ROLE OF ANGIOTENSIN-(1-7) AND DIAPHRAGM VASCULAR FUNCTION IN HEART FAILURE AND PROLONGED MECHANICAL VENTILATION

项目总结 心脏病是美国人的主要死因。横隔膜功能障碍在 心力衰竭(HF)患者，且先于并超过其他运动性骨骼肌患者； 增加对呼吸肌衰竭和运动不耐受的易感性，并使其易于发生 患者发生呼吸机所致的隔膜功能障碍(VIDD)。血管功能受损是有规律的表现 在周围骨骼肌中有HF，影响了支持所需的血流和氧气输送 收缩功能。然而，隔膜血管功能障碍在心衰所致的隔膜疲劳中的作用， 以及延长机械刺激是否会加剧隔膜血管运动控制的这些变化 呼吸机(MV)，通常应用于这类患者，目前尚不清楚。此外，心血管功能障碍 是导致有问题的脱机和MV死亡率增加的重要因素。延长了前后的MV 其本身会引起横隔膜血管功能障碍，从而导致机械通气撤机失败。心力衰竭和风湿性心脏病患者 持续表现为肾素-血管紧张素系统(RAS)激活和循环水平升高 血管紧张素-II(Ang-II)，主要导致骨骼肌血管功能障碍和横隔肌功能障碍 心力衰竭和延长的MV均有萎缩。这些发现表明，心力衰竭患者容易患上更多 明显的MV所致的隔膜血管功能障碍。 初步数据支持HF损害隔膜内皮依赖性血管松弛 小动脉，加上延长的MV几乎取消了内皮依赖的血管松弛。 然而，HF合并延长的MV对隔膜血流和血管运动控制的影响 从未确定过。因此，我们的全球假设是，隔膜阻力血管(即 微动脉)功能(如内皮依赖性血管松弛)在心力衰竭和 用MV加重。因此，从药理上抵消Ang-II的血管效应将 延长MV和HF可改善横隔膜血流灌注和保护血管功能 MV. 该项目将在堪萨斯州立大学(KSU)在布拉德利·J博士的指导下完成。 本克和大卫·C·普尔。制定了培训计划，以促进技术的发展 执行拟议实验所需的熟练程度和批判性思维技能，并结合 申请人过渡到独立的科学事业所必需的要素。本克和普尔 实验室，以及KSU的运动学、解剖学和生理学系代表着丰富的 科学环境，将提供优秀的研究生培训和研究机会，以获得新的 对健康和疾病动物模型中的横隔膜血流调节和血管运动控制的洞察。

PROJECT SUMMARY Heart disease is the leading cause of death in the United States. Diaphragm dysfunction is prevalent in heart failure (HF) patients and both precedes and surpasses that seen in other locomotory skeletal muscles; increasing susceptibility to respiratory muscle failure and exercise intolerance as well as predisposing these patients to ventilator-induced diaphragmatic dysfunction (VIDD). Impaired vascular function is regularly present in peripheral skeletal muscles with HF, compromising the blood flow and oxygen delivery required to support contractile function. However, the role of diaphragm vascular dysfunction in HF-induced diaphragm fatigue, and whether these changes in diaphragm vasomotor control are exacerbated with prolonged mechanical ventilation (MV), often employed in this patient population, is not known. Further, cardiovascular dysfunction is an important contributor to problematic weaning and increased mortality with MV. Prolonged MV in-and-of itself elicits diaphragm vascular dysfunction, which contributes to weaning failure with MV. HF and MV patients consistently exhibit increased renin-angiotensin system (RAS) activation and elevated levels of circulating Angiotensin-II (Ang-II), which largely contributes to skeletal muscle vascular dysfunction as well as diaphragm atrophy in both HF and prolonged MV. These findings suggest that HF patients are predisposed to more pronounced MV-induced diaphragm vascular dysfunction. Preliminary data supports that HF impairs endothelial-dependent vasorelaxation in diaphragm arterioles, and the added insult of prolonged MV nearly abolishes endothelial-dependent vasorelaxation. However, the impact of HF combined with prolonged MV on diaphragm blood flow and vasomotor control has never been determined. Therefore, our global hypothesis is that diaphragm resistance vessel (i.e. arterioles) function (e.g. endothelial-dependent vasorelaxation) is significantly diminished in HF and exacerbated with MV. As such, pharmacologically counteracting the vascular effects of Ang-II will improve diaphragm perfusion and preserve vascular function with prolonged MV and HF + prolonged MV. This project will be completed at Kansas State University (KSU) under the guidance of Drs. Bradley J. Behnke and David C. Poole. The training plan has been formulated to facilitate the development of technical proficiencies and critical thinking skills needed to execute the proposed experiments and incorporates the elements essential for the applicant to transition into an independent scientific career. The Behnke and Poole Laboratories, and the Departments of Kinesiology and Anatomy and Physiology at KSU represent a rich scientific environment that will provide outstanding graduate training and a research opportunity to gain new insights into diaphragm blood flow regulation and vasomotor control in healthy and diseased animal models.