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 (HF) 患者运动期间调节自主反应的机制。众所周知，正常受试者的交感神经活动（SNA）会随着运动而增加，而心力衰竭患者在休息时和对运动的反应也会增加。肌肉代谢感受器对肌肉 SNA 调节的贡献在 HF 中减弱，而机械感受器的贡献则增强。本提案将探讨根本机制。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点数据。具体目标#1 旨在检查香草酸受体亚型 1 (VR1) 在诱发肌肉升压反射中的作用。我们的数据表明，通过将辣椒素注入后肢肌肉来刺激 VR1 会升高血压。我们预计，当肌肉间质呈酸性时，VR1 诱导的反射反应将会更大。我们进一步假设 VR1 阻断会减弱心血管对肌肉收缩的反应。我们还将研究哪些特定代谢物通过激活 VR1 产生效应。我们预计 VR1 受体拮抗剂辣椒西平会减弱肌肉温度升高引起的升压反应，但不会减弱 HV 磷酸盐引起的升压反应。然而，酸敏感离子通道 (ASIC) 阻断剂阿米洛利会减弱 H+/磷酸盐诱导的反应。在具体目标#2中，将检查正常大鼠和心力衰竭（心肌梗死）大鼠的心血管对代谢刺激的反应。我们预计 HF 大鼠对 VR1 刺激、H+、磷酸盐和热的反应将小于对照大鼠。我们假设心力衰竭时肌肉温度较低和/或传入神经 VR1 表达减弱。在具体目标#3 中，将确定 P2X 受体的 ATP 刺激在诱发肌肉反射中的作用。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 mgscle 温度下响应会更大。在具体目标 4 中，将检查 HF 大鼠和对照大鼠对 P2X 刺激的心血管反应。我们预计 HF 大鼠对 P2X 刺激的反应会比对照大鼠更大。我们推测，心力衰竭时肌肉机械感受增强是由于运动肌肉内间质 ATP 浓度增加和/或传入神经中 P2X 受体表达升高所致。我们的试点工作表明，P2X 受体的激活增强了心血管对肌肉机械感受器刺激的反应，并且静息时 HF 大鼠的 ATPi 高于对照组。为了实现这些目标，我们将采用去大脑大鼠模型来研究充血性心力衰竭大鼠冠状动脉结扎模型中的肌肉反射。据我们所知，此类实验从未在 HF 模型中进行过。完成本提案中的这些研究将为重要心血管疾病运动过程中的循环调节提供系统评估。