Neural and non-neural modulators of skin blood flow and sweating in humans

描述（由申请人提供）：在热应激期间，大部分心输出量（即，大于50%）可分布至皮肤，因此，控制皮肤血流量对于过度激发期间的血压调节至关重要。皮肤血管的神经控制相对于许多血管床是独特的，因为它由交感血管收缩系统和单独的交感胆碱能活性血管扩张系统两者支配。增加了这种复杂性，皮肤的直接局部加热通过完全不同的机制（即非神经和主要依赖一氧化氮）诱导皮肤血管舒张。此外，如果血浆容量充分减少，热应激期间发生的大量出汗会导致血压控制受损。出汗通过交感胆碱能系统的参与而发生，交感胆碱能系统可能与皮肤活性血管扩张系统有关，也可能无关。传统上，这些系统（即血管收缩、血管扩张和出汗系统）被认为是独立的，没有一个系统影响另一个系统。然而，初步数据表明，这些系统之间的显着相互作用。在热应激个体中，这种相互作用的程度以及这种相互作用对血压和体温调节的重要性仍不清楚。为此，本申请中概述的项目将致力于以下三个具体目标：1）测试从皮肤活性血管扩张神经释放的物质通过突触前和突触后机制减弱皮肤血管收缩反应的假设; 2）测试局部加热通过一氧化氮依赖性和非依赖性机制减弱皮肤血管收缩反应的假设; 3）检验汗腺通过与局部加热相关的机制和通过皮肤主动血管扩张系统的参与而致敏的假设。这些目标将通过结合皮内微透析的创新技术来实现，以局部递送药理学试剂和区域性间质液样品，同时评估皮肤血流量和出汗率。这些研究的发现将为皮肤血流和出汗的神经控制以及这些反应如何受到非神经事件的影响提供新的见解。这些信息将在两个方面证明是有价值的：1）它将确定导致热应激个体中昏厥发生率增加的机制，以及2）它将提供有价值的基准，由此可以进行后续研究以更好地理解皮肤血流和出汗的神经和非神经调节剂如何被疾病改变（即糖尿病、心力衰竭等）和非疾病（即衰老）状况。

DESCRIPTION (provided by applicant): A large fraction of cardiac output (i.e. greater than 50%) can be distributed to skin during heat stress, thus control of skin blood flow is vital for blood pressure regulation during a hypotensive challenge. Neural control of the cutaneous vasculature is unique relative to many vascular beds in that it is governed by both a sympathetic vasoconstrictor system and a separate sympathetic cholinergic active vasodilator system. Adding to this complexity, direct local heating of the skin induces cutaneous vasodilation via an entirely different mechanism (i.e. non-neural and primarily nitric oxide dependent). Moreover, profuse sweating that occurs during heat stress contributes to impaired blood pressure control if plasma volume is sufficiently reduced. Sweating occurs through the engagement of a sympathetic cholinergic system that may or may not be related to the cutaneous active vasodilator system. Classically, these systems (i.e. vasoconstrictor, vasodilator, and sweating systems) have been viewed as being independent, without one system affecting the other. However, preliminary data suggest significant interaction between these systems. In heat stressed individuals the degree of interaction and the importance of this interaction with respect to blood pressure and temperature regulation remain unclear. To this end, the projects outlined in this application will address the following three specific aims: 1) Test the hypothesis that substances released from the cutaneous active vasodilator nerve attenuate cutaneous vasoconstrictor responses through pre- and post- synaptic mechanisms; 2) Test the hypothesis that local heating attenuates cutaneous vasoconstrictor responsiveness through nitric oxide dependent and independent mechanisms; 3) Test the hypothesis that sweat glands are sensitized by mechanisms associated with local heating and through engagement of the cutaneous active vasodilator system. These objectives will be accomplished by combining the innovative technique of intradermal microdialysis to locally deliver pharmacological agents and regionally sample interstitial fluid, with the simultaneous assessment of skin blood flow and sweat rate. Findings from these studies will provide new insight into neural control of skin blood flow and sweating and how these responses can be affected by non-neural events. This information will prove valuable on two fronts: 1) it will identify mechanisms contributing to an increased incidence of fainting in heat stressed individuals, and 2) it will provide a valuable benchmark from which subsequent studies can be performed to better understand how neural and non-neural modulators of skin blood flow and sweating may be altered by disease (i.e. diabetes, heart failure, etc) and non-disease (i.e. aging) conditions.