Neurovascular Control and Blood Pressure Regulation in Humans

描述(申请人提供)：HL-83947的总体目标是探索人类血压(BP)的交感神经调节。作为过去5年观察的结果，我们的续订申请集中在关于交感神经系统和绝经后妇女血压上升的新想法上。众所周知，成年初期女性的血压低于男性。然而，这种保护在更年期时就会消失，在更年期之后，与同龄男性相比，女性患高血压的风险更高。沿着这些思路，我们提出绝经后女性存在血压升高的“双重打击”，包括年轻女性的β-肾上腺素能血管扩张功能的丧失，这通常抵消了年轻女性的肾上腺素能收缩作用，同时交感神经血管收缩活动与年龄有关。这些因素共同导致更年期后交感神经调节的血压升高。在此背景下，支持这一应用的主要思想是：1)绝经后，β-肾上腺素能血管扩张的一氧化氮成分显著减少；2)β-肾上腺素能血管扩张的丧失以及与年龄相关的交感活动增加导致绝经后妇女对血压的交感支持增加；3)这些与年龄相关的变化部分是由绝经时女性生殖激素的损失引起的，可被绝经激素疗法(MHT)缓解；以及4)定期运动也可缓解这些变化，这可以恢复血管内皮功能，并可能降低绝经后妇女的交感神经活性。为了解决这些想法，我们将使用我们实验室开发和掌握的一系列实验工具来探索以下具体目标：目标1将测试与年轻女性相比，绝经后女性前臂对异丙肾上腺素的血管扩张是否减弱，以及这种迟钝的血管扩张是否是由于一氧化氮(NO)介导的β-肾上腺素能血管扩张成分的丧失。目的2将测试交感神经对血压的支持是否与年轻和绝经后女性的MSNA有关。我们将在使用曲美沙潘进行神经节阻滞前和期间测量MSNA和动脉压。目标3将测试运动训练是否增强绝经后女性的内皮和肾上腺素能血管扩张，并限制对血压的交感神经支持。我们还将探索培训如何与MHT相互作用。重要的是，大多数关于交感神经和内皮控制血压的想法在女性中只进行了很少的直接测试，我们的初步数据清楚地表明需要更多的数据，特别是在绝经后的女性。由于血压控制是一个具有生物医学意义的问题，我们提出的研究与公共健康高度相关，也旨在为女性心血管危险因素提供基本的机制洞察，而这一因素知之甚少。

DESCRIPTION (provided by applicant): The overall goal of HL-83947 is to explore sympathetic regulation of blood pressure (BP) in humans. As a result of observations made over the last 5 years our renewal application is focused on novel ideas about the sympathetic nervous system and the rise in BP in postmenopausal women. It is well known that women have lower BP than men in early adulthood. However, this protection disappears at menopause, after which women have an accelerating risk of hypertension compared to men of similar age. Along these lines, we propose that there is a BP raising "double hit" in postmenopausal women that includes loss of ?-adrenergic vasodilation which normally offsets ¿-adrenergic constriction in young women coupled with an age related rise in sympathetic vasoconstrictor activity. Together these factors cause a sympathetically mediated rise in blood pressure after menopause. In this context, the major ideas underpinning this application are: 1) after menopause there is a marked reduction in the NO component of ?-adrenergic vasodilation; 2) this loss of ?-adrenergic vasodilation along with age related increases in sympathetic activity leads to increased sympathetic support of BP in postmenopausal women; 3) these age related changes are caused in part by a loss of female reproductive hormones at menopause and can be attenuated by Menopausal Hormone Therapy (MHT); and 4) they can also be mitigated by regular exercise which can restore endothelial function and may reduce sympathetic activity in postmenopausal women. To address these ideas we will use an ensemble of experimental tools developed and mastered in our laboratory to explore the following specific aims: Aim 1 will test whether forearm vasodilation to isoproterenol is blunted in postmenopausal women compared to young women, and whether this blunted vasodilation is due to a loss of the nitric oxide (NO) mediated component of ?-adrenergic vasodilation. Aim 2 will test whether sympathetic support of blood pressure is related to MSNA in young and postmenopausal women. We will measure MSNA and arterial pressure before and during ganglionic blockade with trimethaphan. Aim 3 will test whether exercise training augments endothelial and ?-adrenergic vasodilation and limits sympathetic support of blood pressure in postmenopausal women. We will also explore how training interacts with MHT. Importantly, most ideas about sympathetic and endothelial control of BP have undergone minimal or no direct testing in women and our preliminary data clearly show the need for more data especially in postmenopausal women. Since blood pressure control is a biomedically significant issue, the studies we propose are highly relevant to public health and also designed to provide basic mechanistic insight into an important and poorly understood cardiovascular risk factor in women.