The brain plays an important role in the regulation of arterial pressure (AP) via the autonomic nervous system. The long range goal of the applicant is to understand how the central nervous system (CNS) controls sympathetic vasomotor tone under conditions of normal AP and how the function is altered with hypertension. Many forms of hypertension are linked with elevated sympathetic nerve activity (SNA), although the basis of this sympatho-activation is not well understood. Normally, SNA is restrained by GABAergic neurons in the caudal ventrolateral medulla (CVLM) to maintain a consistent AP. For the short-term control of SNA and AP, these GABAergic CVLM neurons are an essential link in the central pathway for the baroreceptor reflex. However, GABAergic CVLM neurons also are clearly important for setting the long-term level of SNA independent of the baroreflex. We have observed that in the chronic absence of baroreceptor inputs or their site of termination in the nucleus tractus solitarius (NTS), the restoration of a normal mean AP is associated with a normal CVLM-mediated inhibition of SNA and AP. In contrast, spontaneously hypertensive rats have elevated SNA which may be linked with impaired CVLM-mediated inhibition of SNA and AP. Apart from baroreceptor inputs and the NTS, little is known about the central mechanisms regulating the activity of these powerful GABAergic CVLM neurons. This project will use a combination of state-of-the-art methods in rats (i.e. electrophysiological, neuroanatomical, and molecular approaches) to determine how other areas of the brain regulate the activity of GABAergic CVLM neurons under normotensive and hypertensive conditions. Specifically, we will determine whether identified glutamatergic inputs to the CVLM from the paraventricular nucleus of the hypothalamus and ventrolateral periaqueductal gray activate GABAergic CVLM neurons that project to the rostral ventrolateral medulla (RVLM). We will use chronic arterial baroreceptor denervated rats as a normotensive model to examine inputs to GABAergic CVLM neurons that may be masked by powerful baroreceptor inputs. In addition, we will determine whether the CVLM-mediated inhibition of SNA is impaired in spontaneously hypertensive rats. Collectively, these studies will provide a sophisticated analysis of the mechanisms underlying the brainstem's role in the long-term regulation of sympathetic vasomotor tone and AP and will determine functional changes that occur with chronic baroreceptor denervation and spontaneous hypertension. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075174-04
Application #
7224154
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Thrasher, Terry N
Project Start
2004-05-03
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$305,079
Indirect Cost
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Silva, Ana Q; Schreihofer, Ann M (2011) Altered sympathetic reflexes and vascular reactivity in rats after exposure to chronic intermittent hypoxia. J Physiol 589:1463-76
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
Mandel, Daniel A; Schreihofer, Ann M (2009) Modulation of the sympathetic response to acute hypoxia by the caudal ventrolateral medulla in rats. J Physiol 587:461-75
Llewellyn-Smith, Ida J; Martin, Carolyn L; Fenwick, Natalie M et al. (2007) VGLUT1 and VGLUT2 innervation in autonomic regions of intact and transected rat spinal cord. J Comp Neurol 503:741-67
Mobley, Susan C; Mandel, Daniel A; Schreihofer, Ann M (2006) Systemic cholecystokinin differentially affects baro-activated GABAergic neurons in rat caudal ventrolateral medulla. J Neurophysiol 96:2760-8
Mandel, Daniel A; Schreihofer, Ann M (2006) Central respiratory modulation of barosensitive neurones in rat caudal ventrolateral medulla. J Physiol 572:881-96
Schreihofer, Ann M; Ito, Satoru; Sved, Alan F (2005) Brain stem control of arterial pressure in chronic arterial baroreceptor-denervated rats. Am J Physiol Regul Integr Comp Physiol 289:R1746-55