schools of Medicine
United States
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De Miguel, Carmen; Speed, Joshua S; Kasztan, Malgorzata et al. (2016) Endothelin-1 and the kidney: new perspectives and recent findings. Curr Opin Nephrol Hypertens 25:35-41
Heimlich, J Brett; Speed, Joshua S; O'Connor, Paul M et al. (2016) Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species. Br J Pharmacol 173:386-95
Davenport, Anthony P; Hyndman, Kelly A; Dhaun, Neeraj et al. (2016) Endothelin. Pharmacol Rev 68:357-418
Gohar, Eman Y; Giachini, Fernanda R; Pollock, David M et al. (2016) Role of the endothelin system in sexual dimorphism in cardiovascular and renal diseases. Life Sci 159:20-9
Spradley, Frank T; Ho, Dao H; Pollock, Jennifer S (2016) Dahl SS rats demonstrate enhanced aortic perivascular adipose tissue-mediated buffering of vasoconstriction through activation of NOS in the endothelium. Am J Physiol Regul Integr Comp Physiol 310:R286-96
Guan, Zhengrong; Singletary, Sean T; Cha, Haword et al. (2016) Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats. Am J Physiol Renal Physiol 310:F456-65
Heimlich, J B; Speed, J S; Bloom, C J et al. (2015) ET-1 increases reactive oxygen species following hypoxia and high-salt diet in the mouse glomerulus. Acta Physiol (Oxf) 213:722-30
Su, Shaoyong; Wang, Xiaoling; Pollock, Jennifer S et al. (2015) Adverse childhood experiences and blood pressure trajectories from childhood to young adulthood: the Georgia stress and Heart study. Circulation 131:1674-81
Speed, Joshua S; Fox, Brandon M; Johnston, Jermaine G et al. (2015) Endothelin and renal ion and water transport. Semin Nephrol 35:137-44
Speed, Joshua S; Pollock, David M (2015) New clues towards solving the mystery of endothelin and blood pressure regulation. Hypertension 66:275-7

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