EDHF Following Traumatic Brain Injury

内皮细胞通过释放β-肾上腺素调节脑动脉和小动脉的收缩状态， 放松因素。近年来，内皮依赖性扩张过程，而不是一氧化氮（NO）或 前列环素已经被发现。这个新的过程，被称为“内皮衍生的超极化因子”或“内皮细胞的超极化因子”。 EDHF上调以补偿创伤性脑损伤后减少的内皮源性NO。 因此，EDHF可能是一种重要的机制，以维持脑灌注时，NO扩张剂 机制受到损害。该建议涉及EDHF介导的扩张机制， 大鼠创伤性脑损伤后的脑动脉。在具体目标1中，建议开展研究， 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环氧合酶途径代谢。在具体目标2中， 建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（H2 O2）的产生增加。在具体目标3中，建议进行研究， 去甲肾上腺素性心衰时内皮细胞和血管平滑肌细胞内Ca ~（2+）和膜电位的变化 创伤性脑损伤大脑中动脉受压分支的直径变化， 从受伤的（控制性皮质撞击损伤）和未受伤的皮质分离，将进行比较， 激动剂诱导的EDHF扩张。结合药理学干预，光学方法， 选择性测定血管平滑肌和内皮细胞的[Ca 2 +]和膜电位， 电生理学技术和测量P450环氧酶代谢物和H2 O2的分析方法 是为了实现这些目标。在特定目标4中，将在正常 条件和创伤性脑损伤后。我们建议使用激光多普勒研究EDHF响应 流量计和软脑膜小动脉直径的测量。我们推测EDHF的上调是一个重要的 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可以更好地了解脑血流的调节 脑损伤后。此外，它将使我们能够测试EDHF上调是保护性的假设， 并可能为创伤性脑损伤的治疗带来新的治疗策略。

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.