MECHANISMS OF CUTANEOUS ACTIVE VASODILATION

描述（改编自申请人的摘要）：大约70年前， 人类皮肤活性血管扩张系统首次被描述;然而，其 目前机制尚不清楚。该项目的长期目标是 定义影响皮肤主动血管舒张的生理机制 在体温调节反射反应中产生的。这将有助于 对我们理解皮肤循环在适应 炎热的环境和了解增加的发病率和死亡率， 心输出量有限的人，包括老年人和心脏病患者 疾病加强对皮肤循环的了解可以减少 不断增长的患者人群中的死亡率， 可能使他们易患医源性发热的药物治疗 不耐症中暑和死亡以下具体目标将是 探讨了1)确定缓激肽是否参与皮肤活性 热应激时血管舒张。2)阐明一氧化氮（NO）水平是否 在热应激期间增加并引起皮肤主动血管舒张，或者 NO水平保持恒定，并在加热过程中作为一个允许因素发挥作用 应力3)确定皮肤活性所需的一氧化氮 热应激时血管舒张是由内皮一氧化氮产生的 一氧化氮合酶（eNOS）或神经元型一氧化氮合酶（nNOS）。4)确定 血管活性肠肽（VIP）在皮肤活性物质中的作用 热应激时血管舒张。5)确定cAMP在皮肤中的作用 在热应激期间的主动血管舒张。6)确定cGMP的作用， 在热应激期间皮肤主动血管舒张。研究将在 健康的人类皮内微透析将用于治疗小面积的 前臂皮肤用特定的药理学试剂来操纵缓激肽， 一氧化氮VIP和第二信使系统激光多普勒血流仪将 监测皮肤血流反应在正常体温和高温在两个 药物处理的实验部位和相邻的未处理的对照部位。在 此外，皮内微透析将与测量 通过血红蛋白捕获生物可利用的NO，以进一步确定NO系统如何 在皮肤主动血管舒张中起作用。

DESCRIPTION (Adapted from the applicant's abstract):Almost 70 years ago the human cutaneous active vasodilator system was first described; however, its mechanisms remain unclear today. The long term goal of this project is to define the 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 understanding the increased morbidity and mortality of persons with limited cardiac output, including the aged and those with cardiac disease. An enhanced understanding of the cutaneous circulation may reduce mortality in the growing patient population that receives numerous pharmacological therapies that may predispose them to iatrogenic heat intolerance, heat stroke, and death. The following specific aims will be explored. 1) Determine whether bradykinin is involved in cutaneous active vasodilation during heat stress. 2) Clarify whether nitric oxide (NO) levels increase and cause cutaneous active vasodilation during heat stress or whether NO levels remain 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. Studies will be done in healthy humans. Intradermal microdialysis will be used to treat small areas of forearm skin with specific pharmacological agents to manipulate the bradykinin, nitric oxide, VIP, 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 hemoglobin-trapping to define further how the NO system functions in cutaneous active vasodilation.