Yang H, Raizada M K
From the Department of Physiology, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
Hypertension. 1998 Sep;32(3):473-81. doi: 10.1161/01.hyp.32.3.473.
Angiotensin II (Ang II), via its interaction with the angiotensin type 1 (AT1) receptor subtype, causes enhanced stimulation of norepinephrine (NE) neuromodulation. This involves increased transcription of NE transporter, tyrosine hydroxylase, and dopamine ss-hydroxylase genes in Wistar-Kyoto rat (WKY) brain neurons. AT1 receptor-mediated regulation of certain signaling events (such as activation of the Ras-Raf-1-mitogen activated protein (MAP) kinase signaling pathway, nuclear translocation of transcription factors such as Fos and Jun, and the interactions of these factors with AP-1 binding sites) is involved in this NE neuromodulation (Lu et al. J Cell Biol. 1996;135:1609-1617). The aim of this study was to compare the signal transduction mechanism of Ang II regulation of NE neuromodulation in WKY and spontaneously hypertensive rat (SHR) brain neurons, in view of the fact that AT1 receptor expression and Ang II stimulation of NE neuromodulation are higher in SHR neurons compared with WKY neurons. Despite this hyperactivity, Ang II stimulation of Ras, Raf-1, and MAP kinase activities was comparable between the neurons from WKY and SHR. Similarly, central injections of Ang II caused a comparable stimulation of MAP kinase in the hypothalamic and brain stem areas of adult WKY and SHR. Inhibition of MAP kinase by either an MAP kinase kinase inhibitor (PD98059) or an MAP kinase antisense oligonucleotide completely attenuated the stimulatory effects of Ang II on [3H]-NE uptake, NE transporter mRNA, and tyrosine hydroxylase mRNA levels in WKY neurons. These treatments resulted in only 43% to 50% inhibition of [3H]-NE uptake and NE transporter and tyrosine hydroxylase mRNAs in SHR neurons. Thus, Ang II stimulation of NE neuromodulation was completely blocked by MAP kinase inhibition in WKY neurons and only partially blocked in the SHR neurons. These observations suggest the presence of an additional signal transduction pathway involved in NE neuromodulation in SHR neurons that is independent of the MAP kinase pathway.
血管紧张素II（Ang II）通过与1型血管紧张素（AT1）受体亚型相互作用，增强去甲肾上腺素（NE）神经调节作用。这涉及Wistar-Kyoto大鼠（WKY）脑神经元中NE转运体、酪氨酸羟化酶和多巴胺β-羟化酶基因转录增加。AT1受体介导的某些信号事件调节（如Ras-Raf-1-丝裂原活化蛋白（MAP）激酶信号通路的激活、Fos和Jun等转录因子的核转位以及这些因子与AP-1结合位点的相互作用）参与了这种NE神经调节（Lu等人，《细胞生物学杂志》，1996年；135:1609-1617）。鉴于与WKY神经元相比，SHR神经元中AT1受体表达和Ang II对NE神经调节的刺激作用更高，本研究的目的是比较WKY和自发性高血压大鼠（SHR）脑神经元中Ang II调节NE神经调节的信号转导机制。尽管存在这种活性亢进，但WKY和SHR神经元中Ang II对Ras、Raf-1和MAP激酶活性的刺激作用相当。同样，向成年WKY和SHR的下丘脑和脑干区域中枢注射Ang II对MAP激酶的刺激作用相当。用MAP激酶激酶抑制剂（PD98059）或MAP激酶反义寡核苷酸抑制MAP激酶可完全减弱Ang II对WKY神经元中[3H]-NE摄取、NE转运体mRNA和酪氨酸羟化酶mRNA水平的刺激作用。这些处理仅导致SHR神经元中[3H]-NE摄取以及NE转运体和酪氨酸羟化酶mRNA受到43%至50%的抑制。因此，MAP激酶抑制在WKY神经元中可完全阻断Ang II对NE神经调节的刺激作用，而在SHR神经元中仅部分阻断。这些观察结果表明，SHR神经元中存在一种独立于MAP激酶途径的、参与NE神经调节的额外信号转导途径。
