The postmenopausal hot flash: cutaneous and hemodynamic mechanisms

描述(申请人提供)：潮热是女性更年期的主要症状，极大地损害生活质量。尽管潮热给许多女性带来了相当大的问题，特别是考虑到使用激素治疗潮热症状的减少，但关于潮热症状的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，导致皮肤血流量升高和出汗的信号并不完全清楚，可能源于神经。利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，特定的AIM#1将验证以下假设：在潮热期间，SSNA会随着皮肤血流量和出汗的增加而增加，并且SSNA增加的幅度与皮肤血流量和出汗增加的幅度直接相关。潮热时皮肤血流量的变化可能通过以下因素的调节而发生：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；而热潮热期间出汗增加可能发生在胆碱能交感神经兴奋时。具体目的#2将检验以下假设：交感神经血管收缩活性的取消、交感胆碱能活性血管扩张活性的增加和/或与一氧化氮相关的因素在潮热期间介导皮肤血流量的增加。此外，这个特定的目标将检验这样一个假设，即潮热期间出汗是通过胆碱能交感刺激发生的。这些问题将使用皮内微透析的新技术进行评估，以局部输送药物，并持续评估皮肤血流和出汗情况。在一组受试者中，热潮期间血压下降，可能是由于皮肤血管传导性的显著增加。此外，据报道，潮热的症状类似于全身注射硝普钠(一种增加皮肤血管传导性和降低血压的一氧化氮供体)。总而言之，这些观察结果提出了这样一种可能性，即热闪的症状可能与“无激增”有关。因此，特定的AIM#3将检验这一假说，即全身抑制一氧化氮合酶可降低潮热的客观反应的频率和幅度。在完成拟议的工作后，将对突触前和突触后导致皮肤血流量增加和潮热期间出汗的机制有更好的理解。此外，还将确定潮热时调节血压的潜在机制。这些发现将为医疗界提供重要信息，有助于开发非激素治疗方法来减少潮热的频率和改善症状。 公共卫生相关声明：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。尽管潮热给大量女性带来了相当大的问题，特别是考虑到使用激素治疗潮热症状的减少，但对这些症状的机制知之甚少。这项拟议工作的完成将为医疗界提供有关潮热时皮肤血流、出汗和血压反应机制的重要信息，有助于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.