Recent Advances in Neurogenic Hypertension: Dietary Salt, Obesity, and Inflammation.
Recent Advances in Neurogenic Hypertension: Dietary Salt, Obesity, and Inflammation.
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神经源性高血压的最新进展：膳食盐、肥胖和炎症。
DOI：
10.1161/hypertensionaha.117.08936
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Sved,AlanF
中科院分区：
文献类型：
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作者：
Stocker,SeanD;Kinsman,BrianJ;Sved,AlanF
Stocker et al Advances in Neurogenic Hypertension 475方式。[11]重要的是，抑制终板神经元的血管器可大大减弱对高渗NaCl中枢灌注的交感神经兴奋性反应。11中枢性高钠血症增加头端腹外侧延髓（RVLM）中球脊髓神经元的谷氨酸能激活，从而增加SNA。[7]有趣的是，中枢NaCl刺激在RVLM神经元中产生3种不同的反应，包括放电增加、无变化或放电减少。RVLM反应的复杂性可能反映了与血浆或脑脊液NaCl浓度变化相关的交感神经信号。上述研究的一个主要警告是，NaCl浓度的操作是急性的。然而，兴奋性氨基受体或血管紧张素I型受体在RVLM阻断降低ABP在达尔盐敏感大鼠喂食高盐饮食。未来的研究需要确定NaCl浓度慢性升高对不同终末器官SNA水平的影响，NaCl感受神经元的活动，以及这些神经元如何感受NaCl。[17]饮食中的盐摄入也会改变下丘脑加压素（VP）神经元的兴奋性，从而增加VP分泌或调节SNA。神经元通过NKCC 1（钠-钾-2-氯转运蛋白1）的Cl−内流和KCC 2（钾-氯协同转运蛋白2）的Cl−外流维持低细胞内氯浓度。[18]过量的盐摄入会使ECl−向更正的或去极化的方向移动--净效应是GABA能介导的抑制作用丧失。例如，去氧皮质酮盐高血压大鼠的VP神经元表现出去极化的ECl−，VP神经元的GABA能兴奋和升压反应，以及压力感受器介导的抑制对VP神经元活动的兴奋的逆转。19，20在脱氧皮质酮盐高血压中，布美他尼阻断脑NKCC 1可减弱改变的ECl−并降低ABP。19，20通过接触2% NaCl的慢性盐负荷也通过脑源性神经营养因子减少KCC 2表达将VP神经元的ECl−转变为去极化值。21净效应是压力感受器介导的VP神经元抑制的丧失和高血压，至少部分由循环VP水平介导。最后，VP还可以通过下丘脑室旁核（PVH）内的局部释放来调节SNA。22慢性盐负荷后，PVH中V1 a受体的阻断降低了腰椎SNA和ABP。[23]虽然高盐饮食不会提高实验动物的ABP（传统上称为作为盐抗性），但过量的盐摄入会夸大RVLM诱发的交感神经兴奋和交感神经抑制反应。24-27这些反应在功能上是重要的，因为喂食高盐饮食的耐盐大鼠对坐骨神经传入神经的激活、28运动、29主动脉减压神经或迷走神经传入神经的刺激、28容量扩张、28和脑室内输注NaCl显示出放大的SNA和ABP反应。[28]这些效应的发生与基线SNA或平均ABP的变化无关。有趣的是，高盐饮食增加了耐盐动物的ABP变异性。28该观察结果具有显著的临床意义，因为ABP变异性增加是终末器官损伤、CV疾病发展的风险因素，也是未来不良CV事件的预测因素。30，31总的来说，这些数据表明，饮食中的盐可能会对交感神经调节网络的增益产生不利影响。未来的实验需要
Stocker et al Advances in Neurogenic Hypertension 475 manner. 11 Importantly, inhibition of organum vasculosum of the lamina terminalis neurons largely attenuates sympathoexcitatory responses to central infusion of hypertonic NaCl. 11 Central hypernatremia increases glutamatergic activation of bulbospinal neurons in the rostral ventrolateral medulla (RVLM) to increase SNA. 7 Interestingly, central NaCl stimulation produced 3 divergent responses in RVLM neurons, including an increase in discharge, no change, or a decrease in cell discharge. 7 The complexity of the RVLM responses likely reflects the sympathetic signature associated with changes in plasma or cerebrospinal fluid NaCl concentrations. A major caveat of the above studies is that the manipulations in NaCl concentrations were acute. Yet, blockade of excitatory amino receptors or angiotensin type I receptors in the RVLM reduces ABP in Dahl salt–sensitive rats fed a high salt diet. 15, 16 Future investigations need to define the impact of chronic elevation in NaCl concentrations on the level of SNA across different end organs, the activity of NaCl-sensing neurons, and how such neurons sense NaCl. 17Dietary salt intake also alters the excitability of hypothalamic vasopressin (VP) neurons to exaggerate VP secretion or regulate SNA. Neurons maintain low intracellular chloride concentrations through Cl− influx via NKCC1 (sodium-potassium-2-chloride transporter 1) and efflux via KCC2 (potassium-chloride-cotransporter 2). 18 Excess salt intake shifts the ECl− to a more positive or depolarized value—the net effect is a loss of GABAergic-mediated inhibition. For example, VP neurons of deoxycorticosterone-salt hypertensive rats display a depolarized ECl−, a GABAergic excitation of VP neurons and pressor response, and a reversal of baroreceptor-mediated inhibition to excitation of VP neuronal activity. 19, 20 Blockade of brain NKCC1 with bumetanide attenuates the altered ECl− and lowers ABP in deoxycorticosterone-salt hypertension. 19, 20 Chronic salt loading via access to 2% NaCl also shifts ECl− of VP neurons to a depolarized value through a reduction in KCC2 expression via brain-derived neurotrophic factor. 21 The net effect is a loss of baroreceptor-mediated inhibition of VP neurons and hypertension, at least partly, mediated by circulating VP levels. Finally, VP may also regulate SNA through local release within the hypothalamic paraventricular nucleus (PVH). 22 Blockade of V1a receptors in the PVH decreases lumbar SNA and ABP after chronic salt loading. 23 Although a high salt diet does not raise ABP in laboratory animals (classically known as salt resistance), excess salt intake exaggerates sympathoexcitatory and sympathoinhibitory responses evoked from the RVLM. 24–27 These responses are functionally significant as salt-resistant rats fed a high salt diet display exaggerated SNA and ABP responses to the activation of sciatic afferents, 28 exercise, 29 stimulation of the aortic depressor nerve or vagal afferents, 28 volume expansion, 28 and intracerebroventricular infusion of NaCl. 28 These effects occur independently of changes in baseline SNA or mean ABP. 28 Interestingly, a high salt diet increases ABP variability in salt-resistant animals. 28 This observation has significant clinical ramifications as increased ABP variability is a risk factor for end-organ damage, development of CV disease, and predictor for future adverse CV events. 30, 31 Collectively, these data suggest that dietary salt may adversely affect the gain of sympathetic regulatory networks. Future experiments need to