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通气反应是众所周知的，包括向脉管系统的交感放电增加，向心脏和气道的迷走神经放电减少，以及潮汐量和呼吸频率增加。运动肌肉产生的反射被认为是交感神经向脉管系统放电增加的主要原因，并且可能至少在其余效果中起部分作用。拟议实验的总体目的是确定在动态运动肌肉中产生的机械和代谢刺激在刺激细纤维传入神经（即III组和IV组）中所起的作用，这些细纤维传入神经构成反射的传入臂，唤起这些心血管和通气调节。通过对中脑或丘脑下运动区进行电刺激和可能的化学刺激，将在未麻醉的失脑猫中诱导动态运动。将研究三种可能的代谢刺激，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）。III组和IV组传入神经对乳酸的反应将被amiloride和a -317567阻断，a -317567是一种据报道可阻断酸感应离子通道的化合物。同样，对ATP的传入反应将被PPADS和苏拉明阻断[对缓激肽的传入反应将被HOE-140阻断]。每一种阻滞剂都将被注入腘动脉，注入动态运动的肱三头肌。当三头肌表面肌肉自由灌注和其循环闭塞时，从L7-S1背根记录传入活动。我们将特别关注运动后一分钟的循环闭塞，这是对III组和IV组肌肉传入神经的纯粹代谢刺激。提出的研究应阐明机械和代谢刺激在动态运动中刺激III组和IV组肌肉传入神经的作用。

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.