TNF-α in hypothalamic paraventricular nucleus contributes to sympathoexcitation in heart failure by modulating AT1 receptor and neurotransmitters.
Proinflammatory cytokines, including tumor necrosis factor (TNF)-α, augment the progression of heart failure (HF) that is characterized by sympathoexcitation. In this study, we explored the role of TNF-α in hypothalamic paraventricular nucleus (PVN) in the exaggerated sympathetic activity observed in HF. Heart failure rats were made by ligating the left anterior descending coronary artery. The expression levels of angiotensin type 1 receptor (AT1-R) and neurotransmitters were analyzed in the PVN of HF rats that received direct PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle. Sham-operated control (SHAM) or HF rats were treated for 4 weeks through PVN infusion with each TNF-α blocker or vehicle. Rats with HF had higher levels of glutamate, norepinephrine, AT1-R and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), neuronal nitric oxide synthase (nNOS) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared to SHAM rats. Plasma levels of cytokines, norepinephrine and angiotensin II and renal sympathetic nerve activity (RSNA) were increased in HF rats. PVN infusion of pentoxifylline or etanercept attenuated the decreases in PVN GABA, nNOS and GAD67, and the increases in RSNA and PVN glutamate, norepinephrine, TH and AT1-R observed in HF rats. We have developed a novel method for chronic and continuous infusion of drugs directly into the PVN and provided evidence that TNF-α in the PVN modulates neurotransmitters and the expression of AT1 receptor, which could account for exaggerated sympathetic activity in HF.
Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, PR China. ykang@mail.xjtu.edu.cn
Yu-Ming
YM
Kang
Ying
Y
Wang
Li-Min
LM
Yang
Carrie
C
Elks
Jeffrey
J
Cardinale
Xiao-Jing
XJ
Yu
Xiu-Fang
XF
Zhao
Jian
J
Zhang
Li-Hua
LH
Zhang
Zhi-Ming
ZM
Yang
Joseph
J
Francis
D000818:Animals; D005786:Gene Expression Regulation; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006333:Heart Failure / Q000097:blood / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006334:Heart Function Tests; D006439:Hemodynamics; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D018377:Neurotransmitter Agents / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000201:enzymology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000201:enzymology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014463:Ultrasonography
D018836:Inflammation Mediators; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D014409:Tumor Necrosis Factor-alpha; D052248:Nitric Oxide Synthase Type I; D014446:Tyrosine 3-Monooxygenase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1