EDHF Following Traumatic Brain Injury

脑外伤后的 EDHF

基本信息

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
项目类别：
财政年份：
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

项目摘要

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.

内皮通过释放调节脑动脉和小动脉的收缩状态放松因素。近年来，除了一氧化氮（NO）或前列环素，被发现。这种新过程被称为“内皮源性超极化因子”或 EDHF 上调以补偿脑外伤后内皮源性 NO 的减少。因此，EDHF 可能是 NO 扩张器维持脑灌注的重要机制。机制受到损害。该提案解决了 EDHF 介导的扩张机制大鼠脑外伤后的脑动脉。在具体目标 1 中，建议研究确定创伤性脑损伤后 EDHF 介导的扩张机制是否涉及花生四烯酸通过 P450 环氧化酶途径代谢。在具体目标 2 中，研究是提议确定创伤性脑损伤后 EDHF 介导的扩张机制是否涉及过氧化氢（H2O2）的产生增加。在具体目标 3 中，建议进行研究来衡量 EDHF 扩张期间内皮和血管平滑肌中的 Ca2+ 和膜电位脑外伤。大脑中动脉（bMCA）受压分支的直径变化，从受伤的（受控皮质冲击损伤）和未受伤的皮质中分离出来，将进行以下比较激动剂诱导EDHF扩张。药物干预、光学方法的结合选择性测量血管平滑肌和内皮的[Ca2+]和膜电位，电生理学技术以及测量 P450 环氧化酶代谢物和 H2O2 的分析方法提出解决这些目标的建议。在具体目标 4 中，将在正常情况下体内研究 EDHF 扩张。条件和脑外伤后。我们建议使用激光多普勒研究 EDHF 响应流量测定和软脑膜小动脉直径的测量。我们推测 EDHF 上调是一个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有助于更好地了解脑血流的调节脑损伤后。此外，它将使我们能够检验 EDHF 上调具有保护性的假设并可能导致治疗创伤性脑损伤的新治疗策略。