Peripheral Vasoconstriction in Heart Failure: Mechanisms & Modulatory Influences

描述（由申请人提供）：心力衰竭（HF）是一种临床综合征，由多种病因引起的心脏病导致，目前影响近600万美国人，迫切需要进一步研究这种普遍疾病的病理生理学。HF最具破坏性的后果之一是交感神经系统（SNS）活性升高，其通过位于血管平滑肌上的α肾上腺素能受体表达，促进外周血管收缩。在HF患者中，慢性交感神经血管收缩作用于限制运动肌肉中的血流，促进运动不耐受、不活动和随后的疾病进展加速。幸运的是，与疾病相关的交感神经兴奋可能是可以治愈的。在外周SNS表达的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。虽然NO可能是最有名的短暂的血管扩张作用，最近的研究已经确定了一个明确的作用，这种物质作为中枢SNS活动和外周表达的α肾上腺素能受体水平的抑制剂。因此，专注于改善NO生物利用度的干预措施可能为抑制心力衰竭患者的SNS过度活动提供一种新的、未经探索的策略。一系列的实验，采用创新的方法，提出了探索的α肾上腺素能通路的血管收缩在这些患者中的贡献，并随后评估的有益作用，破坏氧化应激（通过AOx管理）交感神经血管收缩在这个病人群体。具体目标1将探讨外周α肾上腺素能血管收缩在HF中过度活跃的假设。将进行动脉内药物输注（α-肾上腺素能激动剂/拮抗剂），以在静息和运动期间探索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。假设急性AOx给药（动脉内维生素C）将以NO依赖性方式促进静息和运动时的血管舒张。我们还假设长期口服AOx（维生素C [1000 mg]、维生素E [400 IU]和α-硫辛酸[600 mg]，每日一次，持续8周）将降低循环自由基水平，随后改善NO生物利用度，进而通过抑制α-肾上腺素能介导的血管收缩减轻外周血管收缩。成功地确定交感神经血管收缩是如何改变的HF是一个重要的一步，更好的病人护理，因为我们预计，从拟议的工作的结果可能有助于完善目前的策略，治疗外周血流量失调的HF，最终导致提高生活质量在这个队列。

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.