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

描述(申请人提供)：在热应激期间，很大一部分心输出量(即大于50%)可以分配到皮肤，因此，在低血压挑战中，控制皮肤血流对血压调节至关重要。与许多血管床相比，皮肤血管的神经控制是独一无二的，因为它既受交感血管收缩系统的支配，又受独立的交感胆碱能活性血管扩张系统的支配。更复杂的是，皮肤的直接局部加热通过一种完全不同的机制(即非神经和主要依赖于一氧化氮)诱导皮肤血管扩张。此外，如果血浆容量足够减少，热应激期间出现的大量汗水会导致血压控制受损。出汗是通过交感胆碱能系统的参与而发生的，该交感胆碱能系统可能与皮肤活性血管扩张系统有关，也可能与皮肤活性血管扩张系统无关。传统上，这些系统(即血管紧缩剂、血管扩张剂和出汗系统)一直被视为相互独立，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，这种相互作用的程度和这种相互作用在血压和温度调节方面的重要性仍不清楚。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和独立机制减弱皮肤血管收缩反应的假设；3)测试汗腺通过与局部加热相关的机制和通过参与皮肤活性血管扩张系统而敏化的假设。这些目标将通过将创新的皮内微透析技术与皮肤血流量和汗率的同步评估相结合来实现，该技术可在局部输送药剂和对组织间液进行局部采样。这些研究的发现将为神经控制皮肤血流和出汗以及非神经事件如何影响这些反应提供新的见解。这些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晕厥发生率增加的机制，2)它将提供一个有价值的基准，可以在此基础上进行后续研究，以更好地了解疾病(如糖尿病、心力衰竭等)和非疾病(如衰老)如何改变皮肤血流和出汗的神经和非神经调节器。

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.