MECHANISMS OF CEREBRAL RESISTANCE ARTERY CONTRACTION

脑阻力动脉收缩的机制

• 批准号: 2901306
• 负责人: JOSEPH ELLIOTT BRAYDEN
• 金额: $ 24.66万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2901306
• 关键词: biological signal transduction; calcium channel; calcium flux; cerebral artery; chloride channels; confocal scanning microscopy; fluorescent dye /probe; laboratory rat; membrane potentials; potassium channel; vascular resistance; vascular smooth muscle; vasoconstriction; voltage /patch clamp; voltage gated channel

DESCRIPTION: (Adapted from the application) The aims of this proposal are to reveal some of the mechanisms of depolarization and constriction of cerebral artery smooth muscle to physiological stimuli. The central hypothesis is that vasoconstrictor stimuli inhibit K+ channels and activate Cl- channels, resulting in smooth muscle depolarization and contraction. The goals of the following 3 specific aims are to demonstrate the involvement of specific K+ and Cl- ion channels in cerebral artery constrictor responses and to define the cellular signaling pathways which regulate these ion channels. Specific Aim #1, will test the hypothesis that inhibition of calcium activated K+ channels is a mechanism of cerebral artery constriction. Calcium-activated potassium channel activity is increased by calcium. One source of this calcium is the sarcoplasmic reticulum which via ryanodine-sensitive channels releases calcium to localized regions near the plasmalemma. The calcium release channels as well as the calcium-activated potassium channel itself are sites where vasoconstrictor generated second messengers could inhibit calcium-activated potassium channels. These possibilities will be examined using activators and inhibitors of established signal transduction pathways. Specific Aim #2 will test the hypothesis that inhibition of voltage-dependent potassium channels is another mechanism of agonist-induced vasoconstriction. Pharmacological inhibition of voltage-dependent potassium channels depolarizes and constricts isolated cerebral arteries. Voltage-dependent potassium channel currents contribute to resting membrane potential in vascular smooth muscle. In this aim the direct and indirect effects of vasoconstrictors on voltage-dependent potassium channels will be determined. Specific Aim #3 will test the hypothesis that chloride channels contribute to regulation of membrane potential in cerebral arteries. Chloride channels are present in vascular smooth muscle. Chloride channel blockers hyperpolarized and dilate cerebral arteries contracted by agonists or pressure. In this aim, the properties and mechanisms of regulation and functional roles of cerebrovascular smooth muscle chloride channels will be evaluated. These studies will employ state-of-the-art techniques to study: 1) localized and global changes in intracellular calcium using conventional digital fluorescence imaging and confocal microscopy, 2) ion channel activity using the patch-clamp technique and 3) correlated electrical and contractile responses of pressurized cerebral resistance arteries. A more complete understanding of the mechanisms of contraction and relaxation of vascular smooth muscle is essential to the development of new strategies for treatment of pathophysiological states that involve excessive vasoconstrictor (hypertension, vasospasm and ischemia). The proposed studies should provide essential new information relevant to these issues.

描述：（改编自应用程序）本提案的目的是 以揭示一些去极化和收缩的机制， 脑动脉平滑肌对生理刺激的反应。 中央 假设血管收缩刺激抑制K+通道并激活 氯离子通道，导致平滑肌去极化和收缩。 以下3个具体目标的目标是证明 脑动脉特异性K ~+和Cl ~-通道参与 收缩反应，并确定细胞信号通路， 调节这些离子通道。 具体目标#1，将检验钙抑制 激活的K+通道是脑动脉收缩的机制。 钙激活的钾通道活性被钙增加。 一 这种钙的来源是肌浆网， ryanodine敏感通道释放钙到局部区域附近的 质膜 钙释放通道和钙激活的 钾通道本身是血管收缩剂产生第二个 信使能抑制钙激活钾通道。 这些 可能性将使用激活剂和抑制剂的研究 建立了信号传导途径。 具体目标#2将测试 假设电压依赖性钾通道的抑制是 激动剂诱导的血管收缩的另一种机制。 药理 电压依赖性钾通道的抑制去极化， 收缩孤立的脑动脉。 电压依赖性钾通道 电流有助于血管平滑肌中的静息膜电位。 在这个目标中，血管收缩剂的直接和间接作用， 将测定电压依赖性钾通道。 具体目标#3 将测试假设，氯离子通道有助于调节 脑动脉膜电位 氯离子通道存在于 血管平滑肌 氯离子通道阻滞剂超极化和扩张 脑动脉收缩激动剂或压力。 为此， 调节的性质和机制以及功能作用 将评价脑血管平滑肌氯离子通道。 这些 研究将采用最先进的技术来研究：1）本地化， 细胞内钙的总体变化，使用传统的数字 荧光成像和共聚焦显微镜，2）离子通道活性， 膜片钳技术和3）相关的电和收缩 加压脑阻力动脉的反应。 更完整 了解血管收缩和舒张的机制 平滑肌对于开发新的策略至关重要， 治疗涉及过度的病理生理状态 血管收缩剂（高血压、血管痉挛和缺血）。 拟议 研究应提供与这些问题有关的重要新资料。