Brain tumour necrosis factor-α modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure
Brain tumour necrosis factor-α modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure
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DOI：
10.1093/cvr/cvp160
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发表时间：
2009-09-01
影响因子：
10.8
通讯作者：
Francis, Joseph
中科院分区：
文献类型：
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作者：
Kang, Yu-Ming;He, Rong-Li;Francis, Joseph
心肌梗死后促炎性细胞因子的增加了心力衰竭（HF）的进展，并具有预后意义。最近，我们证明，增加促炎细胞因子在HF大鼠的大脑增加室旁核（PVN）超氧化物和下调神经元型一氧化氮合酶（nNOS），有助于交感神经兴奋。在本研究中，我们探讨了脑促炎细胞因子的可能作用及其在调节室旁核神经递质中的作用。在HF的Sprague-Dawley大鼠或假手术对照（SHAM）大鼠中，连续脑室内（ICV）输注细胞因子阻断剂-戊茶碱（penvoxifylline）4周，（PTX，10 μ g/h和40 μ g/h）、依那西普（ETN，5 μ g/h和10 μ g/h）或载体。另一组HF和SHAM大鼠用腹膜内（ip）输注相似剂量的PTX或ETN处理。HF大鼠增加神经元兴奋伴随着更高水平的谷氨酸，去甲肾上腺素（NE），酪氨酸羟化酶（TH），和较低水平的γ-氨基丁酸（GABA），nNOS，和67 kDa的谷氨酸脱羧酶（GAD 67）在PVN的亚型相比，SHAM大鼠。HF大鼠血浆细胞因子、NE、肾上腺素、血管紧张素II和肾交感神经活性（RSNA）也增加。低剂量PTX或ETN的ICV治疗减弱了HF大鼠PVN中谷氨酸、NE和TH水平的增加，并且高剂量预防了PVN中GABA、nNOS和GAD 67水平的降低。相同的ICV处理也减弱了HF大鼠中观察到的RSNA增加。IP治疗与类似剂量的PTX或ETN并没有影响谷氨酸，NE，TH，GABA，nNOS，和GAD 67在PVN和RSNA HF rats.This研究，第一次，表明促炎细胞因子调节神经递质在PVN和HF的交感兴奋。
Increased proinflammatory cytokines after myocardial infarction augment the progression of heart failure (HF) and are of prognostic significance. Recently, we demonstrated that increased proinflammatory cytokines in the brains of HF rats increased paraventricular nucleus (PVN) superoxide and down-regulated neuronal nitric oxide synthase (nNOS), contributing to sympathoexcitation. In this study, we explored the possible roles of brain proinflammatory cytokines and their effects on modulating PVN neurotransmitters in the exaggerated sympathetic activity in HF.Sprague-Dawley rats with HF or sham-operated control (SHAM) rats were treated for 4 weeks with a continuous intracerebroventricular (ICV) infusion of the cytokine blockers-pentoxifylline (PTX, 10 mu g/h and 40 mu g/h), etanercept (ETN, 5 mu g/h and 10 mu g/h), or vehicle. Another set of HF and SHAM rats were treated with intraperitoneal (ip) infusion of a similar dose of PTX or ETN. HF rats had increased neuronal excitation accompanied by higher levels of glutamate, norepinephrine (NE), and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), nNOS, and 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared with SHAM rats. Plasma cytokines, NE, epinephrine, angiotensin II, and renal sympathetic nerve activity (RSNA) were also increased in HF rats. ICV treatment with low doses of PTX or ETN attenuated, and high doses prevented, increases in levels of glutamate, NE, and TH, and decreases in levels of GABA, nNOS, and GAD67 in the PVN in HF rats. The same ICV treatments also attenuated the increased RSNA seen in HF rats. IP treatment with similar doses of PTX or ETN did not affect glutamate, NE, TH, GABA, nNOS, and GAD67 in the PVN and had no effect on RSNA of HF rats.This study, for the first time, demonstrates that proinflammatory cytokines modulate neurotransmitters in the PVN and contribute to sympathoexcitation in HF.