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

描述（由申请人提供）：在热应激时，很大一部分心输出量（即大于50%）可以分配到皮肤，因此在低血压挑战期间控制皮肤血流量对血压调节至关重要。相对于许多血管床，皮肤血管系统的神经控制是独特的，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共同控制。增加这种复杂性的是，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，如果血浆量充分减少，在热应激期间发生的大量出汗有助于血压控制受损。出汗是通过交感胆碱能系统发生的，该系统可能与皮肤活性血管扩张系统有关，也可能与之无关。传统上，这些系统（即血管收缩系统、血管舒张系统和出汗系统）被认为是独立的，一个系统不影响另一个系统。然而，初步数据表明这些系统之间存在显著的相互作用。在热应激个体中，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尚不清楚。为此，本申请中概述的项目将解决以下三个具体目标：1)测试从皮肤活性血管舒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)验证局部加热通过一氧化氮依赖和独立机制减弱皮肤血管收缩剂反应性的假设；3)验证汗腺致敏的机制与局部加热和皮肤活性血管扩张剂系统有关的假设。这些目标将通过结合创新的皮内微透析技术来实现，该技术可在局部输送药物和局部取样间质液，同时评估皮肤血流量和出汗率。这些研究结果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。这一信息将在两个方面被证明是有价值的：1)它将确定导致热应激个体昏厥发生率增加的机制，2)它将提供一个有价值的基准，由此可以进行后续研究，以更好地了解皮肤血流量和出汗的神经和非神经调节剂如何被疾病（如糖尿病、心力衰竭等）和非疾病（如衰老）条件改变。

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.