ANESTHESIA AND AIRWAYS

麻醉药物对气道功能的影响是复杂的。这些行动 具有两种益处的潜力（例如，缓解支气管痉挛 哮喘患者）和危害（例如，干扰正常机制 使通气与肺中的灌注相匹配）。这个项目的总体目标是 研究计划是继续研究麻醉剂如何影响这些 航空公司.先前的研究表明，这些药物可以放松气道平滑肌 （AWSM）通过抑制支配平滑肌细胞的神经通路 （神经效应）和通过影响平滑肌细胞本身（直接 效果）。本提案的目的是阐明 这种直接的影响。 将追求两个具体目标， 关于氟烷和氯胺酮的作用，这两种药物是目前推荐的 在哮喘患者的管理中，作为代表性麻醉剂 剂.细胞内钙离子浓度（[Ca 2 +]i）降低， 是AWSM收缩的重要介质，可能在麻醉中起关键作用 方面的影响.目的A将探讨与此行动有关的机制，在孤立的 犬和人AWSM制剂，通过测量细胞外[Ca 2 +]i， 钙内流和从细胞内储存释放钙。 麻醉剂也可以减少给定的力产生的量。 [Ca2+]i（即，降低肌原纤维的“钙敏感性” 收缩系统）。AIM B将检查对此负责的机制 效果透化的AWSM制剂，其中可保持[Ca 2 +]i 通过控制细胞外钙浓度来保持恒定， 来研究这些不依赖钙的作用。实验将 确定哪些调节钙敏感性的系统是 受到麻醉剂的影响平滑肌力学的测量将 深入了解麻醉剂对肌动蛋白-肌球蛋白交联的影响 动力学假设麻醉剂影响[Ca 2 +]i和 钙敏感性，以及这些因素的相对重要性， 机制取决于AWSM膜受体的类型和强度 刺激，麻醉剂给药的时间，以及特定的 麻醉剂对产生这种现象的复杂机制的理解 这些作用可指导这些药物在 围手术期，也可以提供一般的见解 在其他组织中的麻醉作用机制，因为许多 在AWSM中发现的细胞内信号转导途径是常见的， 其他细胞类型。此外，这些麻醉剂可能具有独特的 AWSM的作用机制，可为未来的战略提出建议 治疗性支气管扩张剂的开发。

Anesthetic drugs have complex effects on airway function. These actions have the potential for both benefit (e.g., relief of bronchospasm in asthmatic patients) and harm (e.g., interference with normal mechanisms that match ventilation to perfusion in the lung). The overall goal of this research program is to continue the study of how anesthetics affect these airways. Prior work has shown that these drugs relax airway smooth muscle (AWSM) by depressing neural pathways innervating the smooth muscle cell (neural effects) and by affecting the smooth muscle cell itself (a direct effect). The goal of this proposal is to elucidate mechanisms responsible for this direct effect. Two specific aims will be pursued, concentrating on the actions of halothane and ketamine, two drugs currently recommended in the management of asthmatic patients, as representative anesthetic agents. Reductions in the concentration of cytosolic calcium ([Ca2+]i), an important mediator of AWSM contraction, may play a key role in anesthetic effects. AIM A will explore mechanisms related to this action in isolated canine and human AWSM preparations by measuring [Ca2+]i, extracellular calcium influx, and the release of calcium from intracellular stores. Anesthetics may also decrease the amount of force produced for a given [Ca2+]i (i.e., decrease the "calcium sensitivity" of the myofibrillar contractile system). AIM B will examine mechanisms responsible for this effect. Permeabilized AWSM preparations, in which [Ca2+]i can be held constant by controlling extracellular calcium concentration, will be used to investigate these calcium-independent actions. Experiments will determine which of the systems that regulate calcium sensitivity is affected by anesthetics. Measurements of smooth muscle mechanics will provide insight into anesthetic effects on actin-myosin crossbridge kinetics. It is hypothesized that anesthetics affect both [Ca2+]i and calcium sensitivity, and that the relative importance of each of these mechanisms depends on the type and intensity of AWSM membrane receptor stimulation, the timing of anesthetic administration, and the specific anesthetic agent. An understanding of the complex mechanisms producing these effects may guide the proper application of these drugs in the perioperative period, and may also provide insights into general mechanisms of anesthetic actions in other tissues, as many of the intracellular signal transduction pathways found in AWSM are common to other cell types. In addition, these anesthetics may have unique mechanisms of action in AWSM which may suggest strategies for the future development of therapeutic bronchodilators.