Tohoku J. Exp. Med., 2010, 222(4)

TNF-α in Hypothalamic Paraventricular Nucleus Contributes to Sympathoexcitation in Heart Failure by Modulating AT1 Receptor and Neurotransmitters

YU-MING KANG,¹ YING WANG,¹ LI-MIN YANG,³ CARRIE ELKS,² JEFFREY CARDINALE,² XIAO-JING YU,³ XIU-FANG ZHAO,⁴ JIAN ZHANG,⁵ LI-HUA ZHANG,⁶ ZHI-MING YANG³ and JOSEPH FRANCIS²

¹Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, P.R. China
²Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, USA
³Department of Physiology, Shanxi Medical University, Taiyuan, P.R. China
⁴Department of Internal Medicine, The General Hospital of Chinese People's Armed Police Forces, Beijing, P.R. China
⁵Department of Heart Failure Care Unit, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China
⁶Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, P.R. China

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.

keywords —— tumor necrosis factor-alpha; hypothalamic paraventricular nucleus; neurotransmitters; angiotensin type 1 receptor; heart failure

© 2010 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2010, 222, 251-263

Correspondence: Yu-Ming Kang, M.D., Ph.D., Department of Physiology & Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an 710061, P.R. China.

e-mail: ykang@mail.xjtu.edu.cn