Endothelial dysfunction predisposes spontaneously hypertensive stroke prone rats to spreading depolarization and spreading ischemia

扩散去极化（SD）是神经元跨膜离子梯度几乎完全击穿的波的总称，引起脑灰质中的细胞毒性水肿。SD连续范围从完整组织中的短SD到严重缺血组织中的中间持续时间SD到终末SD。SD诱导正常组织中的短暂过度灌注（正常反应）;或风险组织中的严重灌注不足（逆血流动力学反应=扩散性缺血）。我们先前发现，在蛛网膜下腔出血（SAH）患者中，当硬膜下光电电极直接位于新发展的迟发性梗死上方时，观察到持久的扩散性缺血，这表明它们导致这些梗死。在之前的项目中，我们发表了世界上最大的SD研究，DISCHARGE-1，在180例SAH患者中进行。上一个项目是翻译。例如，在一个示例中，使用DISCHARGE-1数据并基于主成分和路径分析，一个重要的临床发现是SD是蛛网膜下腔血容量和延迟梗塞体积之间的统计学中介。在α2Na+/K+-ATP酶（纳卡）功能障碍小鼠（Na+敏感性高血压的遗传模型）中，我们发现SD的易感性更高，血流动力学反应更逆。我们研究了易卒中的自发性高血压大鼠（SHRsp），以确定SD阈值/血流动力学反应是否也改变了其他遗传模型的Na+敏感性，并发现他们。许多SAH患者医源性暴露于静脉高渗盐水（HS），因为目前认为这是基于NaCl的渗透特性控制颅内压（ICP）的一种具有成本效益的选择。三分之一的人对Na+敏感。在本项目中，我们前瞻性收集了197例SAH患者的临床、神经监测、成像和结局数据，包括> 18，000个血浆Na+值，这将使我们能够详细检查血浆Na+。在SHRsp和对照大鼠（WKY）中，（i）我们将继续研究半暗带扩散性缺血再灌注，并通过使用增强灌注和O2饱和度（EPOS）的新技术对微循环进行深层表型分析，（ii）将确定HS是否会增强扩散性缺血，特别是在SHRsp中，以及这是否可能与SHRsp中的α2NaKA功能障碍有关，和（iii）将检查HS是否向大分子而不是小分子开放血脑屏障（BBB），并且通过Na+转运到脑脊液和胶质淋巴系统而导致脑间质Na+延迟增加。我们的项目建立在来自先前工作的可靠证据的基础上，即SD和扩散性缺血具有显著的临床重要性，并且具体地解决了使用HS控制ICP的常见做法是否加剧了扩散性缺血和BBB功能障碍，这可以解释我们在与高中位血浆Na+水平相关的临床数据中看到的不良结局，尽管ICP控制良好。

Spreading depolarization (SD) is the generic term for waves of near-complete breakdown of neuronal transmembrane ion gradients causing cytotoxic edema in brain gray matter. The SD continuum ranges from short SDs in intact tissue to SDs of intermediate duration to terminal SD in severely ischemic tissue. SD induces either transient hyperperfusion in normal tissue (normal response); or severe hypoperfusion (inverse hemodynamic response=spreading ischemia) in tissue at risk. We previously found in patients with subarachnoid hemorrhage (SAH) that long-lasting spreading ischemias are observed when subdural optoelectrodes are located directly over newly developing delayed infarcts, suggesting that they cause these infarcts. In the previous project, we published the world's largest SD study, DISCHARGE-1, in 180 SAH patients. The previous project was translational. E.g., using DISCHARGE-1 data and based on principal component and path analyses, an important clinical finding was that SDs are a statistical mediator between subarachnoid blood volume and delayed infarct volume. In α2Na+/K+-ATPase (NaKA)-dysfunctional mice, a genetic model of Na+-sensitive hypertension, we found higher susceptibility to SD and a shift toward more inverse hemodynamic responses. We examined stroke-prone spontaneously hypertensive rats (SHRsp) to determine whether SD thresholds/hemodynamic responses are also altered in other genetic models of Na+ sensitivity and found that they are. Many SAH patients are iatrogenically exposed to intravenous hypertonic saline (HS), as this is currently considered a cost-effective option to control intracranial pressure (ICP) based on the osmotic properties of NaCl. One third of the population is Na+-sensitive. In the present project, our prospectively collected database of clinical, neuromonitoring, imaging and outcome data from 197 SAH patients, including >18,000 plasma Na+ values, will allow us to examine plasma Na+ in detail. In SHRsp and control rats (WKY), (i) we will continue a work package studying penumbral spreading ischemia pharmacologically and via deep phenotyping of the microcirculation using the novel technology of enhanced perfusion and O2 saturation (EPOS), (ii) will determine whether HS enhances spreading ischemia, particularly in SHRsp, and whether this might be related to α2NaKA dysfunction in SHRsp, and (iii) will examine whether HS opens the blood-brain barrier (BBB) to macromolecules but not to small molecules and yet leads to a delayed increase in brain interstitial Na+ by Na+ transport to the cerebrospinal fluid and glymphatic system. Our project builds on solid evidence from previous work that SD and spreading ischemia are of salient clinical importance and specifically addresses whether the common practice of ICP control with HS exacerbates spreading ischemia and BBB dysfunction, which may explain the poor outcome we see in our clinical data associated with high median plasma Na+ levels despite excellent ICP control.