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首页> 外文期刊>Physiological Reports >Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na + /H + exchanger‐1 antagonism
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Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na + /H + exchanger‐1 antagonism

机译：在缺血性中风后电压门控质子通道HV1敲除大鼠的神经血管保护：与Na + / H +交换剂-1拮抗作用的相互作用

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Experimental studies have demonstrated protective effects of NHE‐1 inhibition on cardiac function; however, clinical trials utilizing NHE‐1 antagonists found an increase in overall mortality attributed to thromboembolic strokes. NADPH oxidase‐derived reactive oxygen species (ROS) from microglial cells have been shown to contribute to injury following stroke. We have recently demonstrated that NHE‐1 inhibition enhances ROS in macrophages in a Hv1‐dependent manner. As Hv1 protein is highly expressed in microglia, we hypothesized that “NHE‐1 inhibition may augment neurovascular injury by activating Hv1,” providing a potential mechanism for the deleterious effects of NHE‐1. The goal of this study was to determine whether neurovascular injury and functional outcomes after experimental stroke differed in wild‐type and Hv1 mutant Dahl salt‐sensitive rats treated with an NHE‐1 inhibitor. Stroke was induced using both transient and permanent of middle cerebral artery occlusion (MCAO). Animals received vehicle or NHE‐1 inhibitor KR32568 (2?mg/kg, iv) either 30?min after the start of MCAO or were pretreated (2?mg/kg, iv, day) for 3?days and then subjected to MCAO. Our data indicate that Hv1 deletion confers both neuronal and vascular protection after ischemia. In contrast to our hypothesis, inhibition of NHE‐1 provided further protection from ischemic stroke, and the beneficial effects of both pre‐ and post‐treatment with KR32568 were similar in wild‐type and Hv1 ?/? rats. These data indicate that Hv1 activation is unlikely to be responsible for the increased incidence of cerebrovascular events observed in the heart disease patients after NHE‐1 inhibition treatment.
机译：实验研究表明了NHE-1抑制对心脏功能的保护作用;然而，利用NHE-1拮抗剂的临床试验发现归因于血栓栓塞中风的总体死亡率增加。已经显示来自小胶质细胞的NADPH氧化酶衍生的反应性氧物质（ROS）有助于卒中后损伤。我们最近证明NHE-1抑制以HV1依赖性方式增强巨噬细胞中的ROS。由于HV1蛋白在微胶质细胞中高度表达，我们假设“NHE-1抑制可以通过激活HV1增加神经血管损伤”，为NHE-1的有害作用提供潜在机制。本研究的目标是确定在实验中风后的神经血管损伤和功能性结果不同，用NHE-1抑制剂处理的野生型和HV1突变体DAHL敏感大鼠不同。使用瞬态和永久性的中脑动脉闭塞（MCAO）诱导中风。在MCAO开始或预处理（2×Mg / kg，IV，日）后，动物接受载体或NHE-1抑制剂KR32568（2？Mg / kg，iv）30？min 3？天，然后对MCAO进行预处理。我们的数据表明HV1缺失在缺血后赋予神经元和血管保护。与我们的假设相比，抑制NHE-1进一步保护缺血性卒中，并且在KR32568的野生型和HV1中具有预处理和治疗后的有益效果？/？老鼠。这些数据表明HV1活化不太可能对NHE-1抑制治疗后心脏病患者观察到的脑血管事件的发病率增加不大。

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