The postmenopausal hot flash: cutaneous and hemodynamic mechanisms

描述（由申请人提供）：潮热是女性更年期的主要症状，严重影响生活质量。尽管潮热给大量妇女带来了相当大的问题，特别是考虑到使用基于激素的疗法来治疗潮热症状的减少，但关于潮热症状机制的知识与问题的严重程度极不相称。本研究的主要目的是研究潮热期间皮肤血管、出汗和全身血流动力学反应的机制。引起潮热时皮肤血流量和出汗增加的信号尚不完全清楚，可能是神经系统的原因。利用节后皮肤交感神经活动（SSNA）与皮肤血流量和出汗率测量同时进行的多纤维记录的创新技术，SPECIFIC AIM #1将检验在潮热期间，SSNA随着皮肤血流量和出汗的升高而增加的假设，并且SSNA增加的幅度与皮肤血流量和出汗的增加幅度直接相关。潮热时皮肤血流的变化可能通过以下调节发生：i)交感血管收缩系统，ii)单独的交感胆碱能活性血管扩张系统，和/或iii)与一氧化氮（NO）相关的局部因素；而潮热时出汗的增加可能是由于胆碱能交感神经的兴奋引起的。SPECIFIC AIM #2将检验交感血管收缩活性的消退、交感胆碱能活性血管扩张活性的增加和/或与NO相关的因素介导潮热期间皮肤血流量的增加的假设。此外，这一特定的目的将验证在潮热期间出汗是通过胆碱能交感神经刺激发生的假设。这些问题将使用皮内微透析的新技术来评估，该技术局部递送药物，同时持续评估皮肤血流量和出汗。有一部分受试者在潮热时血压下降，这可能是由于皮肤血管传导明显增加所致。此外，据报道，潮热症状与全身施用硝普钠（一种一氧化氮供体，可增加皮肤血管传导并降低血压）相似。总之，这些观察结果提出了一种可能性，即潮热的症状可能与“一氧化氮激增”有关。因此，SPECIFIC AIM #3将检验NO合成酶的系统性抑制降低潮热客观反应的频率和幅度的假设。在完成所提出的工作后，将获得对引起热潮热期间皮肤血流量和出汗增加的突触前和突触后机制的更深入了解。此外，将确定在潮热期间调节血压的潜在机制。这些发现将为卫生保健界提供重要的信息，有助于开发非激素治疗方法，以减少潮热的频率并改善潮热的症状。

DESCRIPTION (provided by applicant): Hot flashes are a primary symptom of the female menopause that greatly impairs quality of life. Despite the considerable problem hot flashes pose for a large number of women, especially given decreased use of hormonal based therapies to treat hot flash symptoms, knowledge regarding the mechanisms of hot flash symptoms is greatly disproportional relative to the extent of the problem. The primary objective of this proposal is to examine mechanisms of cutaneous vascular, sweating, and systemic hemodynamic responses during hot flashes. The signal responsible for elevations in skin blood flow and sweating during a hot flash is not entirely clear and may be neural in origin. Using the innovative technique of multifiber recordings of postganglionic skin sympathetic nerve activity (SSNA) concurrently with skin blood flow and sweat rate measurements SPECIFIC AIM #1 will test the hypothesis that SSNA increases, concomitant with elevations in skin blood flow and sweating, during a hot flash and that the magnitude of the increase in SSNA is directly related to the magnitude of the rise in skin blood flow and sweating. Changes in skin blood flow during a hot flash may occur through modulation of: i) a sympathetic vasoconstrictor system, ii) a separate sympathetic cholinergic active vasodilator system, and/or iii) local factors related to nitric oxide (NO); while increases in sweating during a hot flash may occur upon excitation of cholinergic sympathetic nerves. SPECIFIC AIM #2 will test the hypothesis that withdrawal of sympathetic vasoconstrictor activity, increases in sympathetic cholinergic active vasodilator activity, and/or factors related to NO mediate increases in skin blood flow during a hot flash. Furthermore, this specific aim will test the hypothesis that sweating during a hot flash occurs through cholinergic sympathetic stimulation. These questions will be evaluated using the novel technique of intradermal microdialysis to locally deliver pharmacological agents coupled with continuous assessment of skin blood flow and sweating. In a subset of subjects blood pressure decreases during a hot flash, perhaps due to pronounced increases in cutaneous vascular conductance. Furthermore, symptoms of a hot flash have been reported to be similar to systemic sodium nitroprusside administration (an NO donor that increases cutaneous vascular conductance and lowers blood pressure). Together, these observations raise the possibility that symptoms of a hot flash may be associated with an "NO surge". Therefore, SPECIFIC AIM #3 will test the hypothesis that systemic inhibition of NO synthase reduces the frequency as well as magnitude of objective responses of hot flashes. Upon completion of the proposed work a greater understanding of pre- and post-synaptic mechanisms causing increases in skin blood flow and sweating during a hot flash will be obtained. Moreover, potential mechanisms that modulate blood pressure during hot flashes will be identified. These findings will provide vital information to the health care community that could aid in the development of non-hormonal treatments to decrease the frequency and ameliorate symptoms of hot flashes. Public Health Relevance Statement: Hot flashes are one of the most significant physiological symptoms of the female menopause that greatly impairs the quality of life. Despite the considerable problem hot flashes pose for a large number of women, especially given decreased use of hormonal based therapies to treat hot flash symptoms, relatively little is known regarding the mechanisms of these symptoms. The completion of the proposed work will provide important information regarding mechanisms of skin blood flow, sweating, and blood pressure responses during hot flashes to the health care community that could aid in the development of non-hormonal treatments to reduce hot flash frequency and related symptoms.