Davel Ana Paula C, Fukuda Livia E, De Sá Larissa Lima, Munhoz Carolina D, Scavone Cristoforo, Sanz-Rosa David, Cachofeiro Victoria, Lahera Vicente, Rossoni Luciana V
Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas I, Universidade de São Paulo, Sala 225, São Paulo 05508-900, Brazil.
Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H211-9. doi: 10.1152/ajpheart.00581.2007. Epub 2008 May 16.
The aim of the present study was to evaluate the effect of overstimulation of beta-adrenoceptors on vascular inflammatory mediators. Wistar rats were treated with the beta-adrenoceptor agonist isoproterenol (0.3 mg.kg(-1).day(-1) sc) or vehicle (control) for 7 days. At the end of treatment, the right carotid artery was catheterized for arterial and left ventricular (LV) hemodynamic evaluation. Isoproterenol treatment increased LV weight but did not change hemodynamic parameters. Aortic mRNA and protein expression were quantified by real-time RT-PCR and Western blot analysis, respectively. Isoproterenol enhanced aortic mRNA and protein expression of IL-1beta (124% and 125%) and IL-6 (231% and 40%) compared with controls but did not change TNF-alpha expression. The nuclear-to-cytoplasmatic protein expression ration of the NF-kappaB p65 subunit was increased by isoproterenol treatment (51%); in addition, it reduced the cytoplasmatic expression of IkappaB-alpha (52%) in aortas. An electrophoretic mobility shift assay was performed using the aorta, and increased NF-kappaB DNA binding (31%) was observed in isoproterenol-treated rats compared with controls (P < 0.05). Isoproterenol treatment increased phenylephrine-induced contraction in aortic rigs (P < 0.05), which was significantly reduced by superoxide dismutase (150 U/ml) and sodium salicylate (5 mM). Cotreatment with thalidomide (150 mg.kg(-1).day(-1) for 7 days) also reduced hyperreactivity to phenylephrine induced by isoproterenol. In conclusion, overstimulation of beta-adrenoceptors increased proinflammatory cytokines and upregulated NF-kappaB in the rat aorta. Moreover, local oxidative stress and the proinflammatory state seem to play key roles in the altered vascular reactivity of the rat aorta induced by chronic beta-adrenergic stimulation.
本研究的目的是评估β-肾上腺素能受体过度刺激对血管炎症介质的影响。将Wistar大鼠用β-肾上腺素能受体激动剂异丙肾上腺素（0.3mg·kg⁻¹·天⁻¹，皮下注射）或赋形剂（对照）处理7天。在处理结束时，将右颈动脉插管以进行动脉和左心室（LV）血流动力学评估。异丙肾上腺素处理增加了左心室重量，但未改变血流动力学参数。分别通过实时RT-PCR和蛋白质印迹分析对主动脉mRNA和蛋白质表达进行定量。与对照相比，异丙肾上腺素增强了主动脉中IL-1β（124%和125%）和IL-6（231%和40%）的mRNA和蛋白质表达，但未改变TNF-α表达。异丙肾上腺素处理使NF-κB p65亚基的核与细胞质蛋白质表达比率增加（51%）；此外，它降低了主动脉中IκB-α的细胞质表达（52%）。使用主动脉进行电泳迁移率变动分析，与对照相比，在异丙肾上腺素处理的大鼠中观察到NF-κB DNA结合增加（31%）（P<0.0５）。异丙肾上腺素处理增加了主动脉条中去氧肾上腺素诱导的收缩（P<0.05），超氧化物歧化酶（150U/ml）和水杨酸钠（5mM）可使其显著降低。与沙利度胺共同处理（150mg·kg⁻¹·天⁻¹，共7天）也降低了异丙肾上腺素诱导的对去氧肾上腺素的高反应性。总之，β-肾上腺素能受体的过度刺激增加了大鼠主动脉中的促炎细胞因子并上调了NF-κB。此外，局部氧化应激和促炎状态似乎在慢性β-肾上腺素能刺激诱导的大鼠主动脉血管反应性改变中起关键作用。
