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系统（AVD）首次被描述;然而，其机制至今仍不清楚。本项目的长期目标是确定在体温调节反射反应中影响皮肤主动血管舒张的综合生理机制。这将有助于我们了解皮肤循环在适应热环境中的作用，并了解在“热浪”中因热相关疾病而增加的发病率和死亡率。除了在理解人类体温调节方面获得的具体好处外，该项目还将大大增加我们对复杂的神经共递质系统如何控制心血管系统的理解。对控制人类皮肤血管系统的AVD共递质系统的研究可用于深入了解共递质神经控制系统如何工作。直接从人体体内获得这种知识，不可能在任何其他人体组织中实现，在体内，没有重大风险。将探讨以下具体目的：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)确定在高热期间是否VPAC 1和/或PAC 1受体的激活介导皮肤主动血管舒张。3)探讨热应激下皮肤主动性血管舒张过程中，内源性乙酰胆碱释放激活毒蕈碱受体是否导致一氧化氮水平升高。4)为了解决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）和/或神经型一氧化氮合酶（nNOS）在热应激过程中产生。5)探讨cAMP在热应激时皮肤主动性血管舒张中的作用。6)探讨cGMP在热应激时皮肤主动性血管舒张中的作用。研究将在健康人和囊性纤维化患者中进行。皮内微透析将用于治疗前臂皮肤的小区域，使用特定的药理学试剂来操纵胆碱能、神经肽能、一氧化氮和第二信使系统。激光多普勒血流仪将监测药物治疗的实验部位和相邻未治疗的对照部位在常温和高温期间的皮肤血流反应。此外，皮内微透析将与NO选择性安培电极的生物可利用的NO的测量相结合，以进一步定义NO系统在皮肤主动血管舒张中的功能。

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.