Autonomic Regulation of Muscle Reflex in Heart Failure

心力衰竭肌肉反射的自主调节

• 批准号: 7234368
• 负责人: JIANHUA LI
• 金额: $ 24.31万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7234368
• 关键词: ASIC channel; Amiloride; Animals; Attenuated; Autonomic nervous system; Biological Assay; Blood Pressure; Capsaicin; Cardiovascular Diseases; Cardiovascular system; Classification; Congestive Heart Failure; Coronary artery; Data; Elevation; Evaluation; Exercise; Felis catus; Fiber; Goals; Grant; Heart failure; Heating; High Pressure Liquid Chromatography; Hindlimb; Human; Injection of therapeutic agent; Intervention; Knowledge; Laboratories; Ligation; Literature; Localized; Measures; Mechanoreceptors; Mediating; Metabolic; Methods; Microdialysis; Modeling; Muscle; Muscle Contraction; Myocardial Infarction; Nerve; Nerve Fibers; P2X-receptor; Patients; Peripheral Nerves; Play; Publishing; Range; Rate; Rattus; Reflex action; Regulation; Research Personnel; Resiniferatoxin; Rest; Role; Sampling; Skeletal Muscle; Spinal Ganglia; Stretching; Temperature; Testing; Western Blotting; Work; afferent nerve; base; capsazepine; cold temperature; design; immunocytochemistry; inorganic phosphate; interstitial; programs; pyridoxal phosphate-6-azophenyl-2' ,4' -disulfonic acid; receptor; receptor expression; research study; response; vanilloid receptor subtype 1

DESCRIPTION (provided by applicant): The long-term goal of the PI is to better understand the mechanisms that regulate the autonomic responses during exercise in normal subjects and patients with heart failure (HF). It is known that sympathetic nervous activity (SNA) is increased with exercise in normal subjects and is increased in HF patients at rest and in response to exercise. The muscle metaboreceptor contribution to regulation of muscle SNA is blunted in HF whereas the mechanoreceptor contribution is augmented. The underlying mechanisms will be explored in this proposal. The proposed experiments are based on recently published studies from our laboratory as well as pilot data that have been gathered. Specific aim #1 is designed to examine the role the vanilloid receptor subtype 1 (VR1) plays in evoking the muscle pressor reflex. Our data suggests that stimulation of VR1 by administration of capsaicin into the hindlimb muscle elevates blood pressure. We anticipate that VR1 induced-reflexive responses will be greater as the muscle interstitium is acidic. We further hypothetize that cardiovascular responses to muscle contraction will be attenuated by VR1 blockade. We will also examine what specific metabolites evoke an effect via activation of VR1. We anticipate that a VR1 receptor antagonist capsazepine will attenuate the pressor response induced by elevated muscle temperature but will not attenuate that by HVphosphate. However, a blocker of acid sensing ion channel (ASIC) amiloride will attenuate H+/phosphate-induced responses. In specific aim #2, cardiovascular responses to the metabolic stimulation in normal and HF (myocardial infarct) rats will be examined. We anticipate that the responses to VR1 stimulation, H+, phosphate and heat will be smaller in HF rats than in control rats. We hypothesize that in HF muscle temperature is lower and/or afferent nerve VR1 expression is attenuated in HF. In specific aim #3, the role ATP stimulation of P2X receptors plays in evoking the muscle reflex will be determined. We will further examine the role of muscle temperature in ATP-induced responses. We anticipate that the response will be greater at a lower mgscle temperature. In specific aim #4, cardiovascular responses to P2X stimulation in HF rats and control rats will be examined. We anticipate that the response to P2X stimulation will be larger in HF rats than in control rats. We hypothesize that muscle mechanoreflex is enhanced in HF is due to an increase in interstitial ATP concentration within exercising muscle and/or an elevation of P2X receptor expression in afferent nerves. Our pilot work suggests that activation of P2X receptors enhances the cardiovascular responses to stimulation of muscle mechanoreceptors and ATPi at rest is higher in HF rats than in controls. To accomplish these goals we will employ a decerebrate rat model to study the muscle reflex in the well-characterized rat coronary artery ligation model of congestive HF. To the best of our knowledge, experiments such as these have never been performed in an HF model. Completion of these studies in this proposal will provide a systematic evaluation of circulatory regulation during exercise in an important cardiovascular disease.

描述（由申请人提供）：PI的长期目标是更好地了解正常受试者和心力衰竭患者运动过程中调节自主反应的机制（HF）。众所周知，正常受试者的运动随着运动而增加交感神经活动（SNA），并且在休息时和运动中响应于HF患者中会增加。肌肉代素受体对肌肉SNA调节的贡献在HF中钝化，而机械感受器的贡献得到了增强。该提案将探讨基本机制。拟议的实验基于我们实验室最近发表的研究以及已收集的试验数据。特定的目标＃1旨在检查香草素受体亚型1（VR1）在唤起肌肉压力反射中的作用。我们的数据表明，通过将辣椒素施加到后肢肌肉刺激VR1会升高血压。我们预计，由于肌肉间质是酸性的，VR1引起的反射反应会更大。我们进一步假设，VR1封锁会减弱对肌肉收缩的心血管反应。我们还将检查哪些特定代谢产物通过激活VR1引起效果。我们预计，VR1受体拮抗剂辣椒粉会减轻肌肉温度升高所引起的压力反应，但不会通过HVPhosphate削弱它。但是，酸性感应离子通道（ASIC）的阻滞剂将减弱H+/磷酸盐诱导的反应。在特定的目标＃2中，将检查对正常和HF（心肌梗死）大鼠代谢刺激的心血管反应。我们预计，HF大鼠对VR1刺激，H+，磷酸盐和热的反应将比对照大鼠小。我们假设在HF肌肉温度较低，并且/或传入神经VR1表达在HF中衰减。在特定的目标＃3中，将确定P2X受体对肌肉反射的作用。我们将进一步研究肌肉温度在ATP诱导的反应中的作用。我们预计在较低的MGSCL温度下响应会更大。在特定的目标＃4中，将检查对HF大鼠和控制大鼠P2X刺激的心血管反应。我们预计HF大鼠对P2X刺激的反应将比对照大鼠大。我们假设HF中的肌肉机械曲线增强了，这是由于锻炼肌肉和/或传入神经中P2X受体表达升高的间隙ATP浓度增加所致。我们的试点工作表明，P2X受体的激活增强了HF大鼠中对肌肉机械感受器刺激的心血管反应，而在HF大鼠中，ATPI高于对照组。为了实现这些目标，我们将采用杂交大鼠模型来研究充血HF的良好特征大鼠冠状动脉连接模型。据我们所知，诸如此类的实验从未在HF模型中进行。在重要的心血管疾病中，该提案中这些研究的完成将对运动过程中的循环调节进行系统的评估。