Zhou et al. [1] recently reported in Hypertension Research that N-methyl-D-aspartate (NMDA) or α-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/ kainate receptor expression and glutamate concentrations in the rostral ventrolateral medulla (RVLM) were increased in a rat model of stress-induced hypertension (SIH). Chronic intracerebroventricular (ICV) perfusion of the angiotensin II type 1 (AT1) receptor antagonist candesartan blunted this increase. Moreover, the blockade of NMDA or AMPA/ kainate receptors in the RVLM caused a depressor response in this SIH rat model. They concluded that AT1 receptor antagonists downregulate enhanced glutamatergic activity in the RVLM and hypothesized that central angiotensin II (Ang II) may elicit local release of glutamate via AT1 receptors, resulting in the activation of glutamatergic neurons within the RVLM, thereby increasing sympathetic tone. There is indeed increasing evidence that brain Ang II, glutamate and gamma-aminobutyric acid (GABA) interact within different brain nuclei to control sympathetic tone and blood pressure (BP) (Fig. 1). These interactions may be important in the pathogenesis of elevated sympathetic tone seen in many forms of hypertension [2]. The RVLM, the socalled “pressor area”, is the major source of excitatory sympathetic drive through spinally projecting glutamatergic neurons. These RVLM neurons receive tonic excitatory signals from other brain areas, including glutamatergic neurons in the hypothalamic paraventricular nucleus (PVN), inhibitory GABAergic signals from the caudal ventrolateral medulla (CVLM) and, indirectly, the nucleus tractus solitarius [3]. It is well-established that brain Ang II increases BP by stimulating sympathetic activity through AT1 receptors on spinally projecting glutamatergic neurons located in the RVLM [2, 4]. Microinjections of Ang II within the RVLM were reported to increase BP, heart rate and sympathetic activity [2]. Neuronal excitability in the RVLM is mainly modulated by the “classic” excitatory and inhibitory amino acids glutamate and GABA, respectively. Sympathetic hyperactivity is related to increased excitatory glutamatergic and angiotensinergic actions [2, 3, 5]. Recent results from our research group are in line with the observations of Zhou et al. [1] and seem to confirm their hypothesis. We performed microdialysis in conscious normotensive Wistar rats for the perfusion of Ang II into the RVLM and for the measurement of extracellular glutamate and GABA levels by liquid chromatography, as described previously [6]. The administration of Ang II into the RVLM resulted in a significant increase in local glutamate concentrations, and this response was abolished by local co-perfusion with the selective AT1 receptor antagonist candesartan (Fig. 2). Therefore, we postulate that Ang II may stimulate presynaptic AT1 receptors on glutamatergic nerve terminals originating in the PVN, resulting in increased glutamate levels within the RVLM. Local Ang II administration in the RVLM did not induce significant changes in local GABA concentrations, although a tendency for decreased GABA concentrations was noted (data not shown). AT1 receptors are expressed on both glutamatergic and GABAergic neuronal cell bodies within the RVLM, as well as on glutamatergic projections from the PVN and GABAergic projections from the CVLM [2]. This suggests that the AT1-receptor-mediated effect of brain Ang II on the RVLM may depend on a balance between the activation of * Laura Légat laura.legat@vub.be

中文翻译：

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血管紧张素-II 介导的 AT1 受体刺激增加了正常血压大鼠延髓腹外侧的谷氨酸释放

周等人。[1] 最近在 Hypertension Research 中报道了 N-甲基-D-天冬氨酸 (NMDA) 或 α-氨基3-羟基-5-甲基-4-异恶唑丙酸 (AMPA)/红藻氨酸受体表达和延髓腹外侧的谷氨酸浓度（ RVLM) 在应激性高血压 (SIH) 大鼠模型中增加。血管紧张素 II 1 型 (AT1) 受体拮抗剂坎地沙坦的慢性脑室内 (ICV) 灌注减弱了这种增加。此外，在该 SIH 大鼠模型中，RVLM 中 NMDA 或 AMPA/红藻氨酸受体的阻断引起了抑制反应。他们得出结论，AT1 受体拮抗剂下调 RVLM 中增强的谷氨酸能活性，并假设中枢血管紧张素 II (Ang II) 可能通过 AT1 受体引起谷氨酸的局部释放，导致 RVLM 内谷氨酸能神经元的激活，从而增加交感神经张力。确实有越来越多的证据表明，脑血管紧张素 II、谷氨酸和 γ-氨基丁酸 (GABA) 在不同的脑核内相互作用以控制交感神经张力和血压 (BP)（图 1）。这些相互作用可能在多种形式的高血压中出现的交感神经张力升高的发病机制中很重要 [2]。RVLM，即所谓的“加压区”，是通过脊髓投射谷氨酸能神经元的兴奋性交感神经驱动的主要来源。这些 RVLM 神经元接收来自其他脑区的强直兴奋信号，包括下丘脑室旁核 (PVN) 中的谷氨酸能神经元、来自尾侧腹外侧髓质 (CVLM) 的抑制性 GABA 能信号，以及间接地，孤束核 [3]。众所周知，脑血管紧张素 II 通过刺激位于 RVLM 的脊髓投射谷氨酸能神经元上的 AT1 受体的交感神经活动来增加血压 [2, 4]。据报道，在 RVLM 内微量注射 Ang II 会增加血压、心率和交感神经活动 [2]。RVLM 中的神经元兴奋性主要分别由“经典”兴奋性和抑制性氨基酸谷氨酸和 GABA 调节。交感神经过度活跃与兴奋性谷氨酸能和血管紧张素能作用增加有关 [2, 3, 5]。我们研究组的最新结果与 Zhou 等人的观察结果一致。[1] 并且似乎证实了他们的假设。我们在有意识的血压正常的 Wistar 大鼠中进行了微透析，以将 Ang II 灌注到 RVLM 中，并通过液相色谱法测量细胞外谷氨酸和 GABA 水平，如前所述 [6]。向 RVLM 中施用 Ang II 导致局部谷氨酸浓度显着增加，并且通过与选择性 AT1 受体拮抗剂坎地沙坦的局部共同灌注消除了这种反应（图 2）。因此，我们假设 Ang II 可能刺激起源于 PVN 的谷氨酸能神经末梢上的突触前 AT1 受体，导致 RVLM 内的谷氨酸水平增加。尽管注意到 GABA 浓度降低的趋势（数据未显示），但 RVLM 中的局部 Ang II 给药并未引起局部 GABA 浓度的显着变化。AT1 受体表达在 RVLM 内的谷氨酸能和 GABA 能神经元细胞体上，以及来自 PVN 的谷氨酸能投射和来自 CVLM 的 GABA 能投射 [2]。这表明 AT1 受体介导的大脑 Ang II 对 RVLM 的影响可能取决于 * Laura Légat laura.legat@vub.be 激活之间的平衡