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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目将确定人皮肤循环中交感神经和血管舒张器控制的发射器的身份和功能意义。 目的：阐明皮肤活性血管扩张系统起作用的机制。 该项目要检验的一般假设是，人皮肤循环中的活跃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糖质变质剂介导的。 具体目的：1）确定在热应激期间，在热应激期间，缓激肽是否参与皮肤活性血管舒张； 2）阐明一氧化氮水平是否增加并在热应激过程中引起皮肤活性血管舒张，还是一氧化氮的水平保持恒定并在热应激过程中起允许因素的作用； 3）确定在热应激过程中皮肤活性血管舒张所需的一氧化氮是由内皮一氧化氮合酶（ENOS）还是由神经元一氧化氮合酶（NNOS）产生的； 4）确定血管活性肠多肽（VIP）在热应激过程中皮肤活性血管舒张中的作用； 5）确定cAMP在热应激过程中的皮肤活性血管舒张中的作用； 6）确定CGMP在热应激过程中的皮肤活性血管舒张中的作用； 7）确定皮肤血管舒张对囊性纤维化中胆碱能传播的依赖程度。 研究计划：通过应用新颖的技术组合来解决上述具体目标：皮内微透析和激光多普勒流量指标（LDF）。 协议将在人类中进行。 皮内微透析将用于将药理学剂输送到皮肤中。 可生物利用的无浓度将通过无选择的，过滤器电极来测量。 微透析部位的血流将通过LDF同时测量。 将在基础（Normothermia）和刺激（全身加热）活性血管扩张器系统的（全身加热）活动期间进行测量。 通过比较基础和刺激活性之间的响应以及对照（未处理）与实验（药物治疗）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）德马尔内电极将用于测量皮肤间质空间中的间隙生物可利用水平。 2）德乳内微透析将用于将药物输送到间质空间中。 3）激光多普勒流量测量将用于测量对近炎和全身加热过程中血管舒张机制的药理操纵的血流反应。 4）通过分别用冷，中性或温水灌注，将使用水灌注的西装（覆盖除手臂，脚和头部以外的整个身体）来实现整个身体冷却，正常热或高温。 5）测量位点的局部温度控制将通过电阻加热器完成。 6）汗液速率是通过放置在皮肤表面上的相对湿度监测器来测量的。 临床相关性：交感神经系统导致高温期间皮肤血流增加的特定机制仍然神秘。 提出的实验涉及有关人类这些机制性质的基本问题。 这些研究应阐明使用替代疗法治疗可能有与热有关疾病风险的人的心血管疾病的机械原理。 此外，老年人人口的热死亡发生率更大。 在退伍军人中，老年人的百分比是美国人口的两倍。 该项目将提供与大量退伍军人相关的知识。