Obesity is a nationwide epidemic and a leading cause of cardiovascular disease. Obese people display hypertension, impaired baroreflex control of arterial pressure (AP), and exaggerated pressor responses to stress, which contribute to end-organ injury and increased morbidity in obese patients. Altered sympathetic regulation of the heart and vasculature is integral to obesity-associated impairment of cardiovascular regulation, but mechanisms underlying deficits in sympathetic control are poorly understood. Obese Zucker rats (OZR) have autonomic deficits analogous to those observed in obese people: increased sympathetic nerve activity (SNA) with hypertension, blunted baroreflex-mediated changes in SNA, and exaggerated increases in SNA and AP with other sympatho-excitatory reflexes. Exaggerated sympatho-excitatory responses persist in the absence of baroreceptor feedback, suggesting additional baroreflex-independent alterations in the control of SNA in OZR. The opposing effects of obesity upon baroreflex versus other sympathetic reflexes are likely due to their disparate underlying mechanisms. Baroreflex-mediated increases in SNA are elicited by a withdrawal of GABAergic inhibition from the caudal ventrolateral medulla (CVLM) to the brainstem neurons that drive SNA in rostral ventrolateral medulla (RVLM). In contrast, other sympatho-excitatory stimuli raise SNA by glutamatergic or angiotensinergic stimulation of the RVLM. We hypothesize that OZR have a dual deficit in sympathetic regulation of cardiovascular function: impaired baroreflex-mediated GABAergic inhibition of the RVLM, AND enhanced sensitivity of RVLM neurons to excitatory stimuli controlling sympathetic vasomotor tone.
In Aim 1 we will determine if impaired baroreflexes are due to deficits in baroreceptor afferent function or changes in the brain stem.
In Aim 2 we will determine if OZR have a reduced GABAergic inhibition of the RVLM.
In Aim 3 we will determine whether excitation of the RVLM with glutamate or angtiotensin II produces larger increases in SNA and AP in OZR, even without baroreflexes.
In Aim 4 we will determine whether OZR also have exaggerated sympatho- excitatory responses initiated by the forebrain, which activate SNA exciting the RVLM. This proposal will use state-of-the-art anatomical and electrophysiological measures to provide the first mechanistic understanding of deleterious changes in brain stem control of autonomic regulation associated with obesity. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086759-02
Application #
7486850
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mcdonald, Cheryl
Project Start
2007-09-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$348,700
Indirect Cost
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Huber, Domitila A; Schreihofer, Ann M (2016) Exaggerated sympathoexcitatory reflexes develop with changes in the rostral ventrolateral medulla in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 311:R243-53
Fox, Ervin R; Samdarshi, Tandaw E; Musani, Solomon K et al. (2016) Development and Validation of Risk Prediction Models for Cardiovascular Events in Black Adults: The Jackson Heart Study Cohort. JAMA Cardiol 1:15-25
Guimaraes, Priscila S; Huber, Domitila A; Campagnole-Santos, Maria J et al. (2014) Development of attenuated baroreflexes in obese Zucker rats coincides with impaired activation of nucleus tractus solitarius. Am J Physiol Regul Integr Comp Physiol 306:R681-92
Guimaraes, Priscila S; Oliveira, Mariana F; Braga, JanaĆ­na F et al. (2014) Increasing angiotensin-(1-7) levels in the brain attenuates metabolic syndrome-related risks in fructose-fed rats. Hypertension 63:1078-85
Huber, Domitila A; Schreihofer, Ann M (2011) Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats. Am J Physiol Heart Circ Physiol 301:H230-40
Huber, Domitila A; Schreihofer, Ann M (2010) Attenuated baroreflex control of sympathetic nerve activity in obese Zucker rats by central mechanisms. J Physiol 588:1515-25