One important mechanism linking obesity and hypertension is increased sympathetic nerve activity (SNA). It has been assumed that increases in SNA translate directly into vasoconstrictor tone, but we have demonstrated that local sympathetic blockade causes identical forearm vasodilatation in lean and obese subjects (with and without hypertension). Given that systemic adrenergic blockade has a greater depressor effect in obesity, these findings of sympathovascular uncoupling suggest that actions other than vasoconstriction account for the influence of SNA in obesity-hypertension. One plausible candidate is activation of the renin-angiotensin-aldosterone system (RAAS). We have demonstrated that SNA may act directly on adipocytes to stimulate angiotensinogen production. There is evidence that aldosterone as well as angiotensin II has direct vascular effects. We have also shown that obese subjects have profound vascular smooth muscle dysfunction, possibly due to RAAS activation. In addition, we have preliminary evidence that RAAS blockade decreases arterial pressure by more than conventional antihypertensive therapy in obesity-hypertension. We will test the hypothesis that SNS-related RAAS activation plays a critical role in hypertension associated with obesity, with these specific aims: 1) What is the role of the RAAS in obesity-related hypertension and how does it relate to increased SNA? 2) Do angiotensin II or aldosterone have exaggerated direct vascular effects in obesity? 3) Does sympathetic activation increase adipocyte-derived RAAS activity in obesity? We will enroll obese and lean hypertensive subjects in a randomized comparison of angiotensin and mineralocorticoid receptor antagonists, using SNS blockers and a thiazide diuretic as active control groups. In addition to BP, we will perform detailed assessments of vascular function, including endothelial function and responses to intra-arterial angiotensin II and aldosterone. Importantly, recordings of microneurographic SNA will allow exploration of the interactions between the SNS and RAAS in obesity. An important translational aspect of our study is ex vivo measurement of angiotensinogen production in adipose tissue biopsies, and its relationship to the hemodynamic effects of RAAS blockade. This project will provide new information on the causes of high blood pressure in obesity. Our research will examine the possible benefits on blood vessels of drugs that block the hormones angiotensin or aldosterone. These studies should help in the development of new tests and treatments for overweight and high blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL014388-40
Application #
8376390
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
40
Fiscal Year
2012
Total Cost
$446,530
Indirect Cost
$148,844
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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