The sympathetic drive emanating from the brain is increased in animal models of hypertension and in patients with primary hypertension. The paraventricular nucleus (PVN) of the hypothalamus is an important site for the control of sympathetic outflow through its projections to sympathetically related sites in the brainstem and spinal cord. During the previous funding period, we showed that augmented glutamatergic input contributes to increased excitability of PVN presympathetic neurons and elevated sympathetic vasomotor tone in the animal model of hypertension. However, little is known about the molecular mechanisms underlying the sustained increase in glutamatergic input to the PVN in hypertension. Our recent study suggests that group I metabotropic glutamate receptors (mGluRs) in the PVN are critically involved in the support of elevated sympathetic outflow in hypertension. In this competing renewal proposal, we will use spontaneously hypertensive rats and renovascular hypertensive rats as animal models of hypertension to test our central hypothesis that group I mGluRs are upregulated at presynaptic and postsynaptic sites, which leads to increased glutamatergic input and excitability of PVN presympathetic neurons in hypertension.
Our specific aims are to determine (1) the changes in the expression and distribution of group I mGluRs in the PVN during the development of hypertension;(2) the contribution of presynaptic group I mGluRs to augmented glutamatergic synaptic input to PVN presympathetic neurons in hypertension;(3)the downstream mechanisms mediating increased excitability of PVN presympathetic neurons by activation of postsynaptic group I mGluRs in hypertension;and (4) the changes in calcineurin activity and their contribution to increased group I mGluR and NMDA channel activity in the PVN in hypertension. The important roles of group I mGluRs and calcineurin in increased glutamatergic input in the PVN have not been recognized previously. Our proposed studies are expected to unravel a cascade of molecular events responsible for the sustained increase in sympathetic vasomotor tone in hypertension. This new information should have a major impact on our understanding of the fundamental neurogenic mechanisms underlying the development of primary and secondary hypertension and on the design of new treatments for hypertension.

Public Health Relevance

This proposal will study the cellular and molecular mechanisms of changes in the excitatory neuro-transmission in the hypothalamus in hypertension. This project will provide new information about how the brain is involved in hypertension development and will provide a rationale for developing new treatments for patients with hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077400-08
Application #
8320209
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2004-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$429,092
Indirect Cost
$157,515
Name
University of Texas MD Anderson Cancer Center
Department
Anesthesiology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Qi, Yitao; Wang, Jingxiong; Bomben, Valerie C et al. (2014) Hyper-SUMOylation of the Kv7 potassium channel diminishes the M-current leading to seizures and sudden death. Neuron 83:1159-71
Pachuau, Judith; Li, De-Pei; Chen, Shao-Rui et al. (2014) Protein kinase CK2 contributes to diminished small conductance Ca2+-activated K+ channel activity of hypothalamic pre-sympathetic neurons in hypertension. J Neurochem 130:657-67
Li, Li; Li, De-Pei; Chen, Shao-Rui et al. (2014) Potentiation of high voltage-activated calcium channels by 4-aminopyridine depends on subunit composition. Mol Pharmacol 86:760-72
Li, De-Pei; Zhu, Li-Hong; Pachuau, Judith et al. (2014) mGluR5 Upregulation increases excitability of hypothalamic presympathetic neurons through NMDA receptor trafficking in spontaneously hypertensive rats. J Neurosci 34:4309-17
Ye, Zeng-You; Li, De-Pei; Pan, Hui-Lin (2013) Regulation of Hypothalamic Presympathetic Neurons and Sympathetic Outflow by Group II Metabotropic Glutamate Receptors in Spontaneously Hypertensive Rats. Hypertension 62:255-62
Ye, Zeng-You; Li, Li; Li, De-Pei et al. (2012) Casein kinase 2-mediated synaptic GluN2A up-regulation increases N-methyl-D-aspartate receptor activity and excitability of hypothalamic neurons in hypertension. J Biol Chem 287:17438-46
Li, De-Pei; Byan, Hee Sun; Pan, Hui-Lin (2012) Switch to glutamate receptor 2-lacking AMPA receptors increases neuronal excitability in hypothalamus and sympathetic drive in hypertension. J Neurosci 32:372-80
Chen, Zheng; Yoo, Seung-Hee; Park, Yong-Sung et al. (2012) Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening. Proc Natl Acad Sci U S A 109:101-6
Ye, Zeng-You; Li, De-Pei; Li, Li et al. (2011) Protein kinase CK2 increases glutamatergic input in the hypothalamus and sympathetic vasomotor tone in hypertension. J Neurosci 31:8271-9
Li, De-Pei; Pan, Hui-Lin (2010) Increased group I metabotropic glutamate receptor activity in paraventricular nucleus supports elevated sympathetic vasomotor tone in hypertension. Am J Physiol Regul Integr Comp Physiol 299:R552-61

Showing the most recent 10 out of 23 publications