Prolonged exposure to bedrest or microgravity in humans results in a number of adverse cardiovascular consequences, leading to cardiovascular deconditioning. Rat hindlimb unloading (HU) is an animal model of cardiovascular deconditioning and results in similar cardiovascular consequences including orthostatic intolerance. The mechanisms responsible for cardiovascular dysfunction in humans following bedrest or microgravity, and in rats after HU, are not clear, but alterations in regulation of the autonomic nervous system likely play an important role Blunted sympathetic vasoconstriction and enhanced cardiopulmonary receptor inhibition appear to contribute to autonomic dysfunction in deconditioned humans and HU rats. We have evidence that central nervous system mechanisms contribute to altered cardiovascular regulation in HU rats. Specifically, we have observed increased GABA-A and nitric oxide (NO) inhibition at the rostral ventrolateral medulla (RVLM) and increased neuronal nitric oxide synthase in the paraventricular nucleus (PVN) of the hypothalamus. These brain regions are critically important in normal autonomic regulation, and have been implicated in altered autonomic function in a variety of disease states. The proposed studies will test the general hypothesis that cardiovascular deconditioning alters neurohumoral regulatory mechanisms in the medulla and hypothalamus, specifically the RVLM and PVN, that contribute significantly to impaired cardiovascular function. We will address these questions using whole animal studies in conscious and anesthetized control and HU rats (Fos, microinjections, extracellular recording), immunohistochemistry, studies in single dissociated spinally projecting RVLM and PVN neurons, and molecular techniques.
SPECIFIC AIM 1 : Examine central mechanisms within the rostral ventrolateral medulla (RVLM) that contribute to impaired cardiovascular regulation due to deconditioning.
SPECIFIC AIM 2 : Examine central mechanisms within the paraventricular nucleus (PVN) of the hypothalamus that are altered by cardiovascular deconditioning. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055306-11
Application #
7406598
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mcdonald, Cheryl
Project Start
1997-04-01
Project End
2011-03-31
Budget Start
2008-05-05
Budget End
2009-03-31
Support Year
11
Fiscal Year
2008
Total Cost
$333,925
Indirect Cost
Name
University of Missouri-Columbia
Department
Type
Organized Research Units
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Clark, Catharine G; Hasser, Eileen M; Kunze, Diana L et al. (2011) Endogenous brain-derived neurotrophic factor in the nucleus tractus solitarius tonically regulates synaptic and autonomic function. J Neurosci 31:12318-29
Kline, D D; King, T L; Austgen, J R et al. (2010) Sensory afferent and hypoxia-mediated activation of nucleus tractus solitarius neurons that project to the rostral ventrolateral medulla. Neuroscience 167:510-27
Heesch, Cheryl M; Zheng, Hong; Foley, C Michael et al. (2009) Nitric oxide synthase activity and expression are decreased in the paraventricular nucleus of pregnant rats. Brain Res 1251:140-50
Austgen, J R; Fong, A Y; Foley, C M et al. (2009) Expression of Group I metabotropic glutamate receptors on phenotypically different cells within the nucleus of the solitary tract in the rat. Neuroscience 159:701-16
Mueller, Patrick J (2007) Exercise training and sympathetic nervous system activity: evidence for physical activity dependent neural plasticity. Clin Exp Pharmacol Physiol 34:377-84
Mueller, Patrick J; Sullivan, Margaret J; Grindstaff, Regina R et al. (2006) Regulation of plasma vasopressin and renin activity in conscious hindlimb-unloaded rats. Am J Physiol Regul Integr Comp Physiol 291:R46-52
Mueller, Patrick J; Foley, C Michael; Heesch, Cheryl M et al. (2006) Increased nitric oxide synthase activity and expression in the hypothalamus of hindlimb unloaded rats. Brain Res 1115:65-74
Mueller, Patrick J; Hasser, Eileen M (2006) Putative role of the NTS in alterations in neural control of the circulation following exercise training in rats. Am J Physiol Regul Integr Comp Physiol 290:R383-92
Foley, C Michael; Mueller, Patrick J; Hasser, Eileen M et al. (2005) Hindlimb unloading and female gender attenuate baroreflex-mediated sympathoexcitation. Am J Physiol Regul Integr Comp Physiol 289:R1440-7
Mueller, Patrick J; Foley, C Michael; Hasser, Eileen M (2005) Hindlimb unloading alters nitric oxide and autonomic control of resting arterial pressure in conscious rats. Am J Physiol Regul Integr Comp Physiol 289:R140-7

Showing the most recent 10 out of 21 publications