Peripheral Vasoconstriction in Heart Failure: Mechanisms & Modulatory Influences

心力衰竭的周围血管收缩：机制

• 批准号: 9215530
• 负责人: D. Walter Wray
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215530
• 关键词: Acceleration; Accounting; Acute; Address; Adrenergic Agents; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Affect; Age; Aldosterone; American; Angiotensins; Antioxidants; Ascorbic Acid; Biological Availability; Blood Circulation; Blood flow; Cardiac; Cause of Death; Cessation of life; Chronic; Clinical; Disease; Disease Progression; Etiology; Exercise; Exhibits; Free Radicals; Functional disorder; Goals; Healthcare; Heart Diseases; Heart failure; Impairment; Individual; Influentials; Infusion procedures; Intervention; Knowledge; Limb structure; Mediating; Methodology; Morbidity - disease rate; Muscle; Nerve; Nitric Oxide; Nitric Oxide Pathway; Norepinephrine; Oral; Oxidative Stress; Pathway interactions; Patient Care; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physical activity; Productivity; Quality of life; Renin; Research; Rest; Role; Series; Skeletal Muscle; Supplementation; Sympathetic Nervous System; Symptoms; Syndrome; Systolic heart failure; Thioctic Acid; United States; Vascular Endothelium; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Work; alpha-adrenergic receptor; clinical care; cohort; cost; exercise intolerance; experimental study; improved; inhibitor/antagonist; innovation; mortality; novel therapeutic intervention; patient population; peripheral blood; public health relevance; reduce symptoms; response; restraint; treatment strategy; vasoconstriction

DESCRIPTION (provided by applicant): Heart failure (HF), a clinical syndrome that develops as a consequence of heart disease from multiple etiologies, now affects almost six million Americans, presenting an imminent need for further research addressing the pathophysiology of this pervasive disease. One of the most damaging consequences of HF is an elevation in sympathetic nervous system (SNS) activity, which is expressed through alpha adrenergic receptors located on the vascular smooth muscle, promoting peripheral vasoconstriction. In HF patients, chronic sympathetic vasoconstriction acts to limit blood flow in the exercising muscle, promoting exercise intolerance, inactivity, and a subsequent acceleration in disease progression. Fortunately, disease-related sympathoexcitation may be remediable. Among the most influential modulators of peripheral SNS expression is the nitric oxide (NO) pathway, located at the interface between the vascular smooth muscle and the vascular endothelium. Though NO is perhaps best known for its transient vasodilator effects, recent studies have identified a clear role for this substance as an inhibitor of both central SNS activity and peripheral expression at the level of the alpha adrenergic receptor. Interventions focused on improving NO bioavailability may thus offer a new, unexplored strategy for inhibiting SNS overactivity in HF. A series of experiments using innovative methodologies are proposed to explore the contribution of the alpha adrenergic pathway to vasoconstriction in these patients and to subsequently evaluate the beneficial role of disruptions in oxidative stress (via AOx administration) on sympathetic vasoconstriction in this patient group. Specific Aim 1 will explore the hypothesis that peripheral alpha adrenergic vasoconstriction is overactive in HF. Intra-arterial drug infusions (alpha-adrenergic agonists/antagonists) will be undertaken to pharmacologically probe disease-related changes in alpha adrenergic-mediated vasoconstriction, both at rest and during exercise. Specific Aim 2 will study the direct and modulatory effects of oxidative stress on skeletal muscle vasoconstriction. It is hypothesized that acute AOx administration (intra-arterial Vitamin C) will promote vasodilation at rest and during exercise in an NO-dependent manner. We also hypothesize that chronic oral AOx administration (Vitamins C [1000mg], E [400 IU], and Alpha Lipoic Acid [600 mg], daily for 8 weeks) will reduce circulating free radical levels and subsequently improve NO bioavailability, which will in turn lessen peripheral vasoconstriction through inhibition of alpha adrenergic-mediated vasoconstriction. Successfully defining how sympathetic vasoconstriction is altered in HF is an important step towards better patient care, as we anticipate that findings from the proposed work may serve to refine current strategies for the treatment of peripheral blood flow dysregulation in HF, ultimately leading to enhanced quality of life in this cohort.

描述（由申请人提供）：心力衰竭（HF），这是一种临床综合征，由于多种病因的心脏病而发展，现在影响了近600万美国人，这迫在研究这种普遍疾病的病理生理学的进一步研究。 HF最具破坏性的后果之一是交感神经系统（SNS）活性的抬高，该活动通过位于血管平滑肌上的α肾上腺素能受体表达，从而促进外周血管收缩。在HF患者中，慢性交感神经血管收缩起来限制运动肌肉中的血液流动，促进运动不耐受，不活动性和随后疾病进展的加速。幸运的是，与疾病相关的交感神经兴趣可能是可以补救的。外周SNS表达最有影响力的调节剂之一是位于血管平滑肌和血管内皮之间的界面上的一氧化氮（NO）途径。尽管NO也许以其瞬时血管扩张效应而闻名，但最近的研究已经确定了该物质在α肾上腺肾上腺素能受体水平上同时成为中央SNS活性和外周表达的抑制剂。侧重于改善无生物利用度的干预措施可能会提供一种新的，未开发的策略，以抑制HF中的SNS过度活动。提出了一系列使用创新方法的实验，以探索这些患者中α肾上腺素能途径对血管收缩的贡献，并随后评估该患者组中氧化应激中破坏氧化应激中的干扰作用（通过AOX给药）。具体目标1将探讨以下假设：HF中外周α肾上腺肾上腺素能血管收缩过度活跃。动脉内药物输注（α-肾上腺素能激动剂/拮抗剂）将在静止和运动过程中进行药理学探测与疾病相关的药理探测与疾病相关的变化。具体目标2将研究氧化应激对骨骼肌血管收缩的直接和调节作用。假设急性AOX给药（动脉内维生素C）将以无关的方式促进休息和运动过程中的血管舒张。我们还假设慢性口服AOX（维生素C [1000mg]，E [400 IU]和α脂肪酸[600毫克]每天，每天8周）将降低循环自由基水平，随后没有提高生物利用性，而无生物掌握性会通过抗周围性血管施加降低而抑制Alpha vasiftion Alphaectiftion Alphaectiftion rifection Alphaegriendectiftion。成功地定义HF中的交感神经血管收缩是如何改变的，这是迈向更好的患者护理的重要一步，因为我们预计拟议的工作的发现可能有助于完善当前HF外周血流动失调失调的策略，最终导致该队列中增强的生活质量。