Potassium Channel Dysfunction in Cerebral Arteries

描述（由申请人提供）：血管平滑肌（VSM）中的钾(K)通道激活促进动脉对生理刺激的扩张。我们的新发现是胰岛素抵抗（IR）损害脑动脉对刺激的扩张反应，这依赖于VSM中K通道的开放。IR中K通道功能障碍的潜在基础可能与活性氧（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/或恢复受损的原因。然而，这些问题尚未得到充分调查。我们建立了两个特定的目标来研究这些问题在祖克肥胖大鼠IR模型的原位基底动脉：特定目标1。脑循环VSM中K功能紊乱的机制探讨。我们将测试IR以亚型特异性方式损害脑动脉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。首先，我们将在体内研究选择性K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通道亚基的血管水平。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，我们将确定ROS的代谢来源。第五，我们将确定受损的K通道介导的扩张是否会导致收缩效应增强。第六，我们将使用电生理学方法来表征IR大鼠大脑动脉中VSM膜电位与直径之间的关系。具体目标2。实验性SAH后IR对脑动脉功能影响的研究。我们将验证以下假设，即潜在的IR会增强SAH对基线动脉直径的不利影响，并逆转对K通道依赖性扩张剂的增强血管反应。首先，我们将检查SAH对IR患者基线直径和血管反应性的影响。其次，我们将探讨K通道在IR中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中脑VSM的膜电位和直径的关系。

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.