Neurotransmitter Metabolism in Intermittent Hypoxia

描述(申请人提供)：人类，经历慢性间歇性低氧(CIH)，容易发生高血压。先前的研究表明，接触CIH的大鼠和小鼠血压升高，循环中的儿茶酚胺(CA)增加，肾上腺髓质中的血管活性物质包括去甲肾上腺素和神经肽Y(NPY)水平增加。为了确定脑出血引起心血管变化的机制(S)，我们建议检验以下相互关联的假设：i)脑出血促进NPY的合成和刺激诱导的释放；ii)外源性释放的NPY通过激活神经肽Y受体亚型和下游G蛋白介导的信号级联促进脑出血引起的CA释放增加；以及iii)脑出血引起的交感神经系统中神经肽Y和CA之间的功能相互作用参与脑出血引起的心血管变化。这些假说将在暴露于CIH的大鼠的肾上腺髓质中得到验证。在目标1中，将评估CIH在mRNA(PreproNPY)和肽水平上对生物活性NPY合成的影响，以及肽甘氨酸a-酰胺化单加氧酶(PAM)在CIH诱导的NPY水平变化中的潜在贡献。在目标2中，将确定CIH对刺激诱导的NPY释放的影响以及细胞内钙在诱导这一反应中的作用。目标3的研究将探讨神经肽Y受体(Y1和Y2)和G蛋白介导的细胞信号在CIH诱导的低氧促进CA释放中的关键作用(S)。为了阐明NPY受体亚型的潜在贡献，我们将评估NPY受体亚型特异性拮抗剂和NPY受体亚型的靶向缺失对CIH引起的CA释放变化的影响。AIM 4中的研究旨在评估NPY及其受体亚型和PAM在未麻醉清醒动物的CIH诱发的心血管变化中的直接和/或间接贡献。预计拟议的研究将为CIH引起的外周交感神经系统功能改变提供新的机械学见解，并有助于确定有效干预与复发性呼吸暂停相关的心血管异常的新治疗靶点。与公共卫生相关。睡眠呼吸紊乱伴反复呼吸暂停是美国人口发病率和死亡率的主要原因，估计有1800万人受到影响。睡眠呼吸暂停引起的慢性间歇性低氧(CIH)患者发生全身性高血压的风险大大增加。然而，引起反复呼吸暂停的脑出血导致心肺疾病的机制(S)还不完全清楚。该提案旨在阐明外周交感神经系统中两种强大的血管活性物质如神经肽Y和儿茶酚胺之间的功能相互作用在CIH引起的血压升高中的作用。这些研究有望为减轻与复发性呼吸暂停相关的心血管发病率提供新的治疗靶点。

DESCRIPTION (provided by applicant): Humans, experiencing chronic intermittent hypoxia (CIH), are prone to develop hypertension. Previous studies showed that rats and mice exposed to CIH have increased blood pressure, elevated circulating catecholamines (CA) and increased levels of vasoactive substances including norepinephrine and neuropeptide Y (NPY) in the adrenal medulla. To begin to define the mechanism(s) by which CIH evokes cardiovascular changes, we propose to test the following interlinked hypotheses: i) CIH facilitates the synthesis and stimulus-evoked release of NPY; ii) Exogenously released NPY, in turn, via activation of NPY receptor subtypes and the downstream G-protein mediated signaling cascade contributes to CIH-induced increases in CA release, and iii) CIH-evoked functional interaction between NPY and CA in the sympathetic nervous system contributes to cardiovascular changes elicited by CIH. These hypotheses will be tested in the adrenal medulla of rats exposed to CIH. In Aim 1, the effects of CIH on the synthesis of bioactive NPY both at the mRNA (preproNPY) and at the peptide levels and the potential contribution of peptidylglycine a-amidating monooxygenase (PAM) in CIH-induced alterations in NPY levels will be assessed. In Aim 2, the effects of CIH on stimulus-evoked NPY release and the role of cytosolic calcium in eliciting this response will be determined. Studies in Aim 3 will examine the critical role(s) of NPY Y receptors (Y1 and Y2) and G-protein mediated cell signaling in CIH-induced facilitation of CA release by hypoxia. To delineate the potential contribution of NPY receptor subtypes, the effects of NPY receptor subtype specific antagonists and targeted deletion of NPY receptor subtypes on CIH-evoked changes in CA release will be assessed. Studies in Aim 4 are designed to assess the direct and/or indirect contributions of NPY and its receptor subtypes and PAM to CIH-evoked cardiovascular changes in unanesthetized, awake animals. It is anticipated that the proposed studies will provide new mechanistic insights into CIH-evoked functional alterations in the peripheral sympathetic nervous system and aid in the identification of novel therapeutic targets for effective intervention of cardiovascular abnormalities associated with recurrent apneas. PUBLIC HEALTH RELEVANCE. Sleep-disordered breathing with recurrent apneas is a major cause of morbidity and mortality in the United States population, affecting an estimated 18 million people. Patients with chronic intermittent hypoxia (CIH) caused by sleep apnea have a greatly increased risk for the development of systemic hypertension. The mechanism(s) by which CIH associated with recurrent apneas are initiated leading to cardio-respiratory morbidity, however, are not fully understood. The proposal aims to elucidate the role of functional interactions between two potent vasoactive substances such as neuropeptide Y and catecholamines in the peripheral sympathetic nervous system in CIH-evoked elevation in blood pressure. These studies are expected to provide new therapeutic targets for alleviating the cardiovascular morbidity associated with recurrent apneas.