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，是美国的主要死亡原因。估计有7600万美国人和>50%的>65岁的人口患有高血压。导致高血压广泛性血管损害的潜在机制包括交感神经流出的中枢控制和血管功能的外周调节异常，特别是对应激的反应。然而，在全身冷暴露期间，缺乏关于高血压（HTN）人中这些反射通路的潜在异常调节的信息，这是一种生理应激，其导致血压（BP）和交感神经活动（SNA）增加以及皮肤血流量减少。先前的数据表明，肾上腺素能和RhoA/Rho激酶信号传导的改变对人类高血压的血管功能受损有重要贡献，并且可能对全身冷却期间神经血管功能的反射控制具有重要的功能意义。全面检查HTN成人对冷应激的神经血管反应改变的机制具有临床相关性和重要性，因为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。这在必要的HTN成人中尤其成问题，因为在已经升高的基线BP之上，对冷暴露的过度BP反应赋予更大的心血管风险。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。我们建议调查的综合神经心血管反应，全身冷暴露，除了外周血管反应的血流控制，在必要的HTN和血压正常（NTN）的人。我们假设，反射冷却引起的血压和SNA的增加，以及皮肤血流量的减少，在HTN成人中会更大。我们进一步假设，在HTN成人中，RhoA/Rho激酶对生理学（全身冷却）和热休克诱导（局部去甲肾上腺素输注）的皮肤血管收缩有更大的贡献。将获得皮肤血管（皮肤活检样品）以评估RhoA/Rho激酶表达和活化。这些假设将在40-65岁的HTN和NTN成人中进行测试。肌肉和皮肤SNA（腓神经显微神经造影术）和皮肤血流（激光多普勒流量）的变化将用于评估全身冷却期间的神经血管反应性。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。综合神经血管反应反射冷却在必要的HTN成人检查多个点沿着传出反射轴的全面评估，并将使我们能够确定是否在中枢和外周机制的改变，有助于受损的血压控制和皮肤血流调节在寒冷暴露在人类高血压。

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.