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，极大地损害了生活质量。尽管潮热对大量女性造成了相当大的问题，特别是考虑到减少使用基于激素的疗法来治疗潮热症状，但关于潮热症状机制的知识与问题的程度非常不成比例。本研究的主要目的是探讨潮热时皮肤血管、出汗和全身血流动力学反应的机制。在潮热期间引起皮肤血流量升高和出汗的信号并不完全清楚，可能是神经源性的。使用多纤维记录节后皮肤交感神经活动（SSNA）的创新技术，同时测量皮肤血流量和出汗率，具体目标#1将测试以下假设：在潮热期间，SSNA增加，伴随皮肤血流量和出汗的升高，SSNA增加的幅度与皮肤血流量和出汗的增加的幅度直接相关。在热潮红期间皮肤血流的变化可以通过以下的调节而发生：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;而在热潮红期间出汗的增加可以在胆碱能交感神经兴奋时发生。具体目的#2将检验以下假设：在潮热期间，交感神经血管收缩剂活性的撤回、交感神经胆碱能活性血管舒张剂活性的增加和/或与NO相关的因素介导皮肤血流量的增加。此外，这个特定的目标将测试的假设，出汗在潮热发生通过胆碱能交感神经刺激。这些问题将使用皮内微透析的新技术进行评估，以局部提供药物制剂，并连续评估皮肤血流量和出汗。在一个子集的主题血压下降，在潮热，可能是由于显着增加皮肤血管传导。此外，据报道，潮热的症状与全身性硝普钠给药（一种NO供体，可增加皮肤血管传导并降低血压）相似。总之，这些观察结果提高了热闪症状可能与“NO激增”相关的可能性。因此，具体目标#3将检验系统性抑制NO合酶降低潮热客观反应的频率和幅度的假设。完成这项工作后，将更好地了解在潮热期间引起皮肤血流量增加和出汗的突触前和突触后机制。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信息，有助于开发非激素治疗方法，以减少潮热的频率和改善潮热的症状。 公共卫生相关性声明：潮热是女性更年期最重要的生理症状之一，极大地损害了生活质量。尽管潮热对大量女性造成了相当大的问题，特别是考虑到减少使用基于激素的疗法来治疗潮热症状，但关于这些症状的机制知之甚少。拟议工作的完成将为卫生保健界提供有关潮热期间皮肤血流，出汗和血压反应机制的重要信息，这些信息可以帮助开发非激素治疗方法，以减少潮热频率和相关症状。

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.