Reducing blood pressure in mid-life adult binge drinkers: the role of microvascular function and sympathetic activity

候选人致力于确定/开发酒精的预防和治疗方法- 诱发性高血压和心血管疾病。这份申请将提供5年的职业发展 为优化机会和发展独特的研究技能而量身定做的计划，这是 镜像到任何其他环境中。在K99阶段，候选人将接受研究培训和 酒精研究领域的专业发展。候选人将进行一项独特的研究 综合血管生理学、理疗和与酒精相关的人类健康的战略。这个 应聘者将应用该策略来解决在基础提升的机制方面的知识差距 以中年成年人(50-)为研究对象，与酗酒有关的收缩压。五分之一 据报道，中年成年人酗酒，超过一半的人报告患有高血压。然而，这个时代 该集团在酒精研究方面一直未得到充分研究。在SBP正常的健康年轻人(18-30岁)中， 候选人发现，反复酗酒与微血管功能降低有关，测量 AS小阻力动脉的血流诱导血管扩张(FIV)。这位候选人还发现，反复出现的 酗酒与尿去甲肾上腺素水平升高有关，去甲肾上腺素是一种血管收缩物质，也是一种 交感神经活动。在中年后期，反复酗酒和衰老的协同效应 可能会加重FIV和交感神经活动的这些不利变化，导致SBP升高。建议数 研究将确定反复酗酒对微血管功能、交感神经活动和 中年成年人的血压和这些不利变化的可逆性。目标1将决定角色 去甲肾上腺素作为与反复酗酒相关的小动脉FIV减少的潜在缓和剂。 FIV将在阻力动脉中进行测量，阻力动脉是SBP的主要调节部位，从年中的脂肪活检中分离出来。 生活中的成人酗酒者与戒酒者/适度饮酒者。目标2将确定交感神经 中年酗酒者的活动(直接通过显微神经学检查)和SBP(静息和活动)与 戒酒者/适度饮酒者。这种方法的发现可能会建立治疗靶点。 可归因于酒精对SBP升高的贡献，对理解 中年成年人的高血压发展。这些发现还将启动R00阶段的独立 在目标3中，候选人将调查高强度间歇训练的可行性和有效性 改善FIV和减少交感神经活性的训练，从而降低中年成人狂欢的SBP 酒鬼。临床和力学数据将为研究R01的机制奠定基础。 酒精引起的SBP升高，以及侧重于微血管功能和交感神经活动的干预。 这项研究对于理解中年心血管风险的形成机制具有重要意义。 它是一名成年人，对国家酒精滥用和酒精中毒问题研究所的使命作出了高度响应。

The candidate is committed to identifying/developing preventative and therapeutic approaches for alcohol- induced hypertension and cardiovascular disease. This application will provide a 5-year career development plan which has been tailored to optimize opportunities and to develop unique research skills that could not be mirrored in any other environment. During the K99 phase, the candidate will obtain research training and professional development in the field of alcohol research. The candidate will develop a unique research strategy that integrates vascular physiology, physical therapies and alcohol-related human health. The candidate will apply the strategy to address the gaps in knowledge of the mechanisms underlying elevated systolic blood pressure (SBP) associated with binge drinking targeting mid-life adults (50-64 years). One fifth of mid-life adults reported binge drinking and more than half reported having hypertension. However, this age group has been understudied in alcohol research. In healthy young adults (18-30 years) with normal SBP, the candidate has found that repeated binge drinking is associated with reduced microvascular function, measured as flow-induced vasodilation (FIV) in small resistance arteries. The candidate has also found that repeated binge drinking is associated with increased levels of urinary norepinephrine, a vasoconstrictor and a marker of sympathetic nerve activity. In a later mid-life stage, the synergistic effect of repeated binge drinking and aging may aggravate these adverse changes in FIV and sympathetic activity, causing elevated SBP. The proposed study will determine the effect of repeated binge drinking on microvascular function, sympathetic activity, and blood pressure in mid-life adults and the reversibility of these adverse changes. Aim 1 will determine the role of norepinephrine as a potential moderator of reduced arteriolar FIV associated with repeated binge drinking. FIV will be measured in resistance arteries, the major regulatory site of SBP, isolated from fat biopsies of mid- life adult binge drinkers vs. alcohol abstainers/moderate drinkers. Aim 2 will determine sympathetic nerve activity (directly via microneurography) and SBP (resting and ambulatory) in mid-life adult binge drinkers vs. alcohol abstainers/moderate drinkers. The findings of this approach will potentially establish therapeutic targets for alcohol-attributable contribution to elevated SBP and have broader implications for understanding hypertension development in mid-life adults. The findings will also launch the R00 phase of independent research where in Aim 3 the candidate will investigate the feasibility and effectiveness of high-intensity interval training on improving FIV and reducing sympathetic activity, thereby reducing SBP in mid-life adult binge drinkers. The clinical and mechanistic data will build the foundation for an R01 studying the mechanisms of alcohol induced elevated SBP, and an intervention focusing on microvascular function and sympathetic activity. The study has high impact for understanding the mechanisms of cardiovascular risk development in mid-life adults and is highly responsive to the mission of the National Institute on Alcohol Abuse and Alcoholism.