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) 是一种由多种病因引起的心脏病引起的临床综合征，目前影响着近 600 万美国人，迫切需要进一步研究解决这种普遍疾病的病理生理学问题。心力衰竭最具破坏性的后果之一是交感神经系统（SNS）活性升高，该活性通过位于血管平滑肌上的α肾上腺素能受体表达，促进周围血管收缩。在心力衰竭患者中，慢性交感血管收缩会限制运动肌肉中的血流，导致运动不耐受、不活动，并随后加速疾病进展。幸运的是，与疾病相关的交感神经兴奋可能是可以治愈的。外周 SNS 表达最有影响力的调节剂是一氧化氮 (NO) 途径，位于血管平滑肌和血管内皮之间的界面。尽管 NO 最出名的可能是其短暂的血管舒张作用，但最近的研究已经确定了这种物质作为中枢 SNS 活性和 α 肾上腺素受体水平外周表达抑制剂的明确作用。因此，专注于提高 NO 生物利用度的干预措施可能为抑制心力衰竭中 SNS 过度活跃提供一种新的、未经探索的策略。提出了一系列使用创新方法的实验来探索α肾上腺素能途径对这些患者血管收缩的贡献，并随后评估氧化应激中断（通过AOx给药）对该患者组交感血管收缩的有益作用。具体目标 1 将探讨心力衰竭时外周 α 肾上腺素能血管收缩过度活跃的假设。将进行动脉内药物输注（α-肾上腺素能激动剂/拮抗剂），以药理学探讨静息时和运动期间α-肾上腺素能介导的血管收缩的疾病相关变化。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。据推测，急性 AOx 给药（动脉内维生素 C）会以一氧化氮依赖性方式促进休息时和运动期间的血管舒张。我们还假设长期口服 AOx（维生素 C [1000 毫克]、维生素 E [400 IU] 和硫辛酸 [600 毫克]，每天服用 8 周）将降低循环自由基水平，从而提高一氧化氮的生物利用度，这将在通过抑制α肾上腺素能介导的血管收缩来减轻外周血管收缩。成功定义心力衰竭中交感血管收缩如何改变是朝着更好的患者护理迈出的重要一步，因为我们预计拟议工作的结果可能有助于完善当前治疗心力衰竭外周血流失调的策略，最终导致提高治疗质量生活在这个群体中。