MECHANISMS OF CUTANEOUS ACTIVE VASODILATION IN HUMANS

人类皮肤主动血管舒张的机制

• 批准号: 7627529
• 负责人: DEAN L KELLOGG
• 金额: $ 2.54万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627529
• 关键词: Acetylcholine; Address; Alternative Therapies; Bioavailable; Blood Circulation; Blood flow; Bradykinin; Cardiovascular Diseases; Cessation of life; Cholinergic Agents; Computer Retrieval of Information on Scientific Projects Database; Cutaneous; Cyclic AMP; Cyclic GMP; Cystic Fibrosis; Dependence; Dermal; Disease; Elderly; Electrodes; Fever; Funding; Grant; Head; Heat Stress Disorders; Heating; Human; Humidity; Incidence; Institution; Knowledge; Laser-Doppler Flowmetry; Measurement; Measures; Mediating; Microdialysis; Monitor; Nature; Neuropeptides; Nitric Oxide; Nitric Oxide Synthase Type I; Numbers; Persons; Pharmaceutical Preparations; Population; Protocols documentation; Rate; Relative (related person); Research; Research Personnel; Resources; Risk; Role; Site; Skin; Source; Surface; Sweat; Sweating; Sympathetic Nervous System; System; Techniques; Temperature; Testing; United States National Institutes of Health; Upper arm; Vasoactive Intestinal Peptide; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Veterans; Water; Work; cholinergic; clinically relevant; foot; human NOS3 protein; hyperthermia treatment; interstitial; novel; research study; response; transmission process

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目将确定人体皮肤循环中交感血管收缩剂和血管舒张剂控制的递质的身份和功能意义。 目的：阐明皮肤活性血管舒张系统的工作机制。 该项目要测试的一般假设是，人体皮肤循环中的主动温度调节血管舒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期间皮肤主动血管舒张； 2）澄清热应激期间一氧化氮水平是否增加并导致皮肤主动血管舒张，或者一氧化氮水平是否保持恒定并在热应激期间充当许可因素； 3)确定热应激时皮肤主动血管舒张所需的一氧化氮是由内皮型一氧化氮合酶(eNOS)产生还是由神经元型一氧化氮合酶(nNOS)产生； 4）确定血管活性肠肽（VIP）在热应激时皮肤主动血管舒张中的作用； 5)确定cAMP在热应激期间皮肤主动血管舒张中的作用； 6)确定cGMP在热应激期间皮肤主动血管舒张中的作用； 7)确定囊性纤维化中皮肤血管舒张对胆碱能传递的依赖性程度。 研究计划：上述具体目标将通过应用新型技术组合来实现：皮内微透析和激光多普勒血流测定（LDF）。 协议将在人类身上进行。 皮内微透析将用于将药物输送到皮肤中。 生物可利用的 NO 浓度将通过 NO 选择性安培电极进行测量。 LDF 将同时测量微透析部位的血流量。 将在主动血管舒张系统的基础（正常体温）和刺激（全身加热）活动期间进行测量。 通过比较基础活性和刺激活性之间以及对照（未处理）和实验（药物处理）微透析部位之间的反应，将阐明活性血管舒张的机制。 方法： 1) 皮内电极将用于测量皮肤间质间隙中生物可利用的一氧化氮水平。 2) 皮内微透析将药物输送到组织间隙中。 3) 激光多普勒血流计将用于测量常温和全身加热期间血管舒张机制的药理学操作的血流反应。 4）使用水灌注服（覆盖除手臂、脚和头部之外的整个身体），通过分别灌注冷水、中性水或温水来实现全身降温、常温或高温。 5) 测量部位的局部温度控制将通过电阻加热器来完成。 6) 出汗率是通过放置在皮肤表面的相对湿度监测器来测量的。 临床相关性：交感神经系统在高温期间导致皮肤血流量增加的具体机制仍然是个谜。 拟议的实验解决了有关人类这些机制本质的基本问题。 这些研究应阐明使用替代疗法治疗潜在热相关疾病风险人群的心血管疾病的机制原理。 此外，老年人口因高温而死亡的发生率更高。 在退伍军人中，老年人的比例是美国人口的两倍。 该项目将为大量退伍军人提供相关知识。