We hypothesize that a central nervous system (CNS) """"""""set point"""""""" exists for the long-term control of mean arterial pressure (MAP), and many forms of hypertension are due to primary resetting of the """"""""CNS-MAP set point"""""""" by sodium retaining hormones such as aldosterone. We propose that this resetting occurs in response to hormonal activation of circumventricular organs (CVOs), which stimulate downstream sympathetic pathways by activation of amiloride-sensitive sodium channels. To test this hypothesis, we will use continuous 24hr/day recordings of MAP and either cardiac output or renal blood flow to characterize the temporal profile of systemic and renal hemodynamics, respectively in the DOCA-salt hypertensive rats.
In Specific Aim 1, we will compare the effects of lesions of the CVOs, the area postrema (AP) and subfornical organ (SFO), and the chronic intracerebroventricular administration of a mineralocorticoid receptor (MR) antagonist and an antagonist of amiloride-sensitive sodium channels (benzamil) on these hemodynamic profiles and Fos immunoreactivity of key central regulatory sites.
In Specific Aim 2, we will establish the effect of interruption of peripheral sympathetic pathways on the systemic and renal hemodynamic profiles using surgical and pharmacological methods, to determine the contribution of renal and """"""""non-renal"""""""" sympathetic targets to the long-term regulation of MAP and the development of DOCA-salt hypertension.
In Specific Aim 3, we will use a combination of frequency domain (i.e., power spectra and coherence analyses) and transfer function analyses on data collected in Specific Aims 1 and 2 to quantitatively determine the dynamic relative contributions of neurogenic and autoregulatory control of vascular tone in DOCA-salt hypertension. Taken together, this integrative physiological approach will advance our understanding of the neural mechanisms for long-term control of arterial pressure and pathogenesis of neurogenic hypertension. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL064178-05
Application #
6827078
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Velletri, Paul A
Project Start
1999-12-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
5
Fiscal Year
2004
Total Cost
$334,125
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Averina, Viktoria A; Othmer, Hans G; Fink, Gregory D et al. (2014) A mathematical model of salt-sensitive hypertension: the neurogenic hypothesis. J Physiol :
Wehrwein, Erica A; Yoshimoto, Misa; Guzman, Pilar et al. (2014) Role of cardiac sympathetic nerves in blood pressure regulation. Auton Neurosci 183:30-5
Kuroki, Marcos T; Fink, Gregory D; Osborn, John W (2014) Comparison of arterial pressure and plasma ANG II responses to three methods of subcutaneous ANG II administration. Am J Physiol Heart Circ Physiol 307:H670-9
Osborn, John W; Olson, Dalay M; Guzman, Pilar et al. (2014) The neurogenic phase of angiotensin II-salt hypertension is prevented by chronic intracerebroventricular administration of benzamil. Physiol Rep 2:e00245
Veitenheimer, Britta; Osborn, John W (2013) Effects of intrathecal kynurenate on arterial pressure during chronic osmotic stress in conscious rats. Am J Physiol Heart Circ Physiol 304:H303-10
Veitenheimer, Britta J; Engeland, William C; Guzman, Pilar A et al. (2012) Effect of global and regional sympathetic blockade on arterial pressure during water deprivation in conscious rats. Am J Physiol Heart Circ Physiol 303:H1022-34
Osborn, John W; Kuroki, Marcos T (2012) Sympathetic signatures of cardiovascular disease: a blueprint for development of targeted sympathetic ablation therapies. Hypertension 59:545-7
Kuroki, Marcos T; Guzman, Pilar A; Fink, Gregory D et al. (2012) Time-dependent changes in autonomic control of splanchnic vascular resistance and heart rate in ANG II-salt hypertension. Am J Physiol Heart Circ Physiol 302:H763-9
Averina, Viktoria A; Othmer, Hans G; Fink, Gregory D et al. (2012) A new conceptual paradigm for the haemodynamics of salt-sensitive hypertension: a mathematical modelling approach. J Physiol 590:5975-92
Brooks, Virginia L; Osborn, John W (2012) High-fat food, sympathetic nerve activity, and hypertension: danger soon after the first bite? Hypertension 60:1387-8

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