Autonomic Regulation of Muscle Reflex in Heart Failure

描述（由申请人提供）：该项目的长期目标是更好地了解正常受试者和心力衰竭（HF）患者运动时自主神经反应的调节机制。众所周知，在正常受试者中，交感神经活动（SNA）随着运动而增加，而在HF患者休息时和运动后交感神经活动增加。在心力衰竭中，肌肉代谢受体对肌肉SNA调节的作用减弱，而机械受体的作用增强。本建议将探讨其基本机制。拟议的实验是基于我们实验室最近发表的研究以及已经收集到的试点数据。特异性目的#1旨在检查香草受体亚型1 （VR1）在唤起肌肉压力反射中的作用。我们的数据表明，通过向后肢肌肉注入辣椒素刺激VR1可以提高血压。我们预计，当肌间质呈酸性时，VR1诱导的反射反应会更大。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的代谢物通过激活VR1来引起影响。我们预计VR1受体拮抗剂辣椒平会减弱肌肉温度升高引起的压力反应，但不会减弱HVphosphate引起的压力反应。然而，一种酸感应离子通道（ASIC）阻断剂氨酰胺会减弱H+/磷酸盐诱导的反应。在特定目的#2中，将检查正常和心肌梗死大鼠对代谢刺激的心血管反应。我们预计HF大鼠对VR1刺激、H+、磷酸盐和热的反应会比对照大鼠小。我们假设在HF中肌肉温度较低和/或传入神经VR1表达减弱。在特定目的#3中，将确定ATP刺激P2X受体在唤起肌肉反射中的作用。我们将进一步研究肌肉温度在atp诱导反应中的作用。我们预计，在较低的温度下，反应会更大。在特定目的#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刺激的反应将比对照组大。我们假设HF患者肌肉机械反射增强是由于运动肌肉间质ATP浓度的增加和/或传入神经中P2X受体表达的升高。我们的前期研究表明，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，心衰大鼠静止时的ATPi高于对照组。为了实现这些目标，我们将采用无脑大鼠模型来研究具有良好特征的充血性心力衰竭大鼠冠状动脉结扎模型的肌肉反射。据我们所知，这样的实验从未在HF模型中进行过。本研究的完成将对运动期间循环调节在重要心血管疾病中的作用提供系统的评价。

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.