EDHF Following Traumatic Brain Injury

脑外伤后的 EDHF

• 批准号: 7551880
• 负责人: ROBERT M BRYAN
• 金额: $ 17.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7551880
• 关键词: Acids; Address; Agonist; Animals; Arachidonic Acids; Arteries; Attenuated; Blood flow; Brain; Brain Injuries; Caliber; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Characteristics; Condition; Cytochrome P450; Dilator; Endothelium; Endothelium-Dependent Relaxing Factors; Epoprostenol; Estrogens; Goals; Heart; Hydrogen Peroxide; Injury; Intervention; Ischemia; Laser-Doppler Flowmetry; Lasers; Lead; Localized; Measurement; Measures; Mediating; Membrane Potentials; Metabolism; Methods; Middle Cerebral Artery Branch; Nitric Oxide; Nitric Oxide Pathway; Numbers; Optical Methods; Organ; Pathway interactions; Perfusion; Peripheral; Physiological reperfusion; Process; Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins I; Range; Rattus; Regulation; Reperfusion Therapy; Research Personnel; Smooth Muscle; System; Techniques; Testing; Tissues; Traumatic Brain Injury; Up-Regulation; Vascular Endothelium; Vascular Smooth Muscle; arteriole; cerebral artery; controlled cortical impact; cyclooxygenase 1; cyclooxygenase 2; in vivo; injured; insight; neuroprotection; novel therapeutics; programs; relaxing factor; response

The endothelium regulates the contractile state of cerebral arteries and arterioles through the release of relaxing factors. In recent years, an endothelial-dependent dilator process, other than nitric oxide (NO) or prostacyclin, has been discovered. This new process, termed "endothelium-derived hyperpolarizing factor" or EDHF, is upregulated to compensate for diminished endothelial-derived NO following traumatic brain injury. Thus, EDHF could be an important mechanism to maintain cerebral perfusion when the NO dilator mechanism is compromised. This proposal addresses the mechanism of the EDHF-mediated dilations in cerebral arteries following traumatic brain injury to the rat. In Specific Aim 1, studies are proposed to determine if the mechanism of EDHF-mediated dilations following traumatic brain injury involves the metabolism of arachidonic acid through the P450 epoxygenase pathway. In Specific Aim 2, studies are proposed to determine if the mechanism of EDHF-mediated dilations following traumatic brain injury involves an increased production of hydrogen peroxide (H2O2). In Specific Aim 3 studies are proposed to measure Ca2+ and membrane potential in endothelium and vascular smooth muscle during EDHF dilations following traumatic brain injury. Diameter changes of pressurized branches of middle cerebral arteries (bMCAs), isolated from injured (controlled cortical impact injury) and non-injured cortex, will be compared following agonist induced EDHF dilations. A combination of pharmacological interventions, optical methods for selectively measuring [Ca2+] and membrane potential of vascular smooth muscle and endothelium, electrophysiological techniques, and analytic methods to measure P450 epoxygenase metabolites and H2O2 are proposed to address the aims. In Specific Aim 4 EDHF dilations will be studied in vivo during normal conditions and following traumatic brain injury. We propose to study the EDHF response using laser Doppler flowmetry and measurement of pial arteriole diameter. We speculate that EDHF upregulation is an important intrinsic mechanism to maintain cerebral perfusion. Understanding the mechanism of EDHF-mediated dilations following traumatic brain injury will allow better insight into the regulation of cerebral blood flow following brain injury. Further, it will allow us to test the hypothesis that the EDHF upregulation is protective and could lead to new therapeutic strategies for treatment of traumatic brain injury.

内皮通过释放来调节脑动脉和动脉的收缩状态 放松因素。近年来，除一氧化氮（NO）或 Prostacyclin已被发现。这个新过程称为“内皮衍生的超极化因子”或 EDHF被上调以补偿内皮衍生的脑损伤后降低的脑损伤。 因此，当无扩张器时，EDHF可能是维持脑灌注的重要机制 机制受到损害。该建议涉及EDHF介导的扩张的机制 大鼠创伤性脑损伤后的大脑动脉。在特定目标1中，提出了研究 确定创伤性脑损伤后EDHF介导的扩张的机制是否涉及 通过P450环氧酶途径对蛛网膜酸的代谢。在特定目标2中，研究是 提议确定EDHF介导的脑损伤后EDHF介导的扩张的机制是否涉及 过氧化氢的产生增加（H2O2）。在特定目标中提出了3个研究以衡量 EDHF扩张期间内皮和血管平滑肌的Ca2+和膜潜力 创伤性脑损伤。脑动脉加压分支（BMCA）的直径变化， 从受伤的受伤（受控皮质撞击损伤）和无损伤的皮质中分离出来，将进行比较 激动剂诱导EDHF扩张。药理干预措施的结合，光学方法 有选择地测量血管平滑肌和内皮的[Ca2+]和膜电位， 电生理技术和测量P450环氧酶代谢产物和H2O2的分析方法 建议解决目标。在特定目标中，将在正常情况下在体内研究EDHF扩张 条件和脑部外伤后。我们建议使用激光多普勒研究EDHF响应 流动仪和小动脉直径的测量。我们推测EDHF上调是重要的 维持脑灌注的内在机制。了解EDHF介导的机制 创伤性脑损伤后的扩张将使您可以更好地了解脑血流的调节 脑损伤后。此外，这将使我们能够检验EDHF上调具有保护性的假设 并可能导致新的治疗策略来治疗创伤性脑损伤。