PMID- 25223692 OWN - NLM STAT- MEDLINE DCOM- 20170904 LR - 20180102 IS - 1096-0333 (Electronic) IS - 0041-008X (Linking) VI - 281 IP - 1 DP - 2014 Nov 15 TI - Inhibition of TNF-alpha in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats. PG - 101-8 LID - S0041-008X(14)00337-8 [pii] LID - 10.1016/j.taap.2014.09.004 [doi] AB - We hypothesized that chronic inhibition of tumor necrosis factor-alpha (TNF-alpha) in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), decreasing nuclear factor-kappaB (NF-kappaB) p65 and NAD(P)H oxidase activities, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar-Kyoto (WKY) and SHR rats received bilateral PVN infusion of a TNF-alpha blocker (pentoxifylline or etanercept) or vehicle for 4weeks. SHR rats showed higher mean arterial pressure and cardiac hypertrophy compared with WKY rats, as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (beta-MHC) mRNA expressions. Compared with WKY rats, SHR rats had higher PVN levels of tyrosine hydroxylase, PICs, the chemokine monocyte chemoattractant protein-1 (MCP-1), NF-kappaB p65 activity, mRNA expressions of NOX-2 and NOX-4, and lower PVN levels of IL-10 and 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma norepinephrine. PVN infusion of pentoxifylline or etanercept attenuated all these changes in SHR rats. These findings suggest that SHR rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN; and chronic inhibition of TNF-alpha in the PVN delays the progression of hypertension by restoring the balances of neurotransmitters and cytokines in the PVN, and attenuating PVN NF-kappaB p65 activity and oxidative stress, thereby attenuating hypertension-induced sympathetic hyperactivity and cardiac hypertrophy. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Song, Xin-Ai AU - Song XA AD - Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China. FAU - Jia, Lin-Lin AU - Jia LL AD - Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China. FAU - Cui, Wei AU - Cui W AD - Department of Endocrinology and Metabolism, First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an 710061, China. FAU - Zhang, Meng AU - Zhang M AD - Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China. FAU - Chen, Wensheng AU - Chen W AD - Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. FAU - Yuan, Zu-Yi AU - Yuan ZY AD - Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an 710061, China. FAU - Guo, Jing AU - Guo J AD - Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China. FAU - Li, Hui-Hua AU - Li HH AD - Key Laboratory of Remodeling-related Cardiovascular Diseases, Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. FAU - Zhu, Guo-Qing AU - Zhu GQ AD - Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029, China. FAU - Liu, Hao AU - Liu H AD - Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an 710061, China. Electronic address: haoliu75@163.com. FAU - Kang, Yu-Ming AU - Kang YM AD - Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China. Electronic address: ykang@mail.xjtu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140916 PL - United States TA - Toxicol Appl Pharmacol JT - Toxicology and applied pharmacology JID - 0416575 RN - 0 (Neurotransmitter Agents) RN - 0 (Tumor Necrosis Factor-alpha) RN - SD6QCT3TSU (Pentoxifylline) SB - IM MH - Animals MH - Cardiomegaly/*metabolism/prevention & control MH - Hypertension/*metabolism/prevention & control MH - Male MH - Neurotransmitter Agents/antagonists & inhibitors/*metabolism MH - Paraventricular Hypothalamic Nucleus/drug effects/*metabolism MH - Pentoxifylline/pharmacology/therapeutic use MH - Rats MH - Rats, Inbred SHR MH - Rats, Inbred WKY MH - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/*metabolism OTO - NOTNLM OT - Cardiac hypertrophy OT - Hypertension OT - Hypothalamic paraventricular nucleus OT - Neurohormonal excitation OT - Tumor necrosis factor-alpha EDAT- 2014/09/17 06:00 MHDA- 2014/09/17 06:01 CRDT- 2014/09/17 06:00 PHST- 2014/07/12 00:00 [received] PHST- 2014/08/20 00:00 [revised] PHST- 2014/09/04 00:00 [accepted] PHST- 2014/09/17 06:00 [entrez] PHST- 2014/09/17 06:00 [pubmed] PHST- 2014/09/17 06:01 [medline] AID - S0041-008X(14)00337-8 [pii] AID - 10.1016/j.taap.2014.09.004 [doi] PST - ppublish SO - Toxicol Appl Pharmacol. 2014 Nov 15;281(1):101-8. doi: 10.1016/j.taap.2014.09.004. Epub 2014 Sep 16.