Peripheral Vasoconstriction in Heart Failure: Mechanisms & Modulatory Influences

描述(申请人提供)：心力衰竭(HF)是一种临床综合征，由多种原因引起的心脏病发展而成，目前影响着近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)活动增加，这是通过位于血管平滑肌上的α肾上腺素能受体表达的，促进外周血管收缩。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液流动，促进运动不耐受、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。一氧化氮(NO)途径是最有影响力的外周SNS表达调节因子之一，位于血管平滑肌和血管内皮细胞之间的交界处。虽然NO可能最为人所知的是其短暂的血管扩张作用，但最近的研究发现，这种物质在α肾上腺素能受体水平上明显抑制中枢SNS活动和外周表达。因此，以提高NO生物利用度为重点的干预措施可能会提供一种新的、尚未探索的策略来抑制心力衰竭中SNS的过度活动。采用创新的方法进行了一系列实验，以探索阿尔法肾上腺素能通路对这些患者血管收缩的作用，并随后评估氧化应激中断(通过AOX给药)对该患者交感神经血管收缩的有益作用。具体目标1将探索外周肾上腺素能血管收缩在心衰时过度活跃的假说。将进行动脉内药物注入(α-肾上腺素能激动剂/拮抗剂)，从药理学上探索与疾病相关的α-肾上腺素能介导的血管收缩的变化，无论是在静息状态还是在运动中。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(动脉内注射维生素C)将以一种不依赖的方式促进静息和运动时的血管扩张。我们还假设，长期口服AOX(维生素C[1000 mg]，E[400IU]和α-硫辛酸[600 mg]，每天8周)将降低循环中的自由基水平，随后提高NO的生物利用度，这反过来将通过抑制α肾上腺素能介导的血管收缩来减轻外周血管收缩。成功地确定心衰时交感血管收缩是如何改变的，这是朝着更好的患者护理迈出的重要一步，因为我们预计，拟议工作的发现可能有助于完善目前治疗心衰外周血流调节障碍的策略，最终提高这一队列中的生活质量。

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.