Transmitters in Altered Carotid Body Function

描述（由申请人提供）：人类经历慢性间歇性缺氧（CIH）作为复发性呼吸暂停的结果，并发展为自主神经疾病。有人提出颈动脉化学感受器触发cih诱导的心肺异常。我们的研究表明，CIH诱导持久的化学受体激活（即感觉长期促进LTF），这反过来可能引发交感神经张力反射性增加和高血压。本研究的目的是确定与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LTF是由于CIH募集了某些递质/调节剂，而这些递质/调节剂在颈动脉正常身体功能中起次要作用或没有作用。具体来说，5-羟色胺（5-HT）和随后的NADPH氧化酶激活在cih诱导的感觉LTF中的作用将被检查。实验将在大鼠和转基因小鼠身上进行。将采用综合方法，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途径。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的大小方面起重要作用的假设。AIM 2的研究验证了以下假设：A) 5-HT通过5- ht2受体在CIH诱发的感觉LTF中起关键作用；b) CIH募集IP-3受体机制诱导颈动脉体释放5-HT。AIM 3中的方案验证了cih诱发的感觉LTF需要5-HT2受体激活NADPH氧化酶和随后产生的O2的假设。-在颈动脉体内。AIM 4的实验验证了阻断颈动脉体5-HT和NADPH氧化酶可减弱或消除cih引起的持久心肺变化的假设。评估递质在CIH诱导的颈动脉体感觉LTF中的作用以及评估感觉LTF的生理意义的拟议研究对于开发缓解和/或延缓与CIH相关的自主神经异常的新治疗策略具有重要意义。

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.