CGRP, NO, AND SEPSIS INDUCED MICROVASCULAR DYSFUNCTION

描述：（改编自申请人的摘要） 该提案的长期目标是确定 创伤、局部缺血和 循环性休克 研究者关注的是 血管活性神经肽降钙素基因相关肽（CGRP） 内毒素诱导的循环性休克中的动脉功能障碍。 根本 要解决假设是脉管系统在体内暴露于 LPS导致CGRP从感觉神经末梢释放， 血管和CGRP与增强的血管NO 产生有助于观察到的血管舒张和减少 阻力血管反应性。 这项调查有两个主要的 相关目标：1）进一步确定细胞机制， CGRP对阻力动脉平滑肌细胞的作用， 定义CGRP和NO之间的相互作用; 2）确定是否有原因和 增加血管周围CGRP的释放量与增加血管周围CGRP的释放量之间存在效应关系 感染性休克和进行性微血管功能障碍 这些 假设和目标将受到严格的审查， 包括全身血液动力学记录在内的方法组合， 麻醉大鼠，提睾肌的体内视频显微镜检查 微循环，评估孤立的插管的功能状态 提睾肌小动脉和血管的数字荧光比率成像 完整提睾肌小动脉平滑肌钙反应。 这些 技术将允许研究人员确定是否发生变化， 血管反应与细胞内钙介导的 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.