Metabolite Effects on Group III and IV Afferents

描述（由申请人提供）：对动态运动的心血管和呼吸反应是众所周知的，包括对脉管系统的交感神经放电增加，对心脏和气道的迷走神经放电减少以及潮气量和呼吸频率增加。由运动肌肉引起的反射被认为是增加对血管系统的交感神经放电的主要原因，并且可能至少部分地促成了剩余的效应。所提出的实验的总体目的是确定在动态锻炼肌肉中产生的机械和代谢刺激在刺激细纤维传入（即，组III和IV）包括引起这些心血管和排泄调节的反射的传入臂。在去大脑的未麻醉猫中，通过对中脑或丘脑底运动区进行电刺激和可能的化学刺激来诱导动态运动。将研究[三种假定的]代谢刺激物，即乳酸、ATP（一种刺激P2受体的嘌呤）和缓激肽（一种刺激B2受体的肽）。第III组和第IV组传入对乳酸的反应将被阿米洛利和A-317567阻断，A-317567是一种据报道阻断酸敏感离子通道的化合物。同样，PPADS和苏拉明将阻断对ATP的传入反应[HOE-140将阻断对缓激肽的传入反应]。将每种阻断剂注射到灌注动态锻炼的小腿三头肌的腘动脉中。当小腿三头肌自由灌注时和当其循环被阻塞时，将记录来自L7-S1背根的传入活动。将特别注意一分钟的运动后循环阻断，这是一个纯粹的代谢刺激组III和IV肌肉传入。拟议中的研究应阐明在动态运动中刺激第III和IV组肌肉传入的机械和代谢刺激所发挥的作用。 公共卫生相关性：我们建议确定机械和代谢刺激在引起对动态运动的心血管和呼吸反应中所起的作用（即，运行）。这些反应很重要，因为它们支持我们在正常情况下锻炼的能力，但也可能导致心律不齐，导致冠状动脉疾病患者死亡。增加我们对导致这些影响的机制的理解可能会导致改善运动期间发生的心脏问题的治疗。

DESCRIPTION (provided by applicant): The cardiovascular and ventilatory responses to dynamic exercise are well known and include increases in sympathetic discharge to the vasculature, decreases in vagal discharge to the heart and airways as well as increases in tidal volume and breathing frequency. A reflex arising from the exercising muscles is believed to be mostly responsible for increases in sympathetic discharge to the vasculature, and probably contributes at least in part to the remaining effects. The overall aim of the proposed experiments is to determine the role played by mechanical and metabolic stimuli that arise in the dynamically exercising muscles in stimulating the thin fiber afferents (i.e., group III and IV) comprising the afferent arm of the reflex evoking these cardiovascular and ventilatory adjustments. Dynamic exercise will be induced in decerebrated unanesthetized cats by electrical and possibly chemical stimulation of the mesencephalic or subthalamic locomotor regions. [Three putative] metabolic stimuli will be investigated, namely lactic acid, ATP, a purine which stimulates P2 receptors, and bradykinin, a peptide that stimulates B2 receptors. The responses of group III and IV afferents to lactic acid will be blocked by both amiloride and A-317567, a compound reported to block acid sensing ion channels. Likewise, the responses of the afferents to ATP will be blocked by PPADS and suramin [and those to bradykinin will be blocked by HOE-140]. Each of the blocking agents will be injected into the popliteal artery perfusing the dynamically exercising triceps surae muscles. Afferent activity will be recorded from the L7-S1 dorsal roots both when the triceps surae muscles are freely perfused and when their circulation is occluded. Particular attention will be paid to a one minute period of post-exercise circulatory occlusion, which is a pure metabolic stimulus to group III and IV muscle afferents. The proposed studies should shed new light on the roles played by mechanical and metabolic stimuli in stimulating group III and IV muscle afferents during dynamic exercise. PUBLIC HEALTH RELEVANCE: We propose to determine the role played by mechanical and metabolic stimuli in evoking the cardiovascular and ventilatory responses to dynamic exercise (i.e., running). These responses are important because they support our ability to exercise in normal circumstances, but also can cause irregular heart rhythms, leading to death in patients with coronary artery disease. Increasing our understanding of the mechanisms causing these effects may lead to improved treatments for the cardiac problems occurring during exercise.