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.
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