Neurovascular Responses to Reflex Cooling in Essential Hypertensive Humans

描述（由申请人提供）：心血管疾病仍然是一个主要的公共卫生问题，是美国死亡的主要原因。据估计，有7600万美国人患有高血压，占总人口的50%。高血压普遍血管损伤的潜在机制包括交感神经流出的中枢控制异常和血管功能的外周调节异常，尤其是在应激反应中。然而，关于高血压（HTN）患者在全身冷暴露时这些反射通路的潜在异常调节的信息缺乏，这种生理应激会导致血压（BP）和交感神经活动（SNA）升高以及皮肤血流量减少。先前的数据表明，肾上腺素能和RhoA/Rho激酶信号的改变在高血压患者血管功能受损中起重要作用，并且可能对全身降温过程中神经血管功能的反射控制具有重要的功能意义。对HTN成人神经血管对冷应激反应改变的机制进行全面研究具有重要的临床意义，因为在冷暴露期间过度的心脏需求进一步增加了易感个体发生急性心血管事件的风险。这在基本HTN的成年人中尤其成问题，因为在已经升高的基线血压之上，对寒冷暴露的夸大的血压反应，增加了更大的心血管风险。因此，我们的总体假设是神经血管反应性在HTN成人中被夸大了。我们建议研究HTN和正常血压（NTN）的人对全身低温暴露的综合神经心血管反应，以及控制血流的外周血管反应。我们假设，在HTN成人中，反射性冷却引起的血压和SNA升高以及皮肤血流量减少会更大。我们进一步假设，在HTN成人中，RhoA/Rho激酶对生理性（全身冷却）和药理学诱导（局部去甲肾上腺素输注）皮肤血管收缩的贡献更大。将获得皮肤血管（皮肤活检样本）以评估RhoA/Rho激酶的表达和激活。这些假设将在40-65岁的HTN和NTN成年人中进行检验。肌肉和皮肤SNA（腓神经微成像）和皮肤血流（激光多普勒通量）的变化将用于评估全身降温过程中神经血管的反应性。皮内微透析将用于评估特定的下游细胞机制（肾上腺素能和Rho激酶介导的途径）有助于改变血管功能的外周调节。这项对HTN成人对反射冷却的综合神经血管反应的综合评估检查了沿出射反射轴的多个点，并将使我们能够确定在人类高血压患者冷暴露期间，中枢和外周机制的改变是否导致血压控制和皮肤血流量调节受损。

DESCRIPTION (provided by applicant): Cardiovascular disease remains a major public health problem and is the leading cause of death in the US. Hypertension afflicts an estimated 76 million Americans and >50% of the population >65 years. The underlying mechanisms contributing to the pervasive vascular impairments in hypertension include abnormalities in the central control of sympathetic outflow and the peripheral regulation of vascular function, especially in response to stress. However, there is a dearth of information regarding potential aberrant regulation of these reflex pathways in hypertensive (HTN) humans during whole body cold exposure, a physiologic stress that causes increases in blood pressure (BP) and sympathetic nerve activity (SNA) and reductions in skin blood flow. Previous data suggest that alterations in both adrenergic and RhoA/Rho kinase signaling contribute importantly to impaired vascular function in human hypertension and may have significant functional importance for the reflex control of neurovascular function during whole body cooling. A comprehensive examination of the mechanisms underlying alterations in the neurovascular responses to cold stress in HTN adults is clinically relevant and important because the excessive cardiac demands during cold exposure further increase the risk for an acute cardiovascular event in susceptible individuals. This is especially problematic in essential HTN adults, because an exaggerated BP response to cold exposure, on top of an already elevated baseline BP, imparts even greater cardiovascular risk. Therefore, our global hypothesis is that neurovascular reactivity is exaggerated in HTN adults. We propose to investigate the integrated neural cardiovascular responses to whole body cold exposure, in addition to peripheral vascular responsiveness in the control of blood flow, in essential HTN and normotensive (NTN) humans. We hypothesize that reflex cooling-evoked increases in BP and SNA, and reductions in skin blood flow, will be greater in HTN adults. We further hypothesize that there will be a greater contribution of RhoA/Rho kinase to physiologically- (whole body cooling) and pharmacologically- induced (localized norepinephrine infusion) cutaneous vasoconstriction in HTN adults. Cutaneous vessels will be obtained (skin biopsy samples) to assess RhoA/Rho kinase expression and activation. These hypotheses will be tested in HTN and NTN adults aged 40-65 years. Changes in muscle and skin SNA (peroneal microneurography) and cutaneous blood flow (laser Doppler flux) will be used to assess neurovascular reactivity during whole body cooling. Intradermal microdialysis will be used to assess specific downstream cellular mechanisms (adrenergic- and Rho kinase-mediated pathways) contributing to altered peripheral regulation of vascular function. This comprehensive assessment of integrated neurovascular responses to reflex cooling in essential HTN adults examines multiple points along the efferent reflex axis and will allow us to determine if alterations in central and peripheral mechanisms contribute to impaired BP control and skin blood flow regulation during cold exposure in human hypertension.