Control of Cerebral Blood Flow by KCa2 and KCa3

KCa2 ​​和 KCa3 对脑血流的控制

• 批准号: 8391870
• 负责人: ROBERT M BRYAN
• 金额: $ 23.48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391870
• 关键词: Agonist; Arteries; Biological Availability; Brain; Calcium-Activated Potassium Channel; Caliber; Cardiovascular system; Cell membrane; Cerebrovascular Circulation; Cerebrum; Clinical; Dilator; Endothelium; Erythrocytes; Flow-It; In Vitro; Ischemia; Laser-Doppler Flowmetry; Measures; Mediating; Nitric Oxide; P2Y2 receptor; Plasma; Potassium Channel; Prostaglandin-Endoperoxide Synthase; Prostaglandins I; Regulation; Relative (related person); Reperfusion Therapy; Rest; Role; Site; Stroke; Surface; Testing; Traumatic Brain Injury; Up-Regulation; Vascular resistance; arteriole; base; cerebral artery; cerebrovascular; clinical practice; clinically relevant; in vivo; inhibitor/antagonist; novel; therapeutic target

DESCRIPTION (provided by applicant): A novel endothelium-dependent dilator mechanism was identified in cerebral arteries and arterioles. This dilator mechanism has been called endothelium-derived hyperpolarizing factor (EDHF) or endothelium- dependent hyperpolarization (EDH).This mechanism, which does not involve nitric oxide (NO) or cyclooxygenase metabolites (i.e., prostacyclin), requires the activation of intermediate and/or small conductance calcium-activated K+ channels (IKCa and SKCa respectively) in cerebral vessels. Studies utilizing isolated cerebral arteries and arterioles provide circumstantial evidence that this dilator mechanism, involving IKCa and SKCa, may be as important as endothelium-derived NO in regulating cerebral blood flow (CBF). This idea is based on the key role of IKCa/SKCa in setting the resting diameter of cerebral arteries and arterioles, their contribution to endothelium-mediated dilations, and their relative importance compared to NO in penetrating arterioles, a site of major vascular resistance in the brain. In addition, dilations through IKCa/SKCa are enhanced following ischemia/reperfusion, traumatic brain injury, and other pathological states when NO bioavailability is diminished. Upregulation of IKCa/SKCa-mediated dilations may be an important protective strategy serving to compensate for decreased NO and ultimately limit reductions in CBF during pathological states. Although provocative, it is important to emphasize that studies to date involving IKCa/SKCa-mediated dilations have primarily used isolated cerebral vessels, which were removed from the brain and examined ex vivo in a vessel chamber. In order to fully understand the importance of IKCa and SKCa in controlling CBF, it is imperative that these studies are extended to the in vivo situation where arteries and arterioles function as a coordinated network in the cardiovascular system. Therefore, we propose to test the hypothesis that IKCa and/or SKCa channels regulate CBF in vivo. We propose to demonstrate that activation of IKCa and SKCa increase cerebral blood flow (Specific Aim 1). We will determine the contribution of IKCa and SKCa to resting CBF (Specific Aim 2). Finally, we will determine the contribution of IKCa and SKCa to increases in CBF elicited by ATP, an agonist released by red blood cells into the plasma (Specific Aim 3). Increases in CBF will be measured from the cortical surface using laser Doppler flowmetry following direct stimulation of IKCa and SKCa channels or indirectly through ATP, an agonist for endothelial P2Y2 receptors. For the specific aims, we will utilize selective pharmacological inhibitors to determine the relative contribution of IKCa and SKCa in controlling CBF. The need to conduct the proposed studies in vivo is amplified by the circumstantial evidence indicating an important role for IKCa/SKCa in regulating CBF. IKCa/SKCa channels could be of clinical relevance and a therapeutic target during pathological conditions where the bioavailability of NO is compromised. Furthermore, IKCa/SKCa channels could find their way into clinical practice in a manner similar to that of NO. PUBLIC HEALTH RELEVANCE: The control of cerebral blood flow is an important clinical consideration for a number of pathological states such as stroke and traumatic brain injury. Intermediate and small conductance potassium channels, which allow only K+ to pass across the cell membrane, appear to be an important mechanism for endothelial control of cerebral blood flow. The proposed studies will determine the role of these intermediate and small conductance potassium channels in the regulation of cerebral blood flow.

描述（由申请人提供）：在脑动脉和动脉中鉴定出一种新型的内皮依赖性扩张器机制。该扩张器机制称为内皮衍生的超极化因子（EDHF）或依赖性内皮性超极化（EDH）。这种机制不涉及一氧化氧化物（NO）或环氧酶代谢物（即前列环蛋白）（即，在中间/或小型指数）的激活（即，二氧化酶代谢物），需要分别在脑血管中。利用孤立的脑动脉和动脉的研究提供了间接证据，表明涉及IKCA和SKCA的扩张机制在调节大脑血流（CBF）中可能与内皮衍生的NO一样重要。这个想法是基于IKCA/SKCA在设定脑动脉和动脉静止直径的关键作用，它们对内皮介导的扩张的贡献以及与穿透性小动脉的NO相比，它们的相对重要性是大脑中主要血管耐药性的部位。此外，在没有生物利用性降低时，通过缺血/再灌注，创伤性脑损伤和其他病理状态的扩张会增强。 IKCA/SKCA介导的扩张的上调可能是一种重要的保护策略，可用于补偿NO的减少，并最终限制病理状态下CBF的减少。尽管具有挑衅性，但重要的是要强调，迄今为止涉及IKCA/SKCA介导的扩张的研究主要使用了分离的脑血管，这些血管被从大脑中取出并在容器室内进行了体内检查。为了充分了解IKCA和SKCA在控制CBF中的重要性，必须将这些研究扩展到体内情况，在体内情况下，动脉和小动脉在心血管系统中充当协调的网络。因此，我们建议检验IKCA和/或SKCA通道在体内调节CBF的假设。我们建议证明IKCA和SKCA的激活会增加脑血流（特定目标1）。我们将确定IKCA和SKCA对静止CBF的贡献（特定目标2）。最后，我们将确定IKCA和SKCA对ATP引起的CBF增加的贡献，ATP是红细胞释放到血浆中的激动剂（特定AIM 3）。在直接刺激IKCA和SKCA通道后，将使用激光多普勒流量测量CBF的增加，或通过ATP（一种用于内皮P2Y2受体的激动剂）ATP来测量CBF。对于具体目的，我们将利用选择性的药理学抑制剂来确定IKCA和SKCA在控制CBF方面的相对贡献。间接证据表明IKCA/SKCA在调节CBF中起着重要作用的间接证据来扩大对体内提出的研究的需求。在病理条件下，IKCA/SKCA通道可能具有临床相关性和治疗靶标，而NO的生物利用度受到损害。此外，IKCA/SKCA渠道可以以类似于NO的方式进入临床实践。 公共卫生相关性：对许多病理状态（例如中风和脑外伤）的重要临床考虑，脑血流的控制是一个重要的临床考虑因素。中间和小电导的钾通道（只有K+都可以穿过细胞膜）似乎是对脑血流内皮控制的重要机制。拟议的研究将确定这些中间和小电导钾通道在调节脑血流中的作用。