Neurovascular Responses to Reflex Cooling in Essential Hypertensive Humans

原发性高血压患者对反射冷却的神经血管反应

• 批准号: 8591984
• 负责人: Jody Greaney
• 金额: $ 4.71万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591984
• 关键词: Acute; Adrenergic Agents; Adrenergic Receptor; Adult; American; Biochemical; Biopsy; Biopsy Specimen; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cutaneous; Data; Development; Event; Exposure to; Functional disorder; Goals; Human; Hypertension; Impairment; Individual; Infusion procedures; Investigation; Laboratories; Lasers; Lead; Manuscripts; Mediating; Microdialysis; Muscle; Nerve; Norepinephrine; Outcome; Pathogenesis; Pathology; Pathway interactions; Perfusion; Peripheral; Peripheral Resistance; Physiological; Population; Public Health; Reflex action; Reflex control; Regulation; Rho-associated kinase; Risk; Risk Factors; Seasons; Signal Pathway; Signal Transduction; Skin; Stimulus; Stress; Testing; Therapeutic; adrenergic; aged; blood pressure regulation; cardiovascular risk factor; clinically relevant; insight; mortality; neuropeptide Y; noradrenergic; normotensive; novel; public health relevance; receptor sensitivity; relating to nervous system; response; vasoconstriction

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.

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，并且是美国的主要原因。据估计，有 7600 万美国人患有高血压，其中超过 50% 的人口超过 65 岁。导致高血压广泛性血管损伤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，尤其是对应激的反应。然而，关于高血压（HTN）人群在全身寒冷暴露期间这些反射通路的潜在异常调节的信息缺乏，这是一种导致血压（BP）和交感神经活动（SNA）升高以及皮肤血流量减少的生理压力。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影响，并且可能对全身冷却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变化的机制进行全面检查具有临床相关性和重要意义，因为寒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。这对于患有高血压的成人来说尤其成问题，因为在基线血压已经升高的基础上，血压对寒冷暴露的过度反应会带来更大的心血管风险。因此，我们的总体假设是，成人高血压患者的神经血管反应性被夸大。我们建议研究原发性高血压和正常血压（NTN）人群中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，在高血压成人中，反射性冷却引起的血压和 SNA 增加以及皮肤血流量的减少会更大。我们进一步假设，RhoA/Rho 激酶对 HTN 成人的生理学（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（腓骨显微神经造影）和皮肤血流量（激光多普勒通量）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导致血管功能外周调节改变的特定下游细胞机制（肾上腺素能和 Rho 激酶介导的途径）。这项对原发性高血压成人对反射冷却的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，并使我们能够确定中枢和外周机制的改变是否会导致人类高血压患者在冷暴露期间血压控制和皮肤血流调节受损。