AIRWAY PHARMACOLOGY DURING ONTOGENESIS

本提案的长期目标是确定 负责气道反应性变化的机制 支气管收缩剂和支气管扩张剂， 成熟 我们的假设是，这些成熟的变化是 与血浆氢化可的松水平升高密切相关， 改变了循环中的儿茶酚胺浓度 期间 成熟，血浆氢化可的松和儿茶酚胺将 分别通过放射免疫和放射酶测定法测定。 建议长期对豚鼠股动脉进行导管插入术 静脉，以允许在成熟过程中重复采集血浆。 的 血液中的氢化可的松和儿茶酚胺浓度 与气道反应性的测量在时间上相关， 体内组胺。 气道反应性将使用 通过测量特定气道变化的全身体积描记法 电导 此外，据推测， 氢化可的松浓度影响膜受体 （组胺能、胆碱能、肾上腺素能、5-HT、白三烯和 哇巴因）通过改变它们的亲和力、密度和/或偶联 因此，在受体活化之后，细胞内 第二信使，环磷酸腺苷，环磷酸鸟苷和 肌醇和ATP酶的活化被改变。 因此，委员会认为， 生物反应会发生变化。 膜受体特性 将根据激动剂的剂量反应曲线进行评价， 在不可逆拮抗作用后， 使用放射性配体结合测定法测定组分。 此外该 膜将通过测定膜电位来表征 以及标准产电钠泵的贡献 电生理技术。 激活腺苷酸的能力 将在豚鼠中测定环化酶和环核苷酸， 激动剂前后的牛气管平滑肌 使用放射免疫测定技术体外刺激， 磷脂酰肌醇的形成将使用标记的 底物和随后的色谱分离 用于闪烁计数的代谢产物。 所有这些 将在未成熟和成熟的组织中进行测量 动物以及体内或体外处理的组织 氢化可的松 了解这些监管 过程将提供对事件的更好了解， 相互作用，决定肌肉收缩在健康和 疾病 该提案可能会特别提供进一步的见解 衰老的机制，特别是 支气管哮喘的治疗方法有哪些 青春期

The long term objective of this proposal is to determine the mechanism(s) responsible for the changes in airway reactivity to bronchoconstrictor and bronchodilator agents which occurs during maturation. Our hypothesis is that these maturational changes are closely related to increased levels of plasma hydrocortisone and altered circulating catecholamines concentrations. During maturation, plasma hydrocortisone and catecholamines will determined by radioimmuno and radioenzymatic assays, respectively. It is proposed to chronically catheterize the guinea pig femoral vein to allow repeated samplings of plasma during maturation. The hydrocortisone and catecholamine concentrations in the blood will be temporally related to measurements of airway reactivity to histamine in vivo. Airway reactivity will be determined using whole body plethysmography by measuring changes of specific airway conductance. Further, it is hypothesized that the elevated hydrocortisone concentrations affect membrane receptors (histaminergic, cholinergic, adrenergic, 5-HT, leukotriene and ouabain) by changing their affinities, densities and/or coupling so that, subsequent to receptor activation, intracellular concentrations of the second messengers, cyclic AMP, cyclic GMP and inositol and activation of ATPase are modified. Consequently, biological response will be changed. Membrane receptor properties will be evaluated from dose response curves to agonists before and after irreversible antagonism and in airway muscle membrane fractions using radioligand binding assays. In addition, the membrane will be characterized by determining membrane potential and the contribution of the electrogenic sodium pump using standard electrophysiological techniques. The ability to activate adenylate cyclase and cyclic nucleotides will be determined in guinea pig and bovine tracheal smooth muscles before and subsequent to agonist stimulation in vitro using radioimmunoassay techniques while phosphatidylinositol formation will be determined using labelled substrate and subsequent chromatographic separation of the metabolic products for scintillation counting. All of these measurements will be made in tissues from immature and mature animals as well as in tissues treated either in vivo or in vitro with hydrocortisone. An understanding of these regulatory processes will provide a better knowledge of the events and interactions which determine muscle contractility in health and disease. The proposal may specifically provide further insights Into mechanisms of aging and, in particular, on the mechanisms responsible for the remission of bronchial asthma in children at puberty.