Autonomic Regulation of Muscle Reflex in Heart Failure

描述（由申请方提供）：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神经反应的机制。已知交感神经活动（SNA）在正常受试者中随着运动而增加，并且在HF患者中在休息时和响应于运动而增加。在HF中，肌肉代谢感受器对肌肉SNA调节的贡献减弱，而机械感受器的贡献增强。本提案将探讨基本机制。拟议的实验是基于我们实验室最近发表的研究以及已收集的试点数据。具体目标#1旨在检查香草素受体亚型1（VR 1）在引起肌肉加压反射中的作用。我们的数据表明，刺激VR 1的管理辣椒素到后肢肌肉升高血压。我们预计，VR 1诱导的反射反应将更大的肌肉钙是酸性的。我们进一步假设，心血管对肌肉收缩的反应将通过VR 1阻断而减弱。我们还将研究哪些特定的代谢物通过激活VR 1引起效应。我们预期VR 1受体拮抗剂辣椒平将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）的阻断剂阿米洛利将减弱H+/磷酸盐诱导的反应。在具体目标#2中，将检查正常和HF（心肌梗死）大鼠对代谢刺激的心血管反应。我们预期HF大鼠对VR 1刺激、H+、磷酸盐和热的反应将小于对照大鼠。我们假设，在HF肌肉温度较低和/或传入神经VR 1表达减弱HF。在具体目标#3中，将确定P2 X受体的ATP刺激在引起肌肉反射中所起的作用。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，响应将更大。在具体目标#4中，将检查HF大鼠和对照大鼠对P2 X刺激的心血管反应。我们预计HF大鼠对P2 X刺激的反应将大于对照大鼠。我们假设，肌肉机械反射增强HF是由于运动肌肉和/或传入神经中的P2 X受体表达的升高的间质ATP浓度的增加。我们的试点工作表明，P2 X受体的激活增强了心血管反应的肌肉机械感受器和ATPi的刺激在休息时HF大鼠高于对照组。为了实现这些目标，我们将采用去大脑大鼠模型来研究充分表征的充血性HF大鼠冠状动脉结扎模型中的肌肉反射。据我们所知，像这样的实验从来没有在HF模型中进行过。本提案中这些研究的完成将为重要心血管疾病运动期间的循环调节提供系统评价。

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.