CGRP, NO, AND SEPSIS INDUCED MICROVASCULAR DYSFUNCTION

描述：(改编自申请人的摘要)概述和 这项提案的长期目标是定义 外周血管和微血管功能障碍与创伤、缺血和 循环系统休克。调查者关注的是强者的作用。 血管活性神经肽降钙素基因相关肽在抵抗中的作用 内毒素所致循环休克时的动脉功能障碍。最基本的 需要解决的假设是，血管系统在体内暴露于 内毒素导致感觉神经末梢释放CGRP，使 血管系统和降钙素基因相关肽与增强的血管一氧化氮 产物有助于观察到的血管扩张和减弱 阻力、血管反应性。这项调查有两个主要原因 相互关联的目标：1)进一步定义 降钙素基因相关肽对阻力动脉平滑肌细胞的作用及特异性 定义CGRP和NO之间的相互作用；2)确定原因和 血管周围CGRP释放增多之间存在效应关系 在感染性休克和进行性微血管功能障碍期间。这些 假设和目标将受到严格的审查，使用 一种包括全身血流动力学记录在内的方法组合 麻醉大鼠提睾肌的在体视频显微镜观察 孤立插管的微循环功能状态的评估 提睾肌小动脉与血管数字荧光比值成像 完整提睾肌小动脉的平滑肌钙反应。这些 技术将允许调查员确定是否发生了变化 血管反应与细胞内钙离子介导的变化相关 直接或间接通过CGRP和/或NO。

DESCRIPTION: (Adapted from the applicant's abstract) The broad and long-term objectives of this proposal are to define the mechanisms of peripheral vascular and microvascular dysfunction in trauma, ischemia, and circulatory shock. The investigator focuses on the role of the potent vasoactive neuropeptide calcitonin gene-related peptide (CGRP) in resistant artery dysfunction in endotoxin-induced circulatory shock. The fundamental hypothesis to be addressed is that in vivo exposure of the vasculature to LPS results in release of CGRP from sensory nerve terminals, enervating the vasculature and that CGRP in combination with enhanced vascular NO production contributes to the observed vasodilatation and diminished resistance vascular responsiveness. This investigation has two principal inter-related objectives: 1) to further define the cellular mechanisms of action of CGRP on resistance artery smooth muscle cell and specifically define interactions between CGRP and NO; 2) to establish whether a cause and effect relationship exists between augmented perivascular CGRP release during septic shock and progressive microvascular dysfunction. These hypotheses and objectives will be subjected to a rigorous examination using a combination of methodologies including systemic hemodynamic recordings in anesthetized rats, in vivo video microscopy of the cremaster muscle microcirculation, assessment of the functional state of isolated cannulated cremaster arterioles, and digital fluorescence ratio imaging of vascular smooth muscle calcium responses in intact cremaster arterioles. These techniques will allow the investigator to determine whether changes in vascular responses correlate with changes in intracellular calcium-mediated directly or indirectly by CGRP and/or NO.