C-AMP & CONTRACTILE REGULATION IN AIRWAY SMOOTH MUSCLE

在哮喘治疗中，一个主要目标是实现气道顺畅的逆转。 肌肉痉挛。最常用的支气管扩张剂，β-肾上腺素能 激动剂和甲基黄嘌呤被认为是通过环状AMP起作用的 路径。异丙肾上腺素松弛收缩气道的能力 肌肉因用于收缩的特定激动剂而有所不同 组织。一种可行的假设是，某些制剂(乙酰甲胆碱)会产生 对异丙肾上腺素有抵抗力的宫缩是因为它们直接抑制 环磷酸腺苷途径。其他收缩药剂(5-羟色胺、组胺)有 更容易被异丙肾上腺素逆转，我们将检验这一假设 这些都不会抑制环状AMP途径。我们将会被孤立 用乙酰甲胆碱、5-羟色胺、组胺和 钾，并比较这四种药剂的相对抑制能力 异丙肾上腺素引起的松弛、环磷酸腺苷升高和蛋白激酶 激活。我们将使用犬气管炎，因为许多可比的 制剂可以从一个捐赠者那里收集，因为细胞 样本的均质性允许机械事件与 生化成分的变化。宫颈组织中的β受体密度 气管大于胸三头肌。我们将表演 在这两个地区进行实验，以评估自然 β受体密度的变化对两者之间的功能拮抗 收缩和松弛激动剂。哮喘的一种主要理论认为 哮喘的分子基础是β受体环化酶缺乏。 系统，胸段气管的β受体密度降低。 提供了这一现象的体外模型。我们会做一些实验 为了测试乙酰胆碱、5-羟色胺、组胺和钾的能力 抵抗松弛、环磷酸腺苷升高和蛋白激酶激活 前列腺素E_2，Forsklin，环状AMP类似物诱导， 甲基黄嘌呤和非环AMP介导的松弛药，如 硝普钠。这些松弛药在局部激活环状AMP途径。 在因果顺序中逐渐向前推进。这些结果应该是 促进乙酰甲胆碱作用部位的本地化 在后续部位激活的松弛剂应绕过 乙酰甲胆碱抑制部位，容易松弛收缩。后 系统的基本行为和机械-生化相关性 已经在犬的气管中进行了研究，将进行实验以 将这些原则推广到更多的外围呼吸道。

In asthma therapy a major goal is to achieve reversal of airway smooth muscle spasm. The most commonly used bronchodilators, beta adrenergic agonists and the methylxanthines, are thought to act via the cyclic AMP pathway. The ability of isoproterenol to relax contracted airway smooth muscle differs depending on the particular agonist used to contract the tissue. A working hypothesis is that certain agents (methacholine) produce contractions resistant to isoproterenol because they directly inhibit the cyclic AMP pathway. Other contractile agents (serotonin, histamine) are more easily reversed by isoproterenol and we will test the hypothesis that these do not inhibit the cyclic AMP pathway. We will contract isolated airway smooth muscle strips with methacholine, seratonin, histamine and potassium and compare the relative ability of these four agents to inhibit isoproterenol-induced relaxation, cyclic AMP increases and protein kinase activation. We will use canine trachealis because many comparable preparations can be collected from one donor and because the cellular homogeneity of samples permits valid correlation of mechanical events with changes in biochemical composition. The beta receptor density in cervical trachealis is greater than that in thoracic trachialis. We will perform experiments on both regions in order to evaluate the influence that natural variation in beta receptor density has on the functional antagonism between contractile and relaxant agonists. A major theory of asthma proposes that the molecular basis of asthma is a deficiency in the beta receptor cyclase system, and the reduced beta receptor density in thoracic trachealis provides an in vitro model of such a phenomenon. Experiments will be done to test the ability of methacholine, serotonin, histamine and potassium to resist relaxation, cyclic AMP increases and protein kinase activation induced by prostaglandin E2, Forskolin, cyclic AMP analogues, methylxanthines and non-cyclic AMP-mediated relaxants such as nitroprusside. These relaxants activate the cyclic AMP pathway at sites progressively farther along in the causal sequence. These results should facilitate localization of the site of action of methacholine since a relaxant which activates at a subsequent site should by-pass the methacholine inhibited site and readily relax the contraction. After the basic behavior of the system and mechanical-biochemical correlations have been worked out in the canine trachealis, experiments will be done to extend these principles to more peripheral airways.