The renewal application for this project will follow-up the findings of the parent grant and previous studies which suggest: 1) African-Americans have an impaired natriuretic response to stress;2) this pattern is related to the functioning of the renin-angiotensin-aldosterone system;and 3) is associated with the early development of target organ damage. In addition, these studies 4) indicate increased adiposity contributes to the pattern.
Specific Aims 1 and 2 will examine the effects of an angiotensin receptor blocker on the pressure natriuresis response to stress in African-Americans with impaired stress-induced pressure natriuresis, confirming the role of angiotensin II in the response pattern. Furthermore, this effect will be compared in normal weight versus overweight individuals, with a hypothesized greater effect in overweight subjects.
Aim 3 will compare the effects of an angiotensin receptor blocker between carriers and noncarriers of a functional polymorphism of the angiotensin II receptor type 1 gene. These results will provide additional evidence for the mechanistic role of angiotensin II and continue our gene/environmental approach to the study of mechanisms underlying the development of hypertension. Our fourth and final aim is to test the hypothesis that individuals who displayed impaired stress-induced pressure natriuresis on initial testing will display greater increases in blood pressure and related target organ damage than those who displayed normal stress-induced pressure natriuresis. This follow-up study will provide more direct evidence of the clinical significance of impaired stress-induced pressure natriuresis.

Public Health Relevance

to public health: High blood pressure, or hypertension, remains a significant health problem in industrialized nations. The problem is particularly significant in the African-American population in whom impaired sodium regulation plays an important role. The results of this study will help further define the interactive effects of genetic predisposition and environmental stress on sodium handling in the development of hypertension, particularly in overweight African-Americans. The pharmacologic interventions will also provide evidence for effective management of this potentially clinically significant response pattern.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Georgia Regents University
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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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