Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, PR China.
Tohoku J Exp Med. 2010 Dec;222(4):251-63. doi: 10.1620/tjem.222.251.
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.
促炎细胞因子，包括肿瘤坏死因子 (TNF)-α，可增强以交感神经兴奋为特征的心力衰竭 (HF) 的进展。在这项研究中，我们探讨了 TNF-α在下丘脑室旁核 (PVN) 中的作用，在 HF 中观察到交感神经活性过度增强。通过结扎左前降支冠状动脉来制造 HF 大鼠。HF 大鼠的 PVN 中血管紧张素 1 型受体 (AT1-R) 和神经递质的表达水平，通过直接向 PVN 输注 TNF-α 阻滞剂（己酮可可碱或依那西普）或载体来分析。接受假手术对照 (SHAM) 或 HF 大鼠通过 PVN 输注每种 TNF-α 阻滞剂或载体进行 4 周治疗。与 SHAM 大鼠相比，HF 大鼠的 PVN 中谷氨酸、去甲肾上腺素、AT1-R 和酪氨酸羟化酶 (TH) 的水平升高，而γ-氨基丁酸 (GABA)、神经元型一氧化氮合酶 (nNOS) 和谷氨酸脱羧酶 67-kDa 同工型 (GAD67) 的水平降低。与 SHAM 大鼠相比，HF 大鼠的血浆细胞因子、去甲肾上腺素和血管紧张素 II 水平以及肾交感神经活动 (RSNA) 增加。PVN 输注己酮可可碱或依那西普可减弱 HF 大鼠中 PVN GABA、nNOS 和 GAD67 的减少，以及 RSNA 和 PVN 谷氨酸、去甲肾上腺素、TH 和 AT1-R 的增加。我们开发了一种将药物持续输注到 PVN 的新方法，并提供了证据表明，PVN 中的 TNF-α 调节神经递质和 AT1 受体的表达，这可能是 HF 中交感神经活性过度增强的原因。
