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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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
Harwani, Sailesh C (2018) Macrophages under pressure: the role of macrophage polarization in hypertension. Transl Res 191:45-63
Shaffer Jr, Joseph J; Johnson, Casey P; Fiedorowicz, Jess G et al. (2018) Impaired sensory processing measured by functional MRI in Bipolar disorder manic and depressed mood states. Brain Imaging Behav 12:837-847
Xue, Baojian; Beltz, Terry G; Guo, Fang et al. (2018) Sex differences in maternal gestational hypertension-induced sensitization of angiotensin II hypertension in rat offspring: the protective effect of estrogen. Am J Physiol Regul Integr Comp Physiol 314:R274-R281
Holwerda, Seth W; Holland, Marshall T; Reddy, Chandan G et al. (2018) Femoral vascular conductance and peroneal muscle sympathetic nerve activity responses to acute epidural spinal cord stimulation in humans. Exp Physiol 103:905-915
Persons, Jane E; Coryell, William H; Solomon, David A et al. (2018) Mixed state and suicide: Is the effect of mixed state on suicidal behavior more than the sum of its parts? Bipolar Disord 20:35-41
Kopf, Phillip G; Phelps, Laura E; Schupbach, Chad D et al. (2018) Differential effects of long-term slow-pressor and subpressor angiotensin II on contractile and relaxant reactivity of resistance versus conductance arteries. Physiol Rep 6:
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

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