Neurovascular Responses to Reflex Cooling in Essential Hypertensive Humans

描述(申请人提供)：心血管疾病仍然是一个主要的公共卫生问题，也是美国主要的死亡原因。据估计，美国有7600万人患有高血压，65岁时有50%的人患有高血压。导致高血压弥漫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，关于高血压(HTN)患者在全身冷暴露期间这些反射通路的潜在异常调节的信息缺乏，全身冷暴露是一种生理应激，会导致血压(BP)和交感神经活动(SNA)增加，皮肤血流量减少。先前的数据表明，肾上腺素能和RhoA/Rho激酶信号的改变在人类高血压血管功能受损中起重要作用，并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。全面研究成人HTN患者对冷应激的神经血管反应改变的机制具有临床意义和重要意义，因为在冷暴露期间过多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。这在主要的HTN成人中尤其有问题，因为在已经升高的基线血压之上，夸大的BP对寒冷暴露的反应，会增加更大的心血管风险。因此，我们的全球假设是HTN成人的神经血管反应性被夸大了。我们建议研究高血压性肾炎和正常血压(NTN)人群对全身冷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，反射性降温引起的BP和SNA增加，皮肤血流量减少，在HTN成人中会更明显。我们进一步假设，在HTN成人中，RhoA/Rho激酶在生理(全身降温)和药物诱导(局部注射去甲肾上腺素)皮肤血管收缩中将有更大的贡献。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成年人中进行测试。在全身降温期间，肌肉和皮肤SNA(腓骨显微神经学)和皮肤血流量(激光多普勒流量)的变化将被用来评估神经血管的反应性。皮内微透析将被用于评估特定的下游细胞机制(肾上腺素能和Rho激酶介导的通路)，有助于改变血管功能的外周调节。这项对成人特发性HTN患者反射冷却综合神经血管反应的全面评估检查了传出反射轴上的多个点，并将使我们能够确定在人类高血压患者冷暴露期间，中枢和外周机制的变化是否导致血压控制和皮肤血流调节受损。

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.