AIRWAY PHARMACOLOGY DURING ONTOGENESIS

这项建议的长期目标是确定 呼吸道反应性改变的机制(S) 支气管收缩药和支气管扩张剂发生在 成熟。我们的假设是，这些成熟的变化是 与血浆氢化可的松和 改变循环中的儿茶酚胺浓度。在.期间 成熟，血浆氢化可的松和儿茶酚胺将 分别用放射免疫法和放射酶法测定。 建议对豚鼠股骨进行慢性插管。 静脉，以允许在成熟过程中重复采集血浆。这个 血液中氢化可的松和儿茶酚胺的浓度将 与呼吸道反应性的测量在时间上相关 体内的组胺。将使用以下方法确定呼吸道反应性 测量特定气道变化的全身体积描记法 电导。此外，还假设升高的 氢化可的松浓度影响膜受体 (组胺、胆碱、肾上腺素、5-羟色胺、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，在受体激活后，细胞内 第二信使、环AMP、环GMP和 肌醇和ATPase的激活被修饰。因此， 生物反应将会改变。膜受体特性 将从剂量反应曲线评估激动剂之前和 不可逆拮抗后和在呼吸道肌膜上 使用放射性配基结合分析的组分。此外， 膜将通过测定膜电位来表征 以及电生钠泵使用标准的贡献 电生理技术。激活腺苷的能力 将测定豚鼠体内的环酶和环核苷酸 激动剂作用前后的牛气管平滑肌 使用放射免疫分析技术进行体外刺激 磷脂酰肌醇的形成将用标记的 底物和随后的层析分离 用于闪烁计数的代谢产物。所有这些都是 测量将在未成熟和成熟的组织中进行 动物以及体内或体外治疗的组织中 使用氢化可的松。了解这些法规 流程将更好地了解事件和 决定健康和健康人肌肉收缩能力的相互作用 疾病。该提案可能会具体提供进一步的见解 关于衰老的机制，特别是关于 负责缓解儿童哮喘 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.