Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York 10065, USA.
Am J Physiol Regul Integr Comp Physiol. 2012 May;302(9):R1076-83. doi: 10.1152/ajpregu.00571.2011. Epub 2012 Feb 29.
The medial region of the nucleus tractus solitarius (mNTS) is a key brain stem site controlling cardiovascular function, wherein ANG II modulates neuronal L-type Ca(2+) currents via activation of ANG II type 1 receptors (AT(1)R) and production of reactive oxygen species (ROS). ANG II type 2 receptors (AT(2)R) induce production of nitric oxide (NO), which may interact with ROS and modulate AT(1)R signaling. We sought to determine whether AT(2)R-mediated NO production occurs in mNTS neurons and, if so, to elucidate the NO source and the functional interaction with AT(1)R-induced ROS or Ca(2+) influx. Electron microscopic (EM) immunolabeling showed that AT(2)R and neuronal NO synthase (nNOS) are coexpressed in neuronal somata and dendrites receiving synapses in the mNTS. In the presence of the AT(1)R antagonist losartan, ANG II increased NO production in isolated mNTS neurons, an effect blocked by the AT(2)R antagonist PD123319, but not the angiotensin (1-7) antagonist D-Ala. Studies in mNTS neurons of nNOS-null or endothelial NOS (eNOS)-null mice established nNOS as the source of NO. ANG II-induced ROS production was enhanced by PD123319, the NOS inhibitor N(G)-nitro-l-arginine (LNNA), or in nNOS-null mice. Moreover, in the presence of losartan, ANG II reduced voltage-gated L-type Ca(2+) current, an effect blocked by PD123319 or LNNA. We conclude that AT(2)R are closely associated and functionally coupled with nNOS in mNTS neurons. The resulting NO production antagonizes AT(1)R-mediated ROS and dampens L-type Ca(2+) currents. The ensuing signaling changes in the NTS may counteract the deleterious effects of AT(1)R on cardiovascular function.
孤束核中间区（mNTS）是控制心血管功能的关键脑干部位，其中血管紧张素 II 通过激活血管紧张素 II 型 1 受体（AT1R）和产生活性氧物种（ROS）来调节神经元 L 型 Ca2+电流。血管紧张素 II 型 2 受体（AT2R）诱导一氧化氮（NO）的产生，NO 可能与 ROS 相互作用并调节 AT1R 信号。我们试图确定 AT2R 介导的 NO 产生是否发生在 mNTS 神经元中，如果是这样，阐明 NO 的来源以及与 AT1R 诱导的 ROS 或 Ca2+内流的功能相互作用。电子显微镜（EM）免疫标记显示，AT2R 和神经元一氧化氮合酶（nNOS）在 mNTS 中接收突触的神经元胞体和树突中共同表达。在 AT1R 拮抗剂洛沙坦存在的情况下，ANG II 增加了分离的 mNTS 神经元中的 NO 产生，该作用被 AT2R 拮抗剂 PD123319 阻断，但不被血管紧张素（1-7）拮抗剂 D-Ala 阻断。nNOS 缺失或内皮型一氧化氮合酶（eNOS）缺失小鼠的 mNTS 神经元研究确立了 nNOS 是 NO 的来源。PD123319、NOS 抑制剂 N（G）-硝基-L-精氨酸（LNNA）或 nNOS 缺失小鼠增强了 ANG II 诱导的 ROS 产生。此外，在洛沙坦存在的情况下，ANG II 降低了电压门控 L 型 Ca2+电流，该作用被 PD123319 或 LNNA 阻断。我们的结论是，AT2R 与 mNTS 神经元中的 nNOS 密切相关并具有功能偶联。由此产生的 NO 产生拮抗 AT1R 介导的 ROS 并抑制 L 型 Ca2+电流。NTS 中的这种信号变化可能会抵消 AT1R 对心血管功能的有害影响。
