Wei Shun-Guang, Yu Yang, Zhang Zhi-Hua, Weiss Robert M, Felder Robert B
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Hypertension. 2008 Aug;52(2):342-50. doi: 10.1161/HYPERTENSIONAHA.108.110445. Epub 2008 Jun 23.
Angiotensin II (Ang II), acting via angiotensin type 1 receptors in the brain, activates the sympathetic nervous system in heart failure (HF). We reported recently that Ang II stimulates mitogen-activated protein kinase (MAPK) to upregulate brain angiotensin type 1 receptors in HF rats. In this study we tested the hypothesis that Ang II-activated MAPK signaling pathways contribute to sympathetic excitation in HF. Intracerebroventricular administration of PD98059 and UO126, 2 selective p44/42 MAPK inhibitors, induced significant decreases in mean arterial pressure, heart rate, and renal sympathetic nerve activity in HF rats, but had no effect on these variables in sham-operated rats. Pretreatment with losartan attenuated the effects of PD98059. Intracerebroventricular administration of the p38 MAPK inhibitor SB203580 and the c-Jun N-terminal kinase inhibitor SP600125 had no effect on mean arterial pressure, heart rate, or renal sympathetic nerve activity in HF. The phosphatidylinositol 3-kinase inhibitor LY294002 induced a small decrease in mean arterial pressure and heart rate but no change in renal sympathetic nerve activity. Immunofluorescent staining demonstrated increased p44/42 MAPK activity in neurons of the paraventricular nucleus of the hypothalamus of HF rats, colocalized with Fra-like activity (indicating chronic neuronal excitation). Intracerebroventricular PD98059 and UO126 reduced Fra-like activity in the paraventricular nucleus of the hypothalamus neurons in HF rats. In confirmatory acute studies, intracerebroventricular Ang II increased mean arterial pressure, heart rate, and renal sympathetic nerve activity in baroreceptor-denervated rats and Fra-like immunoreactivity in the paraventricular nucleus of the hypothalamus of neurally intact rats. Central administration of PD98059 markedly reduced these responses. These data demonstrate that intracellular p44/42 MAPK activity contributes to Ang II-induced neuronal excitation in the paraventricular nucleus of the hypothalamus and augmented sympathetic nerve activity in rats with HF.
血管紧张素II（Ang II）通过作用于脑内的血管紧张素1型受体，激活心力衰竭（HF）时的交感神经系统。我们最近报道，Ang II刺激丝裂原活化蛋白激酶（MAPK）上调HF大鼠脑内的血管紧张素1型受体。在本研究中，我们检验了以下假设：Ang II激活的MAPK信号通路促成了HF时的交感神经兴奋。向脑室内注射2种选择性p44/42 MAPK抑制剂PD98059和UO126，可使HF大鼠的平均动脉压、心率和肾交感神经活动显著降低，但对假手术大鼠的这些变量无影响。用氯沙坦预处理可减弱PD98059的作用。向脑室内注射p38 MAPK抑制剂SB203580和c-Jun氨基末端激酶抑制剂SP600125，对HF大鼠的平均动脉压、心率或肾交感神经活动无影响。磷脂酰肌醇3-激酶抑制剂LY294002使平均动脉压和心率略有降低，但肾交感神经活动无变化。免疫荧光染色显示，HF大鼠下丘脑室旁核神经元中的p44/42 MAPK活性增加，与Fra样活性共定位（表明慢性神经元兴奋）。向脑室内注射PD98059和UO126可降低HF大鼠下丘脑室旁核神经元中的Fra样活性。在确证性急性研究中，向脑室内注射Ang II可使压力感受器去神经大鼠的平均动脉压、心率和肾交感神经活动增加，并使神经完整大鼠下丘脑室旁核中的Fra样免疫反应性增加。中枢给予PD98059可显著减弱这些反应。这些数据表明，细胞内p44/42 MAPK活性促成了Ang II诱导的下丘脑室旁核神经元兴奋以及HF大鼠交感神经活动增强。
