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 #
5R01HL086759-04
Application #
7880551
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mcdonald, Cheryl
Project Start
2007-09-01
Project End
2010-08-31
Budget Start
2010-07-01
Budget End
2010-08-31
Support Year
4
Fiscal Year
2010
Total Cost
$107,172
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