DIAPHRAGM NEUROMUSCULAR TRANSMISSION--HYPOXIA & MATURITY

在过去的几年里，我们一直很感兴趣，并专注于 呼吸肌功能的研究，特别是因为它涉及到 年轻人的 从我们最近的工作来看， 神经肌肉（NM）传递失败可能是一个重要的网站， 神经性疲劳。 这是特别真实的不成熟谁可能 容易因传播而出现呼吸衰竭 损伤 最近，我们的初步研究已经证明了这一点。 在我们实验室的一个孤立的隔膜制备观察。 对 根据这些数据和其他研究人员的数据，我们 在这个提议中提出了几个假设：A）神经肌肉 传输故障可以在发展中发挥重要作用， 新生儿的疲劳症。 这将在大鼠中进行测试 膈神经-半膈制备在体外几个年龄和 通过比较肌肉响应于 直接和间接（膈）刺激，并关联力水平 动作电位的大小、数量和形状。 B）机制 新生儿横膈膜中NM传输失败的原因是 与乙酰胆碱（ACH）释放和分解之间的不平衡有关 在突触间隙里 这将通过测量ACH的大小进行测试 量子、特异性和非特异性酯酶的活性以及通过使用 封锁实验。 C）未成熟的NM传输失败是 继发于突触前而不是突触后机制， 对特定肌纤维的神经肌肉接头具有特异性 类型 这将通过分析的幅度和数量进行检查， 不同条件下NM传输的端板电位和安全系数 刺激频率，并将这些与肌纤维类型相关联。 D）NM在年轻人中的传播对急性感染的影响更具抵抗力。 压力，如缺氧或酸中毒。 在本提案中，我们利用 最先进的技术和方法， 正在开发或正在开发中。 由于正常运作的 呼吸系统在很大程度上依赖于 呼吸肌，我们认为，了解机制， 导致肌肉衰竭将是至关重要的治疗和预防 呼吸肌疲劳和随后的呼吸衰竭， 刚出生的

Over the past several years, we have been interested and have focussed on the study of respiratory muscle function, especially as it relates to the young. From our recent work, it has become evident that neuromuscular (NM) transmission failure may be one important site of diaphragmatic fatigue. This is particularly true in the immature who may be predisposed for developing respiratory failure due to transmission impairment. This has been recently demonstrated by our preliminary observations in an isolated diaphragm preparation in our laboratory. On the basis of these data and those of other investigators, we have formulated several hypotheses in this proposal: A) Neuromuscular transmission failure can play a significant role in the development of diaphragmatic fatigue in the newborn. This will be tested in the rat phrenic nerve-hemidiaphragm preparation in-vitro at several ages and examined by comparing the force generated by the muscle in response to direct and indirect (phrenic) stimulation and correlating the force level to the size, number and shape of action potentials. B) The mechanisms responsible for NM transmission failure in the newborn diaphragm are related to an imbalance between Acetylcholine (ACH) release and breakdown in the synaptic cleft. This will be tested by measuring the size of ACH quanta, the activity of specific and nonspecific esterases and by the use of blockade experiments. C) NM transmission failure in the immature is secondary to presynaptic rather than postsynaptic mechanisms and these are specific to the neuromuscular junction of specific muscle fiber types. This will be examined by analyzing the amplitude and number of end plate potentials and the safety factor of NM transmission at various frequency of stimulation and correlating these with muscle fiber type. D) NM transmission in the young is more resistant to the effects of acute stresses such as hypoxia or acidosis. In this proposal, we utilize state-of-the-art techniques and methodologies and these are either operative or currently being developed. Since proper functioning of the respiratory system is vitally dependent on the integrity of the respiratory muscles, we believe that understanding the mechanisms which lead to muscle failure will be crucial for the treatment and prevention of respiratory muscle fatigue and subsequent respiratory failure in the newly born.