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，是美国死亡的主要原因。高血压遭受估计的7600万美国人，> 50％的人口> 65年。导致高血压普遍性血管障碍的基本机制包括交感神经流出的中心控制异常和血管功能的外周调节，尤其是响应压力。然而，缺乏有关在全身冷暴露期间高血压（HTN）人类对这些反射途径的潜在异常调节的信息，这会导致血压升高（BP）和交感神经活性（SNA）和皮肤血液流量减少的生理压力。先前的数据表明，肾上腺素和Rho/Rho激酶信号的改变对人类高血压中的血管功能受损重要，并且在整个身体冷却过程中对神经血管功能的反射控制可能具有显着的功能重要性。对HTN成年人的神经血管反应反应的基础机制的全面检查在临床上是相关且重要的，因为在冷暴露期间的心脏需求过多进一步增加了易感人群急性心血管事件的风险。这在基本的HTN成年人中尤其有问题，因为在已经升高的基线BP之上，夸张的BP对冷暴露的反应会带来更大的心血管风险。因此，我们的全球假设是HTN成年人中神经血管反应性夸大了。我们建议在基本的HTN和正常的（NTN）人类中，还研究除了控制血液流量的外周血管反应外，对全身冷暴露的综合神经心血管反应。我们假设在HTN成年人中，BP和SNA的反射冷却诱发的增加以及皮肤血流的减少将更大。我们进一步假设，RhoA/Rho激酶对HTN成年人的生理（全身冷却）和药理学诱导的皮肤血管收缩的（局部去甲肾上腺素输注）的贡献将有更大的贡献。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的变化（Peroneal微功能学）和皮肤血流（激光多普勒通量）将用于评估全身冷却过程中神经血管反应性。皮内微透析将用于评估特定的下游细胞机制（肾上腺素和RHO激酶介导的途径），这有助于改变血管功能的外周调节。对基本HTN成年人对反射冷却的综合神经血管反应的全面评估，检查了沿传出反射轴的多个点，并将使我们能够确定中枢和外围机制的改变是否有助于BP控制受损和人体血液流动在人类高血压下冷暴露期间的皮肤血流调节。