内分泌学
内科学
谷氨酸受体
化学
NMDA受体
AMPA受体
谷氨酸的
致电离效应
受体
兴奋剂
下丘脑
医学
作者
Megan E. Bardgett,Qing‐Hui Chen,Qing Guo,Alfredo S. Calderon,Mary Ann Andrade,Glenn M. Toney
出处
期刊:American Journal of Physiology-regulatory Integrative and Comparative Physiology
[American Physiological Society]
日期:2014-03-27
卷期号:306 (11): R804-R813
被引量:14
标识
DOI:10.1152/ajpregu.00074.2014
摘要
Autonomic and endocrine profiles of chronic hypertension and heart failure resemble those of acute dehydration. Importantly, all of these conditions are associated with exaggerated sympathetic nerve activity (SNA) driven by glutamatergic activation of the hypothalamic paraventricular nucleus (PVN). Here, studies sought to gain insight into mechanisms of disease by determining the role of PVN ionotropic glutamate receptors in supporting SNA and mean arterial pressure (MAP) during dehydration and by elucidating mechanisms regulating receptor activity. Blockade of PVN N-methyl-d-aspartate (NMDA) receptors reduced ( P < 0.01) renal SNA and MAP in urethane-chloralose-anesthetized dehydrated (DH) (48 h water deprivation) rats, but had no effect in euhydrated (EH) controls. Blockade of PVN α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors had no effect in either group. NMDA in PVN caused dose-dependent increases of renal SNA and MAP in both groups, but the maximum agonist evoked response ( E max ) of the renal SNA response was greater ( P < 0.05) in DH rats. The latter was not explained by increased PVN expression of NMDA receptor NR1 subunit protein, increased PVN neuronal excitability, or decreased brain water content. Interestingly, PVN injection of the pan-specific excitatory amino acid transporter (EAAT) inhibitor dl-threo-β-benzyloxyaspartic acid produced smaller sympathoexcitatory and pressor responses in DH rats, which was associated with reduced glial expression of EAAT2 in PVN. Like chronic hypertension and heart failure, dehydration increases excitatory NMDA receptor tone in PVN. Reduced glial-mediated glutamate uptake was identified as a key contributing factor. Defective glutamate uptake in PVN could therefore be an important, but as yet unexplored, mechanism driving sympathetic hyperactivity in chronic cardiovascular diseases.
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