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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Iowa
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Zhang, Yu-Ping; Huo, Yan-Li; Fang, Zhi-Qin et al. (2018) Maternal high-fat diet acts on the brain to induce baroreflex dysfunction and sensitization of angiotensin II-induced hypertension in adult offspring. Am J Physiol Heart Circ Physiol 314:H1061-H1069
Johnson, Casey P; Christensen, Gary E; Fiedorowicz, Jess G et al. (2018) Alterations of the cerebellum and basal ganglia in bipolar disorder mood states detected by quantitative T1? mapping. Bipolar Disord 20:381-390
Hardy, Rachel N; Simsek, Zinar D; Curry, Brandon et al. (2018) Aging affects isoproterenol-induced water drinking, astrocyte density, and central neuronal activation in female Brown Norway rats. Physiol Behav 192:90-97
Lane-Cordova, Abbi D; Kalil, Graziela Z; Wagner, Christopher J et al. (2018) Hemoglobin A1c and C-reactive protein are independently associated with blunted nocturnal blood pressure dipping in obesity-related prediabetes. Hypertens Res 41:33-38
Larson, Robert A; Chapleau, Mark W (2018) Increased cardiac sympathetic activity: Cause or compensation in vasovagal syncope? Clin Auton Res 28:265-266
Tong, Brian; Abosi, Oluchi; Schmitz, Samantha et al. (2018) Bipolar disorder and related mood states are not associated with endothelial function of small arteries in adults without heart disease. Gen Hosp Psychiatry 51:36-40
Zeng, Wei-Zheng; Marshall, Kara L; Min, Soohong et al. (2018) PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science 362:464-467
DuBose, Lyndsey E; Boles Ponto, Laura L; Moser, David J et al. (2018) Higher Aortic Stiffness Is Associated With Lower Global Cerebrovascular Reserve Among Older Humans. Hypertension 72:476-482
Holwerda, Seth W; Luehrs, Rachel E; Gremaud, Allene L et al. (2018) Relative burst amplitude of muscle sympathetic nerve activity is an indicator of altered sympathetic outflow in chronic anxiety. J Neurophysiol 120:11-22
Sabharwal, Rasna; Mason, Bianca N; Kuburas, Adisa et al. (2018) Increased receptor activity-modifying protein 1 in the nervous system is sufficient to protect against autonomic dysregulation and hypertension. J Cereb Blood Flow Metab :271678X17751352

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