Potassium Channel Dysfunction in Cerebral Arteries

脑动脉钾通道功能障碍

• 批准号: 6905649
• 负责人: DAVID W BUSIJA
• 金额: $ 35.88万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6905649
• 关键词: SDS polyacrylamide gel electrophoresis; brain circulation; cardiovascular pharmacology; cerebral artery; cerebrovascular disorders; comorbidity; free radical oxygen; gene delivery system; hemodynamics; inflammation; insulin sensitivity /resistance; laboratory rat; membrane potentials; oxidation; potassium channel; statistics /biometry; subarachnoid hemorrhage; vascular smooth muscle; vasoconstriction; vasodilation

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.

描述（由申请人提供）：血管平滑肌（VSM）中钾（K）通道的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) 会损害脑动脉对刺激的扩张反应，而这取决于 VSM 中 K 通道的开放。 IR 中 K 通道功能障碍的根本原因可能涉及活性氧 (ROS) 产生的增加。这种血管损伤可能是导致蛛网膜下腔出血（SAH）等脑血管意外发生率增加和/或恢复受损的原因。然而，这些问题尚未得到充分调查。我们创建了 2 个具体目标来检查 Zucker 肥胖大鼠 IR 模型的原位基底动脉中的这些问题： 具体目标 1. 阐明脑循环 VSM 中 K 功能紊乱的机制。我们将检验以下假设：IR 以亚型特异性方式损害脑动脉 K 通道功能，以及血管生成和 ROS 作用介导 K 通道功能障碍。首先，我们将检查选择性 K 通道激动剂和拮抗剂对体内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 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 大鼠脑动脉 VSM 膜电位和直径之间的关系。具体目标 2. 检查 IR 对实验性 SAH 后脑动脉功能的影响。我们将检验以下假设：潜在的 IR 将增强 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 中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可以保护 IR 动物中针对 SAH 的血管反应。第四，我们将检查 IR 和 SAH 中脑 VSM 的膜电位和直径之间的关系。