Potassium Channel Dysfunction in Cerebral Arteries

描述(由申请人提供)：血管平滑肌(VSM)中钾(K)通道的激活促进了动脉对生理刺激的扩张。我们的新发现是，胰岛素抵抗(IR)损害了脑动脉对刺激的扩张器反应，这依赖于VSM中K通道的开放。胰岛素抵抗时钾通道功能障碍的基础可能与活性氧(ROS)的产生增加有关。这种血管损伤可能是脑血管意外(如蛛网膜下腔出血(SAH))发生率增加和/或康复受阻的原因。然而，这些问题还没有得到充分的调查。我们在Zucker肥胖大鼠IR模型的原位基底动脉中建立了两个特定的目标来研究这些问题：特定的目标1.阐明错乱的K功能在脑循环VSM中的作用机制。我们将验证IR以亚型特异性的方式损害脑动脉K通道功能的假设，以及血管生成和ROS的作用介导K通道功能障碍的假设。首先，我们将考察选择性钾通道激动剂和拮抗剂对基底动脉及其分支的影响。其次，我们将确定IR是否会改变K通道亚单位的血管水平。第三，我们将使用药理学和基因转移方法评估ROS在IR中K通道功能障碍中的作用。第四，确定ROS的代谢来源。第五，我们将确定K通道介导的扩张受损是否会导致收缩效应的增强。第六，我们将利用电生理学方法研究IR大鼠脑动脉VSM膜电位与管径的关系。具体目的2.观察IR对实验性蛛网膜下腔出血后脑动脉功能的影响。我们将测试这一假设，即潜在的IR将加强SAH对基线动脉内径的不利影响，并逆转对K通道依赖性扩张剂增强的血管反应。首先，我们将研究蛛网膜下腔出血对IR患者基线内径和血管反应性的影响。其次，我们将探讨K通道在胰岛素抵抗SAH后动脉功能损害中的作用。第三，我们将确定基因转移是否保护IR动物对SAH的血管反应。第四，我们将研究IR和SAH时脑VSM膜电位与直径的关系。

DESCRIPTION (provided by applicant): Potassium (K) channel activation in vascular smooth muscle (VSM) promotes dilation of arteries to physiological stimuli. Our new finding is that insulin resistance (IR) impairs dilator responses of cerebral arteries to stimuli, which are dependent on opening of K channels in VSM. The underlying basis of K channel dysfunction in IR may involve increased production of reactive oxygen species (ROS). This vascular impairment may account for the increased incidence of and/or impaired recovery from cerebrovascular accidents such as subarachnoid hemorrhage (SAH). However, these issues have not been adequately investigated. We have created 2 specific aims to examine these issues in the in situ basilar artery of the Zucker Obese rat model of IR: Specific Aim 1. Elucidation of mechanisms of deranged K function in VSM of the cerebral circulation. We will test the hypotheses that IR impairs K channel function of cerebral arteries in a subtype-specific fashion and that vascular production and actions of ROS mediate K channel dysfunction. First, we will examine effects of selective K channel agonists and antagonists on the basilar artery and its branches in vivo. Second, we will determine whether IR changes vascular levels of K channel subunits. Third, we will assess the role of ROS in K channel dysfunction in IR using pharmacological and gene transfer approaches. Fourth, we will determine the metabolic source of ROS. Fifth, we will determine whether impaired K channel-mediated dilation leads to enhance constrictor effects. And sixth, we will use electrophysiological approaches to characterize the relationship between VSM membrane potential and diameter in cerebral arteries from IR rats. Specific Aim 2. Examination of effects of IR on cerebral arterial function following experimental SAH. We will test the hypothesis that underlying IR will potentiate adverse effects of SAH on baseline artery diameter and reverse augmented vascular responses to K channel-dependent dilator agents. First, we will examine the effects of SAH on baseline diameter and vascular responsiveness in IR. Second, we will explore the role of K channels in impairment of arterial function following SAH in IR. Third, we will determine whether gene transfer protects vascular responses against SAH in IR animals. And fourth, we will examine the relationship between membrane potential and diameter in cerebral VSM in IR and SAH.