Transmitters in Altered Carotid Body Function

描述(申请人提供)：人类经历慢性间歇性低氧(CIH)作为反复呼吸暂停的结果，并发展自主神经疾病。已有研究认为，颈动脉化学感受器可触发CIH引起的心肺功能异常。我们的研究表明，CIH诱导了持久的化学感受器激活(即感觉长期促进LTF)，这反过来可能引发交感神经张力的反射性增加，以及高血压。目前该方案的目的是确定与CIH诱导的感觉LTF相关的机制，并评估感觉LTF在诱发自主神经异常中的意义。我们假设感觉性LTF是由于CIH对某些递质/调节物的募集，而这些递质/调节物在正常的颈动脉体部功能中要么起到很小的作用，要么不起作用。具体地说，5-羟色胺(5-HT)和随后的NADPH氧化酶在CIH诱导的感觉LTF中的作用将被研究。实验将在大鼠和转基因小鼠身上进行。将采用一种综合方法和一系列技术，包括测量颈动脉身体感觉活动、心肺变量、神经递质和第二信使通路。AIM 1的实验验证了低氧暴露方案的频率在决定CIH诱发的感觉LTF的大小中起重要作用的假设。AIM 2的研究验证了以下假设：a)5-HT通过5-HT2受体在CIH引起的感觉LTF中起关键作用；b)CIH利用IP-3受体机制诱导颈动脉小体释放5-HT。AIM 3中的方案验证了这一假设，即CIH引起的感觉性LTF需要5-HT2受体激活NADPH氧化酶，并随后在颈动脉体内产生O2。AIM 4中的实验验证了阻断颈动脉小体中的5-羟色胺和NADPH氧化酶可减弱或消除CIH引起的长期心肺变化的假设。本研究评估了神经递质(S)在脑出血诱导的颈动脉体感觉性长时程转铁中的作用，并评估了感觉性长时相转运蛋白的生理学意义，这对于开发新的治疗策略以减轻和/或延缓脑出血相关的自主神经异常具有重要意义。 公共卫生相关性：睡眠呼吸障碍导致呼吸暂停复发是美国人口发病率和死亡率的主要原因。该领域的主要进展是认识到慢性间歇性低氧(CIH)是与呼吸暂停相关的心肺疾病发病率的主要因素。颈动脉小体是检测动脉血氧的主要感觉器官，介导了CIH引起的发病。目前的提案建议在实验性模型中研究神经递质在脑出血改变颈动脉机体功能中的作用，这可能导致新的治疗策略，有助于预防或延缓脑出血与睡眠障碍呼吸相关的有害后果。

DESCRIPTION (provided by applicant): Humans experience chronic intermittent hypoxia (CIH) as a consequence of recurrent apneas and develop autonomic morbidity. It has been proposed that carotid chemoreceptors trigger CIH-induced cardio-respiratory abnormalities. Our studies showed that CIH induces long lasting chemoreceptor activation (i.e., sensory long-term facilitation LTF), which in turn may trigger reflex increase in sympathetic tone, and hypertension. The goal of the current proposal is to identify the mechanisms associated with CIH-induced sensory LTF and assess the significance of sensory LTF in evoking autonomic abnormalities. We hypothesize that sensory LTF is due to recruitment of certain transmitter/modulators by CIH, which otherwise play either a minor or no role in normal carotid body function. Specifically, the role of 5-hydroxytryptamine (5-HT) and subsequent activation of NADPH oxidase in CIH-induced sensory LTF will be examined. Experiments will be performed on rats as well as genetically engineered mice. An integrated approach with a repertoire of techniques including measurements of carotid body sensory activity, cardio-respiratory variables, neurotransmitters and second messenger pathways will be employed. Experiments in AIM 1 test the hypothesis that frequency of the hypoxic exposure regimen plays an important role in determining the magnitude of CIH-evoked sensory LTF. Studies in AIM 2 test the hypotheses that: A) 5- HT acting via 5-HT2 receptors plays a critical role in CIH evoked sensory LTF and b) CIH recruits IP-3 receptor mechanisms in eliciting 5-HT release from the carotid body. Protocols in AIM 3 test the hypothesis that CIH-evoked sensory LTF requires activation of NADPH oxidase by 5-HT2 receptors and subsequent generation of O2.- in the carotid body. Experiments in AIM 4 test the hypothesis that blockade of 5-HT and NADPH oxidase in the carotid body attenuate or abolish CIH-evoked long-lasting cardio- respiratory changes. The proposed studies assessing the role of transmitter(s) in CIH- induced sensory LTF of the carotid body and assessing the physiological significance of sensory LTF is of importance in developing novel therapeutic strategies for alleviating and/or retarding autonomic abnormalities associated with CIH. PUBLIC HEALTH RELEVANCE: Sleep disordered breathing leading to recurrent apneas is a major cause of morbidity and mortality in U.S. population. Major advance in the field is the identification that chronic intermittent hypoxia (CIH) is the major contributor to the cardio-respiratory morbidity associated with apneas. Carotid bodies, the principal sensory organs for detecting arterial blood oxygen, mediate CIH-induced morbidity. The current proposal proposes to investigate the role of neurotransmitters in altered carotid body function by CIH in experimental models that may lead to novel therapeutic strategies that help in preventing or retarding the deleterious consequences of CIH associated with sleep-disordered breathing.