Mechanisms of Cutaneous Active Vasodilation

描述(申请人提供)：70多年前，人类皮肤主动血管扩张剂系统(AVD)首次被描述；然而，其机制至今仍不清楚。该项目的长期目标是确定在体温调节反射对高温的反应中影响皮肤主动血管扩张的综合生理机制。这将有助于我们了解皮肤循环在适应炎热环境中的作用，并有助于了解在热浪中因与热有关的疾病而增加的发病率和死亡率。除了在了解人体体温调节方面将获得的具体好处外，该项目还将极大地增加我们对复杂的神经协同递质系统如何控制心血管系统的了解。对控制人类皮肤血管的AVD协同递质系统的研究可以用来深入了解协同递质神经控制系统是如何工作的。在活体内直接从人类身上获得这样的知识是不可能在没有重大风险的情况下在任何其他人体组织中完成的。将探讨以下具体目标：1)确定囊性纤维化患者在热应激期间的皮肤AVD是否对阿托品敏感。2)探讨高温时VPAC1和/或PAC1受体激活是否参与皮肤主动血管扩张。3)探讨热应激皮肤主动血管扩张过程中，内源性乙酰胆碱释放激活M受体是否导致一氧化氮水平升高。4)了解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)还是神经型一氧化氮合酶(NNOS)产生的。5)探讨cAMP在热应激时皮肤主动血管扩张中的作用。6)探讨cGMP在热应激时皮肤主动血管扩张中的作用。研究将在健康人和囊性纤维症患者身上进行。皮内微透析将用于治疗前臂皮肤的小区域，使用特定的药物来操纵胆碱能、神经肽能、一氧化氮和第二信使系统。激光多普勒血流计将监测常温和高温期间在药物治疗的实验部位和邻近的未治疗的对照部位的皮肤血流反应。此外，皮内微透析将与NO选择性安培电极测量生物可利用的NO相结合，以进一步确定NO系统如何在皮肤主动血管扩张中发挥作用。

DESCRIPTION (provided by applicant): Over 70 years ago the human cutaneous active vasodilator system (AVD) was first described; however, its mechanisms remain unclear today. The long-term goal of this project is to define the integrative physiological mechanisms that effect cutaneous active vasodilation during thermoregulatory reflex responses to hyperthermia. This will contribute to our understanding of the role of the cutaneous circulation in adaptation to hot environments and to understanding the increased morbidity and mortality of persons due to heat related illness in "heat waves". In addition to the specific benefits to be gained in understanding human thermoregulation, this project will add greatly to our understanding of how complex neural co-transmitter systems can control the cardiovascular system. Study of the AVD co-transmitter system that controls the cutaneous vasculature in humans can be used to gain insights into how co-transmitter neural control systems work. Gaining such knowledge directly from human beings in vivo could not be accomplished in any other human tissue, in vivo, without significant risk. The following specific aims will be explored: 1) To determine whether cutaneous AVD during heat stress is atropine-sensitive in cystic fibrosis patients. 2) To determine whether activation of VPAC1 and/or PAC1 receptors mediate cutaneous active vasodilation during hyperthermia. 3) To resolve whether muscarinic receptor activation by endogenous acetylcholine release contributes to increased nitric oxide levels during cutaneous active vasodilation in heat stress. 4) To resolve whether the nitric oxide required for cutaneous active vasodilation is produced by endothelial nitric oxide synthase (eNOS) and/or by neuronal nitric oxide synthase (nNOS) during heat stress. 5) To define the role of cAMP in cutaneous active vasodilation during heat stress. 6) To define the role of cGMP in cutaneous active vasodilation during heat stress. Studies will be done in healthy humans and patients with cystic fibrosis. Intradermal microdialysis will be used to treat small areas of forearm skin with specific pharmacological agents to manipulate the cholinergic, neuropeptidergic, nitric oxide, and second messenger systems. Laser-Doppler flowmetry will monitor skin blood flow responses during normothermia and hyperthermia at both drug-treated, experimental sites, and at adjacent untreated, control sites. In addition, intradermal microdialysis will be combined with measurements of bioavailable NO by NO-selective amperometric electrode to define further how the NO system functions in cutaneous active vasodilation.