阻断中枢肿瘤坏死因子α合成对缺血诱发心力衰竭大鼠交感神经活动的影响

Effects of Central blockade of TNF-α on sympathetic nerve activity in rats with heart failure

目的观察缺血诱发心力衰竭大鼠心血管中枢肿瘤坏死因子(TNF)α水平的变化,以及采用己酮可可碱(PTX)阻断中枢TNF-α合成对心力衰竭大鼠交感神经活动的影响。方法 48只雄性SD大鼠分为心力衰竭干预组(HF+PTX)、心力衰竭对照组(HF+VEH)、假手术干预组(SHAM+PTX)和假手术对照组(SHAM+VEH),每组12只。心力衰竭组采用冠状动脉结扎诱导心力衰竭,假手术组仅进行手术而不造成缺血状态。干预组通过侧脑室插管给予PTX,对照组给予人工脑脊液。4周后各组大鼠分别进行肾交感神经活动记录及血流动力学、右心室/体质量比值、肺/体质量比值的测量。免疫印迹法检测下丘脑室旁核TNF-α表达,酶联免疫吸附试验(ELISA)检测血浆去甲肾上腺素及细胞因子水平变化。结果 HF+VEH组与SHAM+VEH组相比,下丘脑室旁核中TNF-α水平升高,交感神经活动增强,左室舒张末压(LVEDP)及右心室/体质量比值、肺/体质量比值均明显升高,血浆去甲肾上腺素水平升高(均P<0.05)。左室最大上升速率和最大下降速率(LV±dp/dt_(max))明显降低(P<0.05)、HF+PTX组与HF+VEH组相比,中枢TNF-α水平下降,交感神经活动减弱,心功能改善(均P<0.05),右心室/体质量比值、肺/体质量比值均减小(P<0.05)。结论心力衰竭大鼠中枢TNF-α水平升高,交感神经活动增强,阻断中枢TNF-α合成可在一定程度上降低交感神经兴奋性,改善心力衰竭大鼠心功能。

Objective To investigate the effects of TNF-α blockade in the paraventrieular nucleus of hypothalamus （PVN） on sympathetic nerve activity in rats with heart failure （HF）. Methods Male Sprague-Dawley rats were randomly divided into 4 groups, pentoxifylline （PTX） -treated HF group （ HF ＋ FTX）, HF control group （ HF ＋ VEH）, PTX-treated SHAM group （SHAM ＋ PTX） and SHAM control group （SHAM ＋ VEH）. HF was induced by ligation of coronary artery, and intraeerebroventricular （ICV） cannulae were implanted for the injection of PTX （ 10 μg/h） or VEH （ artificial cerebrospinal fluid）. After 4 weeks intervention, rats were anesthetized for renal sympathetic nerve activity recording and hemodynamic measurements and then euthanized to collect tissue and plasma for further analysis. Results HF induced a significant increase in the expression of TNF-α in the PVN and elevation of norepinephrine level in plasma when compared with SHAM rats. The HF rats also had increased sympathetic nerve activity, left ventricular end-diastolic pressure （LVEDP）, right ventricle （RV）/body weight （BW） and lung/BW ratio. In contrast, ICV PTX reduced TNF-α in the PVN compared with vehicle-treated HF rats. Treatment with PTX also reduced sympathetic nerve activity and plasma level of norepinephrine, and decreased left ventricular end diastolic pressure. Conclusions These findings indicate that the inrease of TNF-α in the PVN contribute to sympathoexcitation in HF rats. Central blockade of TNF-α can attenuates sympathoexcitation in the PVN and improve the heart function in rats with HF.