MECHANISMS OF CUTANEOUS ACTIVE VASODILATION IN HUMANS

人类皮肤主动血管舒张的机制

• 批准号: 7378192
• 负责人: DEAN L KELLOGG
• 金额: $ 1.83万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378192
• 关键词: MECHANISMS; CUTANEOUS; ACTIVE; VASODILATION; HUMANS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project will determine the identity and functional significance of transmitters from sympathetic vasoconstrictor and vasodilator controls in the human cutaneous circulation. OBJECTIVES: To clarify the mechanisms by which the cutaneous active vasodilator system works. The general hypothesis to be tested by this project is that active thermoregulatory vasodilation in the human cutaneous circulation is mediated by a cholinergic co-transmitter system involving acetylcholine and neuropeptides. SPECIFIC AIMS: 1) determine whether bradykinin is involved in cutaneous active vasodilation during heat stress; 2) clarify whether nitric oxide levels increase and cause cutaneous active vasodilation during heat stress or whether the level of nitric oxide remains constant and functions as a permissive factor during heat stress; 3) determine whether the nitric oxide required for cutaneous active vasodilation during heat stress is produced by endothelial nitric oxide synthase (eNOS) or by neuronal nitric oxide synthase (nNOS); 4) Determine the role of vasoactive intestinal polypeptide (VIP) in cutaneous active vasodilation during heat stress; 5) determine the role of cAMP in cutaneous active vasodilation during heat stress; 6) determine the role of cGMP in cutaneous active vasodilation during heat stress; and 7) determine the degree of dependence of cutaneous vasodilation on cholinergic transmission in cystic fibrosis. RESEARCH PLAN: The foregoing specific aims will be addressed by application of a novel combination of techniques: intradermal microdialysis and laser-Doppler Flowmetry (LDF). Protocols will be conducted in humans. Intradermal microdialysis will be used to deliver pharmacological agents into the skin. Bioavailable NO concentrations will be measured by NO-selective, amphometric electrodes. Blood flow at microdialysis sites will be simultaneously measured by LDF. Measurements will be made during basal (normothermia) and stimulated (whole body heating) activity of the active vasodilator system. By comparing the responses between basal and stimulated activity and between control (untreated) and experimental (drug treated) microdialysis sites, the mechanisms of active vasodilation will be elucidated. METHODS: 1) Intra-dermal electrodes will serve to measure interstitial bioavailable NO levels from the cutaneous interstitial space. 2) Intra-dermal microdialysis will serve to deliver drugs into the interstitial space. 3) Laser-Doppler Flowmetry will be used to measure blood flow responses to pharmacological manipulation of vasodilator mechanisms during normothermia and whole body heating. 4) A water perfused suit (covers the entire body except for arms, feet, and head) will be used to effect whole body cooling, normothermia, or hyperthermia by perfusing with cold, neutral, or warm water respectively. 5) Local temperature control of measurement sites will be accomplished with resistive heaters. 6) Sweat rate is measured with relative humidity monitors placed on the skin surface. CLINICAL RELEVANCE: The specific mechanisms whereby the sympathetic nervous system causes increases in skin blood flow during hyperthermia remain enigmatic. The proposed experiments address fundamental questions about the nature of these mechanisms in humans. These studies should clarify the mechanistic rationale for use of alternative therapies to treat cardiovascular disorders in persons potentially at risk for heat related disorders. In addition, elderly populations have a greater incidence of heat related deaths. Among Veterans, the percentage of elderly is twice that of the U.S. population. This project will provide knowledge relevant to a significant number of veterans.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。该项目将确定交感血管收缩和血管扩张控制的递质在人体皮肤循环中的身份和功能意义。目的：阐明皮肤活性血管扩张剂系统的作用机制。该项目要检验的一般假设是，人体皮肤循环中主动的体温调节血管扩张是由涉及乙酰胆碱和神经肽的胆碱能共递质系统介导的。具体目标：1)确定缓激肽是否参与热应激时皮肤的主动血管扩张；2)阐明热应激时一氧化氮水平是否升高并导致皮肤主动血管扩张，或者一氧化氮水平是否保持不变并在热应激时起允许因子的作用；3)确定热应激时皮肤主动血管扩张所需的一氧化氮是由内皮型一氧化氮合酶(ENOS)还是神经元型一氧化氮合酶(NNOS)产生；4)确定血管活性肠多肽(VIP)在热应激时皮肤主动血管扩张中的作用；5)确定cAMP在热应激时皮肤主动血管扩张中的作用；6)确定cGMP在热应激时皮肤主动血管扩张中的作用；7)确定囊性纤维化皮肤血管扩张对胆碱能传递的依赖程度。研究计划：将通过应用一种新的技术组合来解决上述特定目标：皮内微透析和激光多普勒血流仪(LDF)。方案将在人类身上进行。皮内微透析将被用于将药剂输送到皮肤中。生物可利用的NO浓度将通过非选择性的两端测量电极来测量。微透析部位的血流量将由LDF同时测量。将在基础(常温)和刺激(全身加热)主动血管扩张系统的活动期间进行测量。通过比较基础活动和刺激活动之间以及对照(未治疗)和实验(药物治疗)微透析部位之间的反应，将阐明主动血管扩张的机制。方法：1)真皮内电极将用于测量皮肤间质中生物可利用的NO水平。2)真皮内微透析可将药物输送到间质。3)激光多普勒血流计将被用来测量常温和全身加温时血管扩张机制的药物操作的血流反应。4)用水浸泡的衣服(除手臂、脚和头部外覆盖全身)，分别用冷水、中性水或温水进行全身降温、常温或高热。5)用阻性加热器实现对测点的局部温度控制。6)出汗率是用放置在皮肤表面的相对湿度监测器测量的。临床意义：交感神经系统在体温过高时导致皮肤血流量增加的具体机制仍然是个谜。拟议中的实验解决了有关这些机制在人类身上的性质的基本问题。这些研究应该阐明使用替代疗法来治疗可能有高温相关疾病风险的人的心血管疾病的机制基础。此外，老年人口与高温相关的死亡发生率更高。在退伍军人中，老年人的比例是美国人口的两倍。该项目将提供与相当数量的退伍军人有关的知识。